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Q Woods Hole, Mass.
Presented by
Chas, Pfizer and Co., Inc.
Medical Research Lab,
Groton, Conn*
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THE
PFIZER HANDBOOK
OF
MICROBIAL METABOLITES
/■'K 6
THE
PFIZER HANDBOOK
OF
MICROBIAL
METABOLITES
By
MAX W. MILLER, ph.d.
Pfizer Medical Research Laboratories,
Chas. Pfizer & Co., Inc.
The Blakiston Division
McGRAW-HILL BOOK COMPANY, INC.
New York Toronto London
THE PFIZER HANDBOOK OF MICROBIAL METABOLITES
Copyright © 1961 by Chas. Pfizer & Co., Inc. Printed in
the United States of America. All rights reserved. This
book, or parts thereof, may not be reproduced in any
form without permission of the copyright owner.
Library of Congress Catalog Card Number: 61-17138
49755
Foreword
The impressive advances achieved in fermentation techniques
have created new and often highly efficient methods for the
synthesis of organic compounds. It seems clear that in addition
to antibiotics and steroids, an ever-increasing number of struc-
turally less complicated chemicals will be synthesized most eco-
nomically by fermentation of abundant starting materials of
natural or synthetic origin.
The purpose of this handbook is to list the source and physi-
cal, chemical and physiological properties of metabolic products
isolated from bacteria, molds, fungi and lichens. In addition to
this collection of facts and references, it contains chapters out-
Uning the biogenesis of various structural types elaborated
mainly by microorganisms. Although some of our present-day
views on biogenetic pathways may have to be revised in the fu-
ture, these chapters should prove to be exceedingly helpful not
only to chemists working on the structures of new substances
but also to biochemists investigating the mode of action of
physiologically active compounds.
There certainly was an urgent need for such a compilation be-
cause the original reports are scattered through a wide variety
of scientific journals rarely assembled in one place but distrib-
uted in chemical, pharmaceutical and medical libraries. It
seems highly appropriate that an attempt to cover the literature
in this rapidly expanding field should come from the Research
Division of Chas. Pfizer & Co., Inc. The group deserves a great
deal of credit for pioneering work in industrial fermentation
as well as in isolation and structure elucidation of many anti-
biotics.
G. BucHi
Cambridge, Massachusetts
Acknowledgment
A COMPILATION of this soit was suggested by Dr. Ernest M.
Weber in 1956, and the first draft was issued as an intra-
company report the following year. Later, publication was sug-
gested by Dr. Gilbert M. Shull and urged by a number of uni-
versity people interested in microbial metabolites.
Most importantly, publication would not have been possible
without the consent and support of Dr. Karl J. Brunings and
Dr. I. A. Solomons. Other staff members of the Pfizer Medical
Research Laboratories have also been very cooperative. Dr.
Frank A. Hochstein has been most helpful throughout the prepa-
ration for publication, and I wish to thank him especially as
well as Dr. Walter D. Celmer for reading the manuscript at an
early stage and for their comments on the chapter on macrolide
antibiotics.
In addition. Dr. Francis X. Murphy read the entire galley
proof and made many constructive suggestions.
Several other authorities have been kind enough to review
their specialties. Professor Hans Brockmann of Gottingen con-
tributed information on the actinomycins; Professor Konrad
Bloch of Harvard read the sections dealing with lipides; Dr.
T. G. Halsall of Oxford reviewed fungal steroids; Dr. Herchel
Smith of Manchester, sections concerned with the biosynthesis
of various mold metabolites; Professor F. G. Holliman of Cape-
town, the section on phenazines; Dr. J. D. Bu'Lock of Man-
chester, the section on acetylenic substances; and Dr. Edward
Borowsky of the Institut Medycyny Moskiej, Gdansk, the sec-
Acknowledgment viii
tion on polyene macrolides. Professor George Biichi of Massa-
chusetts Institute of Technology read nearly all of the galley
proof and contributed a generous foreword.
We cannot begin to acknowledge all of the assistance re-
ceived, particularly from the Pfizer library staff and other
libraries, from our colleagues on the chemical staff, and from
the secretarial staff. Most of the manuscript typing was done by
Miss Kathryn Beck, Mrs. Loretta Michaud, Mrs. Terry Lunt,
Mrs. Hedy Korst, Mrs. Judith Neff, and Miss Patricia Goepfert.
The references were corrected and much indexing was done by
Miss Claudette Parent, Miss Grace Olimski, and Miss Patricia
French. AU of the copy-editing was done by Mrs. Margaret
Thompson. Patricia Curtis of Editorial Projects, Inc. was very
helpful in coordinating and expediting pubUcation operations.
Max W. Miller
Groton, Connecticut
Contents
Introduction
1. Simple Hydrocarbons, Ketones, Aldehydes,
Esters, etc. 9
2. Alcohols, Glycols and Compounds Related to Sugars 13
3. Aliphatic Acids and Glycolipides 46
4. Tetronic Acids and Other Lactones and Lactams 79
5. Carotenes and Carotenoids 90
6. Polyenes and Polyynes, Excluding
Polyene Macrolides 107
7. Macrocyclic Lactones (Macrolides) 118
a. POLYENE MACROLIDES 123
b. OTHER MACROLIDES 130
8. Alicyclic Compounds Other Than Terpenoids and
Steroids 142
9. Terpenoids and Steroids 154
10. Tropolone Acids 181
11. Phenolic Substances 185
a. PHENOLS AND PHENOL ETHERS (GENERAL) 185
b. DEPSIDES AND DEPSIDONES 212
12. Quinones and Related Compounds 231
a. BENZOQUINONES 239
b. NAPHTHOQUINONES 248
C. ANTHRAQUINONES 254
13. Tetracycline, Analogues and Related Substances 273
14. Aromatic Compounds Not Classified Elsewhere 284
15. Amines 290
16. Amino Acids and Related Compounds 299
17. Polypeptides and Related Compounds 332
18. Heterocycles 398
a. FURANS AND RELATED SUBSTANCES 398
b. DIBENZOFURANS AND RELATED SUBSTANCES 400
C. PYRANS AND RELATED SUBSTANCES 404
d. XANTHONES 416
Contents x
e. COMPOUNDS RELATED TO THIOPHENE, IMIDAZOLE,
THIAZOLE AND ISOXAZOLE 418
f. PYRROLES, PORPHYRINS AND RELATED
COMPOUNDS 434
g. INDOLES 458
h. ERGOT ALKALOIDS 465
i. PYRIDINES 479
j. QUINOLINES 492
k. PYRAZINES, DIKETOPIPERAZINES 496
I. PHENAZINES AND PHENOXAZONES 501
m. PYRIMIDINES 508
n. PURINES 524
O. PTERIDINES AND FLAVINES 548
19. Unclassified Metabolites 572
Bibliography, Reviews and General References 615
Appendixes
A. Chemical Compositions of the Tissues and Large
Molecules of Bacteria and Fungi 623
B. Bacterial and Fungal Carotenes 638
c. The Chemical Constituents of Mycobacteria 645
Addendum 661
Subject Index 715
Empirical Formula Index 748
Microorganism Index 758
THE
PFIZER HANDBOOK
OF
MICROBIAL METABOLITES
Introduction
The culture of bacteria and molds, the collection of higher
fungi and lichens and the isolation and characterization of their
metabolites is a sophisticated sort of research involving several
distinct sciences. As a result the reports of such work are scat-
tered through a variety of chemical, biochemical, microbiologi-
cal, botanical, medical and pharmaceutical journals as well as
general scientific journals and those devoted to antibiotics and
fermentation technology. The published reviews of the struc-
tures of microbial metabolites have been Umited in scope.
It is difficult for the novice to gain a total impression of the
progress that has been made, and difficult even for the specialist
in this area to see the forest entire as well as the trees about him.
Having monitored the literature for several years incidental
to our own work, we felt that it would be useful to publish a
more general list of chemicals produced by microorganisms.
More specifically, what has been attempted is a compilation of
data on the structural and simpler physical properties of all of
the primary microorganism metabolites which have been re-
ported to be produced by the organisms growing either in the
wild state or in culture on artificial sugar-based media. Al-
though many structures are incomplete, generally the com-
pounds in this list have been purified, and at least some physical
properties observed. In view of the difficulties mentioned above
we do not presume to have achieved absolutely complete cover-
age, and we should be pleased to receive structures or references
to appropriate compounds which have been overlooked. Cor-
rections of errors would be appreciated also. The literature
available to us has been watched until the beginning of printing
operations in December 1960.
Organization is by general similarity of chemical structures,
but not in the strictest sense. For example, all carotenes and
carotenoids were grouped together rather than grouping a caro-
Pfizer Handbook of Microbial Metabolites 4
tene alcohol with, e.g., a steroid alcohol. Many substances are
ambiguous and could have been classified in any of several dif-
ferent chapters. A substance which contains a sugar, a benzene
ring, a terpenoid fragment and a heterocycle will most likely be
found under the appropriate heterocycle classification. Some
arbitrary decisions have been necessary, but indexing by name,
by empirical formula and by producing microorganism should
serve most purposes. Again quite generally, progression is from
the simple to the complex; sugarlike compounds being con-
sidered simple because they resemble the substrate, glucose.
In order to make the list more coherent a background has
been sketched in, emphasizing occurrence and biosynthetic
origin. A considerable literature on the biosynthetic origin of
microbial metabolites has accumulated. Familiarity wdth it is
valuable in interpreting experimental results in structure deter-
minations. Several old structures have been revised in the light
of this new knowledge.
Many of the biosynthetic and other metabolic schemes worked
out in microorganisms are quite general in occurrence and have
been found to be operative in mammalian metabolism. Be-
cause bacteria and fungi grow rapidly and are easy and inexpen-
sive to handle, they are among the most useful tools in the ex-
ploration of metabolic routes. Many of the chemicals in this
list were isolated incident to such studies.
Some chemicals of metabolic significance and of a suitable
degree of complexity can be produced economically in quantity
by fermentation methods and have found industrial uses. An
example is citric acid, which now finds an annual market of
thousands of tons.
The discovery of the effectiveness of the mold product, peni-
cilHn, in treating many bacterial infections in man gave tremen-
dous impetus to the isolation and screening of microorganisms
and their metabolites for antibiotics. The isolation and study
of microbial metabolites, formerly a scholarly pursuit in a few
academic laboratories, suddenly was supported by the resources
of a great industry. Experience showed that a genus of filamen-
tous soil organism, the actinomycete ( streptomycete ) , was a
Introduction
particularly prolific source of organisms adaptable to antibiotics
production when grown in suitable media.
Research with the actinomycetes resulted in the discovery of
agents effective against a broad spectrum of pathogens. The
first of these were chloramphenicol, chlortetracycline and oxy-
tetracycline. Since the discovery of oxy tetracycline, no anti-
biotics of broader antibacterial range have been developed.
Prior to the discovery of antibiotics, much work had been
done on the structures of lichen substances, and, as mentioned
above, a few academic laboratories were interested in mold
metabolites. Notable among these was Professor Harold
Raistrick's group at the London School of Hygiene and Tropical
Medicine. Raistrick, now retired, and his collaborators have
published over 100 papers on this topic.
The academic investigators were impelled by no practical
motive except perhaps a hope that comparison of the chemical
metabolites of various ill-defined groups of fungi would assist
in their classification. Some generalizations did become ap-
parent, but on the whole this hope was disappointed. It was
found that the same chemical might even be produced by both
bacteria and fungi. Some of the old classification schemes
based on pigmentation were found to be obsolete.
The structures of the large molecules produced by micro-
organisms have proved to be more specific and of real value to
taxonomy. Since the advent of paper chromatography, the
identification of amino acids, sugars and other fragments from
cell tissue hydrolysates has been facilitated. From the ensuing
proliferation of literature on this subject it is manifest that the
compositions of various cell tissues (capsule, wall, protoplast
membrane, internal proteins), as well as exotoxins and other
high molecular weight exudates, are much more specific. Even
strains of species can sometimes be distinguished by the pres-
ence or absence of one of these fragments, and these molecules
are important in immunology. Work of this sort has become
more important since the discovery of evidence that certain
antibiotics, e.g., penicillin, interrupt growth and cell division in
the bacteria against which they are effective by interfering with
Pfizer Handbook of Microbial Metabolites 6
normal cell wall synthesis. Although we were unable to pursue
this fascinating topic, an appendix of literature titles on the
structure of higher molecular weight products of microorgan-
isms and their cell wall structures has been attached.
In comparing the structures of the hundreds of microorgan-
ism metabolites which have been characterized thoroughly it is
well to remember that the statistical emphasis may be mislead-
ing. It is likely that insoluble compounds, lipophilic materials
easily extractible from aqueous cultures, organic acids which
can be precipitated as insoluble salts and pigments that are
easily observed have probably received a disproportionate degree
of attention. The same, of course, could be said for antibiotics,
which are conspicuous for their biological activity. The most
difficultly discoverable metabolites are the relatively inconspicu-
ous, low molecular weight, hydrophilic, perhaps phosphorylated
compounds. Eventually many of the precursors of more elabo-
rate metabolites will be found in this category.
Also, the metabolites of certain microorganisms have re-
ceived disproportionate study. Examples are Mycobacterium
tuberculosis, the tuberculosis pathogen, and Claviceps purpurea,
the ergot fungus. By permission of Dr. Esmond R. Long and
the Williams and Wilkins Publishing Company a review of the
known metabolites of the former organism has been reproduced
as an appendix, although many of the compounds included in
this review are also to be found in the body of the text and others
in the text which were not in the review. Also an appendix
dealing with the confusing subject of microbial carotenoids has
been attached by permission of the Chemical Publishing Com-
pany and of Professor T. W. Goodwin of the University of Liver-
pool.
Referencing is not exhaustive. It was kept on the lean side
intentionally, and we feel that it is more useful that way. On
some topics the literature is vast. It would have been virtually
impossible to offer complete referencing of, for example, acetic
acid, or even of some of the more complex substances such as
the gibberellins or ^-carotene. Much attention has been given
to choice of useful references, although no doubt there have
Introduction
been lapses, and differences of opinion will probably arise. For
some of the substances carrying a large literature a review
article often is cited. In general an attempt has been made to
cite the isolation, final structure determination and synthesis
papers insofar as they exist. In the references cited care has
been taken to include the complete list of authors as given on
the paper. A bibliography of books, general references and re-
views is included at the end.
Occasional comments may be found at the bottom of an entry,
reflecting the manner in which this material evolved from a
card file with a few notes. These comments were allowed to
stand without expansion for what they are worth. For the most
part the work is uncritical, structures and properties having
been transcribed just as given in the literature. Structures and
empirical formulas designated as tentative or approximate by
the authors have been so designated here.
The indexes were not available prior to printing, and it is
hoped that they will point out hitherto unrecognized relation-
ships.
Simple Hydrocarbons, Ketones,
Aldehydes, Esters, etc.
The simple compounds listed here cannot be treated as
a class. The biogenetic origins of many of them should
become apparent from the introductions to later chapters.
Besides the hydrocarbons shown it might be mentioned
that lactarius species sporophores contain cis-polyiso-
prene, a rubber-like substance.
W. D. Stewart, W. L. Wachtel, J. J. Shipman and J. A.
Yanko, Science 122 1271 (1955).
1 Thiourea, CH4N2S, white crystals, m.p. 180-182°.
S
H2N— C— NH2
Verticillium albo-atrum, Botrytis cinerea
K. Ovcharov, Compt. rend. acad. sci., U.S.S.R. 16 461
(1937).
2 Guanidine, CH5N3, alkaline crystals, generally isolated as salts,
e.g. acetate, m.p. 229°.
NH
H2N— C— NH2
Boletus edulis, Hydnum aspratum Berk.
E. Winterstein, C. Reuter and R. Korolev, /. Chem. Soc. 104
433 (1913).
Seijiro Inagaki, J. Pharm. Soc. Japan 54 824 (1934).
3 Ethylene, C2H4, colorless gas, b.p. —103°.
CH2=CH2
Pfizer Handbook of Microbial Metabolites lO
Penicillium digitatum, Blastomyces dermatitidis , B. bra-
siliensis, Histoplasma capsulatum
Walter J. Nickerson, Arch. Biochem. 17 225 (1948).
Erston V. Miller, J. R. Winston and D. F. Fisher, J. Agr.
Research 60 269 (1940).
Ray E. Young, Harlan K. Pratt and J. B. Biole, Plant
Physiol. 26 304 (1951).
4 Dimethylsulfone, CoHgOoS, colorless prisms, m.p. 107-109°.
CH3SO2CH3
Cladonia deformis Hoffm.
Torger Bruun and Nils Andreas Sorensen, Acta Chem.
Scand. 8 703 (1954).
5 Cellocidin (Aquamycin), C4H4O2N0, white crystals, m.p. 216-
218° (dec).
O O
li II
HoN— C— C=C— C— NH2
Streptomyces chibaensis, S. reticuli var. aquamyceticus
The yield was 16.5 g. from 420 liters of culture fluid.
Saburo Suzuki, Goto Nakamura, Kazuhiko Okuma and Yoke
Tomiyama, J. Antibiotics (Japan) llA 81 (1958).
Hyozo Taniyama, Shoji Takemura, Kimiko Kageyama and
Masanao Funaki, /. Pharm. Soc. Japan 79 1510 (1959).
6 Ethyl Acetate, C^HsOo, colorless liquid, b.p. 77°, 11^^° 1.3719.
CH3COOC2H6
PenicilliuTn digitatum
J. H. BirkinsHaw and H. Raistrick, Trans. Roy. Soc. (Lon-
don) B220 331 (1931).
7 2-Methyl-2-butene, C5H10, colorless liquid, b.p. 38.4°.
CH3
\
C=CH— CH3
/
CH3
Puccinia gram,inis Pers. var. tritici Erikas. and Henn.
(uredospores)
F. R. Forsyth, Can. }. Botany .S3 363 (1955).
1 1 Simple Hydrocarbons, Ketones, Aldehydes, Esters, etc.
8 l-Ethoxy-l,2-ethylenedicarboxamide, CcH,oO;^N2,
O O
II II
HoN— C— C=CH— C— NH2
OC0H5
Streptomyces sp.
Yasuharu Sekizawa, /. Biochem. Japan 45 73 (1958).
9 Isobutyl Acetate, CfiHjoOs, colorless liquid, b.p. 61°, Uo^^ 1.3936.
O CH3
II /
CH,— C— O— CH2— CH
\
CH3
Endoconidiophora coerulescens
J. H. Birkinshaw and E. N. Morgan, Biochem. J. 47 55
(1950).
10 2-Methyl-2-heptene-6-one, CsHi^O, colorless liquid, b.p. 172-174°,
58° (10 mm.), n,r" 1.4445.
O CH3
II /
CH3— C— CH2— CH2— CH=C
\
CH3
Endoconidiophora coerulescens Miinch, E. virescens
Davidson (artificial medium)
Isobutyl acetate and a mixture of methylheptenols were
isolated from the same culture.
J. H. Birkinshaw and E. N. Morgan, Biochem. J. 47 55
(1950).
n Octacosane, CogHsg, colorless crystals, m.p. 61°.
CH3(CH,),bCH3
Amanita phalloides
Heinrich Wieland and Gustav Coutelle, Ann. 548 270
(1941).
12 Actinomycin J2 (Waksman's Actinomycin B, Dodecyl Ester of
5-Oxostearic Acid), C^Jir^gO^, colorless crystals, m.p.
81.5°.
CH3(CH2)l2CO(CH2)3COOCl2H28
Pfizer Handbook of Microbial Metabolites 12
Actinomyces (Streptomyces) fiavus
Yoshimasa Hirata and Koji Nakanishi, Bull. Che-m. Soc.
Japan 22 121 (1949).
13 cts-Palmitenone, CgiHeoO, colorless microcrystals, m.p. 40°.
O
CH3(CH2)i4— C— (CH2)7— CH=CH— (CHslaCHs
Corynebacterium diphtheriae
J. Pudles and E. Lederer, Biochim. et Biophys. Acta 11 602
(1953).
Idem., Bull. soc. chim. biol. 36 759 (1954).
14 Palmitone, CgiHgoO, colorless leaflets, m.p. 82°.
O
II
CH3(CH2)i4— C— (CHsluCHs
Corynebacterium diphtheriae
J. Pudles and E. Lederer, Bull. soc. chim. biol. 36 759
(1954).
Alcohols, Glycols and Compounds
Related to Sugars
Two of the most important routes of sugar metabolism are
the Embden-Meyerhof pathway of anaerobic glycolysis and the
oxidative pentose phosphate cycles. Both occur widely in nature,
and microorganisms were useful in the discovery of each. Many
of the metabolites of this chapter can be pictured as arising
from one of these schemes, which are also the main known
routes of glucose metabolism in mammals. It should be under-
stood that other paths and fragments of paths of glucose metab-
olism have been found in various microorganisms.
Yeast was instrumental in the elucidation of the Embden-
Meyerhof route^ and the yeast alcohol fermentation is repre-
sented as follows, each step catalyzed by a specific enzyme:
Embden-Meyerhof Route of Anaerobic Glycolysis in Yeast
Enzymes
1. Hexokinase
2. Phosphohexoisomerase
3. Phosphohexokinase
4. Aldolase
5. Triosephosphate isomerase
6. Triosephosphate dehydrogenase (Inhibited by iodoacetate)
7. ATP-Phosphoglyceric transphosphorylase
8. Phosphoglyceromutase
9. Enolase (Inhibited by fluoride)
10. ATP-Phosphopyruvic transphosphorylase
11. Carboxylase
12. Alcohol dehydrogenase
^ A. J. Kluyver and C. B. Van Niel, "The Microbe's Contribution to
Biology," Harvard University Press, Cambridge, Massachusetts, 1956.
Pfizer Handbook of Microbial Metabolites
14
Glucose
C
ATP
ADP
Glucose-6-phosphate
jr
Froctose-6-phosphate
C
ATP
ADP
Fructose-l,6-diphosphate
l\
D-Glyceraldehyde-3-phosphafe ;:i Dihydroxyacetone Phosphate
-11 /*DPN©
H3PO4 11 V^DPNH + H©
D-1, 3-Diphosphoglyceric Acid
D-3-Phosphoglyceric Acid
11
D-2-Phosphoglyceric Acid
H2O
Phosphoenoipyruvic Acid
"- S.ATP
Pyruvic Acid
Acetaldehyde + CO2
11 /*DPNH + H©
1^ ^DPN©
Ethanol
Many molds, actinomycetes and bacteria use this system to
some degree. Variations occur, and intermediates may feed in
from other sources, for example, triose phosphate from the pen-
1 5 Alcohols, Glycols and Compounds Related to Sugars
tose phosphate cycle. Some bacteria are able to produce alcohol
by other means.
The pyruvate from anaerobic glycolysis can meet a variety of
fates. In some cases it is transformed into acetoin and its oxi-
dation and reduction products, diacetyl and 2,3-butanediol
(thiamine pyrophosphate coenzyme). ct-Acetolactic acid has
been shown to be an intermediate in certain instances :-
•2CO2
2CH3COCOOH -
* CH3CHO 1 TPP
* CH3CHO
-CO2
/
0 COOH
II 1
CH3C— C— CH3 —
1
-CO2
° /
II /
-♦ CH3— C— CH— CH3
1
1
OH
1
OH
o-Acetolactic Acid
Acetoin
1
CHs— CH-
-CH-
H2
CH3<
[01
»CH3-
0
II
-C-
0
II
-C— CH3
OH OH
2,3-Butanediol
Diacetyl
Acetoin has been found in yeast, in other fungi and in bac-
teria. Large yields of mixtures of these condensation products
can be obtained from some bacteria.
Pyruvate is reduced to D-lactic acid in the homofermentative
bacteria and lower phycomycetes (and to L-lactic acid in mam-
malian muscle).
Another reaction of pyruvate is its conversion to acetylcoen-
zyme A with the participation of lipoic acid; the probable me-
chanism being :^
2 Elliot Juni, /. Biol. Chem. 195 715 (1952); Yutaka Kobayashi
and George Kalnitsky, ibid. 211 473 (1954).
^ I. A. Gunsalus, Lois S. Barton and H. Gruber, /. Am. Chem. Soc.
78 1763 (1956).
Pfizer Handbook of Microbial Metabolites
i6
CH3COCOOH
TPP -^
Mg©> |S> CO2
CH3CHO— \Thiamine
J Pyrophosphate (TPP)
TPP ^ — y ^\
1
-S
1
CH2— CH2-
-CH(CH2)4COOH
■ r
Lipoic Acid
SH S— COCH3 \
1 1 >
^->DPNH + H©
CH2CH2CH(CH2)4COOH
V > DPN©
5-AcetyIdihydrolipoic Acid
\
Coenzyme A
SH
I
CH2— CH2— CH(CH2)4COOH
Dihydroiipoic Acid
CH3CO — Coenzyme A
The nature of the actual catalysis of pyruvate decarboxyla-
tion and of aldol condensations by thiamine pyrophosphate co-
enzyme has been elucidated.^ It is shown below :
NH2
//
Thiamine
Pyrophosphate
Chloride
CH3
O O
CH2— N' I t T
<S^=^CH2— CH2— O— P— O— P— OH
CHa
^.e
e,
OH
CH3— c— cooQ
OH
0
@/^S -H® ®/^~S CH3— C— COO0 ©/^S -CO2
R— N I »R— N; I >R— N/ '
OH
CHi
R— N
/~s
O OH
CH3— C— C—
— C—
* Ronald Breslow, Chem. and Ind., 893 (1957).
I?
Alcohols, Glycols and Compounds Related to Sugars
Thus, the production of acetaldehyde (and subsequently al-
cohol) by yeast, the production of acetoin by certain bacteria,
etc.
Although the lipoic acid mechanism was first demonstrated
in Streptococcus faecalis, all bacteria do not require the cofac-
tor for this transformation.
The role of acetylcoenzyme A in cellular synthesis of fatty
acids will be seen later. Butanol is probably formed by reduc-
tion of acetoacetylcoenzyme A. It is interesting to note that
some microorganisms can synthesize a variety of carbohydrates
by using acetate as the sole carbon source, in effect reversing
the process (e.g.^). Pyruvate is also converted to succinate by
fixation of COo.
Various other fates of pyruvate are known. For example,
there are bacteria which dismutate 2 moles of pyruvate to
1 mole each of acetic and lactic acids. *^ Also Bacillus coli is
known to convert pyruvate to a mixture of acetic and formic
acids. ^
The pentose phosphate cycle mentioned earlier probably oc-
curs in many microorganisms. It is outlined below:
Ribulose-5-P < » Ribose-5-P
TPNH
+H©
TPN©
CO2
6-Phosphogluconic
Acid \ >r TPNH
+ H©
Xylulose-5-P
Glucose
ATP
Dihydroxy-
Qcetone-P
Glyceralde
hyde-3-P
♦ Fructose-6-P
Glyceralde-
hyde-3-P
Sedoheptu-
ose-7-P
Erythrose-4-P
Xylulose-5-P
Enzyme-catalyzed reactions of the pentose
phosphate pathway*
* This diagram together with the summarizing equations is re-
printed with permission from Joseph S. Fruton and Sofia Simmonds,
"General Biochemistry," John Wiley and Sons, Inc., New York, N. Y.,
1958, p. 531.
5 V. I. Lyubimov, Doklady Akad. Nauk SSSR III No. 4 (1956).
" Seymour Karkes, Alice del Campillo, I. C. Gunsalus and Severe
Ochoa, J. Biol. Chem. 193 721 (1952).
^ Kenneth V. Thimann, "The Life of Bacteria," Macmillan Co.,
New York, N. Y. 1955, pp. 441-465.
Pfizer Handbook of Microbial Metabolites i8
These reactions in summary are:
6 Hexose phosphate + 60.- — > 6 Pentose phosphate + 6CO> + 6H2O
4 Pentose phosphate — > 2 Hexose phosphate + 2 Tetrose phosphate
2 Pentose phosphate + 2 Tetrose phosphate — >
2 Hexose phosphate + 2 Triose phosphate
2 Triose phosphate + H2O — > Hexose phosphate + phosphate
Hexose phosphate + 6O2 — > 6CO.; + 5H2O + phosphate
This is, then, a route for the complete degradation of glucose
to carbon dioxide and water. The statistical significance and
prevalence of this oxidative degradation system among micro-
organisms remains to be determined.
Ribose can be synthesized by way of the pentose phosphate
cycle. In B. coli it appears that deoxyribose arises from direct
reduction of ribose.®
Gluconic acid occurs widely, especially in fungi, and can be
formed by enzyme-catalyzed oxidation of the unphosphorylated
glucose substrate.'* In some oxidative bacteria the following
scheme occurs:^"
Glucose — > Gluconic Acid — > 6-Phosphogluconic Acid — >
2-Keto-3-deoxy-6-phosphogluconic Acid -^ Pyruvic Acid
+
Glyceraidehyde-3-phosphate
The glyceraldehyde phosphate is easily convertible to another
mole of pyruvic acid.
Both glucuronic acid" and fucose (6-deoxy-L-galactose)^'-
seem to be formed from glucose without cleavage of the carbon
skeleton.
Glucosamine is probably most commonly formed by gluta-
mine amination of fructose-6-phosphate,^'^ although glucosone
^ Fillmore K. Bagatell, Elmer M. Wright and Henry Z. Sable,
;. Biol. Chem. 234 1369 (1959).
" Vincent W. Cochrane, "Physiology of Fungi," John Wiley and
Sons, Inc., New York, N. Y. 1958, pp. 131-135.
1" Nathan Entner and Michael DoudorofF, /. Biol. Chem. 196 853
(1952); Joseph MacGee and Michael DoudorofF, ibid. 210 617 (1954).
" Frank Eisenberg, Jr. and Samuel Gurin, J. Biol. Chem. 195 317
(1952); Frank Eisenberg, Jr., ibid. 212 501 (1955).
1- J. F. Wilkinson, Nature 180 995 (1957); Stanton Segal and Yale
J. Topper, Biochim. et BiopJiys. Acta 25 419 (1957).
1^ Luis F. Leloir and Carlos E. Cardini, Biochim.. et Biophys. Acta
12 15 (1953).
19
Alcohols, Glycols and Compounds Related to Sugars
(a logical precursor) has been shown to be formed by some
aspergilli.
Mannitol, which is accumulated in quantity by some micro-
organisms and occurs widely, is known in some cases to be in a
reversible equilibrium with fructose, and it probably serves as a
reserve food." This reserve function may be true also of other
reduced sugars.
The inositols are not formed by direct hexose cyclization, but
their detailed biosynthesis is not known.
Many uncommon sugars have been found as moieties of
streptomycete antibiotics. Some of these antibiotics which are
predominantly sugar-like in composition are included at the
end of this chapter. It might be useful to list the individual
sugars here for comparison, including those which occur in
streptomycete antibiotics classified in other chapters :
Sugars from Streptomycete Antibiotics
(showing points of attachment and
stereochemistry where known)
N-Methyl-i-glucosamine
(streptomycins)
HsC
Streptose
(streptomycin)
OH
Streptidine
(streptomycin)
CH2NH
Dihydrostreptose
(dihydrostreptomycin)
HOCH
Hydroxystreptose
(hydroxystreptomycin)
6-Giucosamine
(kanamycin)
^* Vincent W. Cochrane, "Physiology of Fungi," John Wiley and
Sons, Inc., New York, 1958, p. 122.
Pfizer Handbook of Microbial Metabolites
20
CH2OH
Kanosamlne
(kanamycin)
2-Deoxystreptamine
(kanamycin, paromomycin)
CH2OH
D-Glucosamine
(paromomycin,
trehalosamine)
CH2NH
HO 'NH2
Paromose
(paromomycin)
(Neosamine C from
neomycin is also a
2,6-diaminohexose.)
H2N OH
Mycosamine
(nystatin,
amphotericin B,
pimaricin)
(CH3)2N
Desosamine
or
Picrocin
(picromycin, methy-
mycin, neomethymy-
cin, narbomycin, ole-
andomycin, erythro-
mycins A, B, and C.)
CH3O
Oleandrose
(oleandomycin)
CH3O
Cladinose
(erythromycins A, B)
2 1 Alcohols, Glycols and Compounds Related to Sugars
O— O
(CHsl^N
Mycaminose
(carbomycins A, B)
CH3O
H2N— C— O OH
Noviose
(novobiocin)
O— (CHalzN
HO
My CO rose
(carbomycins A, B,
spiramycins)
HOCH
O—
O—
2,3,4,6-Tetradeoxy-4-
dimethylaminohexopy-
ronose (spiramycins)
O—
(CH3)2N OH
Amosamine
(amice tin)
OH
L-2-Ketofucopyranose
(angustmycin A)
CH2OH
OH OH
5-Keto-6-deoxy- D-Talose Neoinosamine-2
arabohexose (hygromycin B) (hygromycin A)
(hygromycin A)
(Two hydroxyl groups in neoinosamine-2 of hygromycin A are connected
in a methylenedioxy bridge. Homomycin contains a similar sugar.)
HOCH
CH2OH
NH OH
HOCH2
3-Deoxy-3-amino-D-
ribose
(puromycin)
Cordycepose
(cordycepin)
a-D-Gulosamine
(streptothricin,
roseothricin)
Pfizer Handbook of Microbial Metabolites
22
CH20CH3
CH— N=
I
CHOH
CHj
CH3
Rhodosamine
(rhodomycin)
Methyl-2,4-dideoxy-2-aminotetroside
(elaiomycin)
Good reviews of aminosugars have been published. ^^'^"^
Other unusual sugars have been identified as components of
the polysaccharides, mucopolysaccharides, etc., which occur in
microbial cell walls and other cell tissues. Information can be
obtained on these by way of Appendix A.
No attempt will be made here to discuss thoroughly the poly-
saccharides. Many references to this subject are listed in Ap-
pendix A and in the Bibliography.
As mentioned above many of the large molecules of micro-
organisms are mucopolysaccharides, etc., which contain sugars
other than glucose. Glucose is in fact a relatively rare com-
ponent of such molecules, but galactose, galacturonic acid,
fucose, mannose and other sugars are common. Many hexoses
and pentoses can be formed from the parent sugar without
chain rupture. The intermediates in these interconversions are
known to be sugar nucleotides:^'
X Sugar
Base (Uracil
or
Guanine)
OH OH
I > > Y Sugar
Epimerization
Oxidation
Reduction
Decarboxylation
i^'T. Naito, Jap. }. Pharm. and Chem. 31 23 (1959).
^''' A. B. Foster and D. Horton, "Advances in Carbohydrate Chem-
23 Alcohols, Glycols and Compounds Related to Sugars
Some of these reactions are reversible. Some of the less com-
mon aminohexoses are formed also in this way from glucosa-
mine.
Certain fatty alcohols are classified in this chapter because
of their functional groups, although biosynthetically they are
more compatible with the fatty acids.
15 Ethanol, C^H^O, colorless liquid, b.p. 78.5°, n^'" 1.3610.
CHsCHoOH
Yeasts, fusaria, mucors, penicillia, aspergilli, etc.
Leland A. Underkofler and Richard J. Hickey, "Industrial
Fermentations," Chemical Publishing Co., Inc., New York,
1954 Vol. I pp. 17-196.
16 Dihydroxyacetone, C;^H,jO;5, colorless microcrystalline powder,
m.p. 75-80° (polymorphic).
HOCH,— C— CH2OH
Acetobacter suboxydans (on glycerol)
Aurel Puskas, Yearbook Inst. Agr. Cheni. Technol. Univ.
Tech. Sci. Budapest, Hung. 3 (1952).
Idem., ibid. 8 150 (1954).
A 90% yield of crude and a 70% recovery on recrystal-
lization was reported.
Dihydroxyacetone has been reported also in cultures
of Penicillium brevi-compactum and Corynebacterium
diphtheriae (on glucose).
Michizo Asano and Hideo Takahashi, /. Pharm. Soc. Japan
68 186 (1948); Paul Godin, Biochim. et Biophys. Acta 11
114 (1953).
17 Glycerol (Glycerin, 1,2,3-Propanetriol), C3H8O3, m.p. 17.8°, b.p.
290° (dec), n,r" 1.4746.
CH.2— CH— CH2
i I I
OH OH OH
Yeasts, Bacillus subtilis, Aspergillus wentii, Clastero-
sporia, Helminthosporia, penicillia, etc.
Numerous recent patents. The glycerol situation is well
summarized in Underkofler and Hickey, "Industrial Fermenta-
tions," Chemical Publishing Co., Inc., New York, N. Y., 1954
Vol. I; L. A. Underkofler, Glycerol, chap. 8, pp. 252-270.
istry," Aspects of the chemistry of the amino sugars. Academic Press,
New York, N. Y., 1959 Vol. 14 pp. 224-233.
^' Saul Roseman, Federation Proc. 18 984 (1959). (A review)
Pfizer Handbook of Microbial Metabolites 24
18 n-Butanol, C4H10O, colorless liquid, b.p. 117°, n^^" 1.3993.
CH3CH2CH2CH2OH
Clostridium acetobutylicum, CI. propylbutylicum,
CI. saccharobutylicum
Yields of about 30% mixed solvents, mainly butanol,
but containing also acetone, isopropanol and ethanol are
common.
Leland A. Underkofler and Richard J. Hickey, "Industrial
Fermentations," Chemical Publishing Co., Inc., New York,
N. Y., 1954 Vol. I; W. N. McCutchan and R. J. Hickey, The
butanol-acetone fermentations, chap. 11, pp. 347-388.
19 2,3-Butanediol, C4H10O0, colorless liquid, b.p. 180°.
The optical isomer produced depends on the micro-
organism.
CH3— CH— CH— CH3
I I
OH OH
Aerobacter aerogenes, Serratia marcescens. Bacillus
polymyxa, Bacillus subtilis, Pseudomonas hydrophila, Ba-
cillus mesentericus, yeasts
Acetoin, diacetyl and alcohol are often produced at the
same time. Approximately 90% yields of butanediol have
been reported.
J. A. Wheat, Ind. Eng. Chem. 45 2387 (1953).
Leland A. Underkofler and Richard J. Hickey, "Industrial
Fermentations," Chemical Publishing Co., Inc., New York,
N. Y., 1954 Vol. II; G. A. Ledingham and A. C. Neish, Fer-
mentative production of 2,3-butanediol, chap. 2, pp. 27-93.
Heikki Suomalainen and Lauri Jannes, Nature 157 336
(1946).
20 Erythritol, C4H10O4.
CH2— CH— CH— CH2
OH OH OH OH
Armillaria mellea
J. H. Birkinshaw, C. E. Stickings and P. Tessier, Bio-
chem. }. 42 329-332 (1948).
Thirteen % of dry myceUum was the D-threitol isomer,
colorless needles, m.p. 88.5°, [aW +4.3° (c 1 in water),
— 11.1° (in 95% ethanol). Other isomers have been re-
25 Alcohols, Glycols and Compounds Related to Sugars
ported, especially z-erythritol (meso-erythritol). Colorless
prisms, m.p. 120° (121.5°) from:
Roccella montagnei (yield 2% ) and other Roccella spe-
cies, Penicillium brevi-compactum, P. cyclopium, Asper-
gillus terreus, etc.
Albert E. Oxford and Harold Raistrick, Biochem. }. 29 1599
(1935).
Yosio Sakurai, /. Pharm. Soc. Japan 61 108 (1941).
21 D-Lyxuronic Acid (isolated as the calcium salt) C-.HjOgCa/
2-2HoO, [aW -23° 30 minutes -53° (in water).
COOH
HOCH
HCOH
HCOH
CHO
Acetobacter melanogenum
Minoru Ameyama and Keiji Kondo, Bull. Agr. Chem. Soc.
(Japan) 22 271 (1958).
22 d-Arabitol, C-HioOr,, colorless spheroid crystals, m.p. 103°, [ajn^"
+7.7° (c 9.26 in saturated borax solution).
CH2— CH— CH— CH— CH2
I I I I I
OH OH OH OH OH
Lobaria pulmonaria Hoffm., Ramalina geniculata Tayl.,
R. sinensis, R. tayloriana, R. scopulorum (Retz. ) Nyl.,
Cladonia impexa Harm., Fistulina hepatica, Lecanora
gangaleoides, Parmelia latissima Fee, Umbilicaria pustu-
lata
Yasuhiko Asahina and Masaichi Yanaglta, Ber. 67B 799
(1934).
T. W. Breaden, J. Keane and T. J. Nolan, Sci. Proc. Roy.
Dublin Soc. 23 6 (1942).
Yngve Johannes Solberg, Acta Chem. Scand. 9 1234 (1955).
Pfizer Handbook of Microbial Metabolites 26
23 2,5-Diketogluconic Acid, CgHgOT, isolated as Ca salt. No good
m.p.
COOH
I
c=o
HOCH
HCOH
c=o
I
CH.OH
Acetobacter melanogenum, Pseudomonas, Phytomonas
spp.
H. Katznelson, S. W. Tanenbaum and E. L. Tatum, J. Biol.
Chem. 204 43 (1953).
24 Glucosone, CgHioOe, levorotatory syrup with reducing properties.
CHO
c=o
I
HOCH
HCOH
HCOH
CHoOH
Aspergillus parasiticus, A. fiavus, some algae
Yields of 13-17% from sucrose have been reported.
Cecil R. Bond, Edwin C. Knight and Thomas K. Walker,
Biochem. J. 31 1033 (1937).
Ross C. Be_an and W. Z. Hassid, Science 124 171 (1956).
25 2-Ketogluconic Acid, C^HioO^, colorless crystals, m.p. 152° (Me
ester, m.p. 172°).
COOH
c=o
1
HOCH
HCOH
HCOH
CH2OH
Acetobacter melanogenum, Pseudomonas, Phytomonas
spp.
27 Alcohols, Glycols and Compounds Related to Sugars
The yields of 2-ketogluconic acid are better than 70%.
2,5-Diketogkiconic acid can be made the principal prod-
uct. This diketo acid is unstable, but can be isolated as a
salt.
Leland A. Underkofler and Richard J. Hickey, "Industrial
Fermentations," Cliemical Publishing Co., Inc., New York,
1954 Vol. II, Lewis B. Lockwood, Ketogenic fermentation
processes, chap. 1, pp. 13-14.
H. Katznelson, S. W. Tanenbaum and E. L. Tatum, /. Biol.
Chem. 204 43 (1953).
26 5-Ketogluconic Acid, CeHmOj, generally isolated as the Ca salt
(no sharp m.p.).
COOH
HCOH
HOCH
HCOH
c=o
CH>OH
Acetobacter suboxydans
Yields of about 90% have been reported.
Shiro Teramato, Riichiro Yagi and Ichiro Hori, /. Fermenta-
tion Technol. (Japan) 24 22 (1946).
Joseph J. Stubbs, Lewis B. Lockwood, Edward T. Roe and
George E. Ward, U. S. Patent 2,318,641 (1943).
Leland A. Underkofler and Richard J. Hickey, "Industrial
Fermentations," Chemical Publishing Co., Inc., New York,
N. Y., 1954 Vol. II, Lewis B. Lockwood, Ketogenic fermenta-
tion processes, chap. 1, pp. 10-12.
27 2-Ketogalactonic Acid, C.-HioO^, colorless crystals, m.p. 170° (K
salt, m.p. 139°; Me ester, m.p. 138°).
COOH
c=o
HOCH
HOCH
HCOH
CHoOH
Pfizer Handbook of Microbial Metabolites 28
Pseudomonas species (on galactose)
Toshinohu Asai, Ko Aida and Yashuiro Ueno, /. Agr. Chem.
Soc. Japan 25 625 (1951-1952).
28 D-GIucuronic Acid, C6H10O7, colorless needles, m.p. 165°, [ccW*
+ 11.7°^ +36.3° (2 hours, c 1 in water).
CHO
I
HCOH
I
HOCH
HCOH
I
HCOH
I
COOH
Ustulina vulgaricus
H. Wunchendoroff and C. Killian, Compt. rend. 187
572 (1928).
Not isolated — manner of identification not mentioned.
Penicillium sp.
Gizin Itto, /. Agr. Chem. Soc. Japan 9 552 (1933).
K. Sivarama Sastry and P. S. Sarma, Nature 179 44 (1957).
29 Saccharic Acid, CeHnjOg, colorless needles, m.p. 125°, [aW^
+6.86° -^ 20.6° (c 1 in water).
COOH
HCOH
I
HOCH
I
HCOH
I
HCOH
I
COOH
Aspergillus niger
T. K. Walker, Vira Subramanian and Frederick Chal-
lenger, J. Chem. Soc, 3044 (1927).
About 3.6 g. of the potassium salt were obtained from
120 g. of glucose by interrupting the fermentation before
the appearance of much citric or oxalic acids. Also fer-
mentation of 20 g. of calcium gluconate gave 3.7 g. of
calcium saccharate.
29 Alcohols, Glycols and Compounds Related to Sugars
Also reported formed from glucose by two yeasts, An-
thomijces renkaufi and Amphierna rubra:
J. Gruss, Jahrb. luiss. Botan. 66 109 (1926).
30 meso-Inositol, C^HjoOo (dihydrate), colorless crystals, m.p. 218°
(anhydrous) 250-253°.
H OH
Pseudomonas fluorescens, Serratia marcescens, Proteus
vulgaris, Clostridium butylicum, yeasts
Yields of 2700-5000 /xg. per gram of dry cell weight are
obtained in brewers' yeast.
Inositol Literature Briefs Tech. Bull. Y3-101, Corn Products
Refining Co., 1953, 44 pp. (A bibliography with titles and
abstracts)
31 D-Gluconic Acid, CgHioO^, colorless syrup, cannot be isolated, but
readily forms (principally) the 8-lactone, white crystals,
m.p. 153°, [aU +63.5° -^ +6.2° (elm water).
COOH
HCOH
HOCH
I
HCOH
I
HCOH
CH2OH
Wide variety of mold species, acetobacter species, etc.
Yields 95% with Aspergillus niger.
A. J. Mayer, E. J. Umberger and J. J. Stubbs, Ind. Eng.
Chem. 32 1379 (1940).
Leland A. Underkofier and Richard J. Hickey, "Industrial
Fermentations," Chemical Publishing Co., Inc., New York,
N. Y., 1954 Vol. I, L. A. Underkofier, Gluconic acid, chap. 14,
pp. 446-469.
Pfizer Handbook of Microbial Metabolites 30
32 D-Mannonic Acid, CfjHioO^, forms y- or 8-lactones, but the free
acid cannot be isolated pure.
COOH
J
HCOH
I
HCOH
HOCH
HOCH
CH,OH
P. purpurogeninn var. rubrisclerotium (on D-mannose)
Acetobacters
Galactonic acid, etc., can be produced similarly from
the corresponding sugar.
A. Angeletti and C. F. Cerruti, Ann. chim. applicata 20 424
(1930).
33 D-Glucosamine (Chitosamine) CeHigOr.N, white needles, m.p.
110° (dec), [a],;-"' +47.5° (c 1 in water).
CHO
I
HC— NH2
I
HOCH
HCOH
HCOH
CH.OH
Many bacteria, fungi and lichens. Present in bound
form in mold mycelium. Produced by the action of cer-
tain streptomyces species on chitin.
Joseph J. Noval and Walter J. Nickerson, Bacteriol. Proc,
125 (1956).
LesUe Ralph Berger and Donald M. Reynolds, Biochim. et
Biophys. Acta 29 522 (1958).
31 Alcohols, Glycols and Compounds Related to Sugars
34 Mesoinositol Monophosphate, C.jHisOgP-SH^O, colorless tablets,
m.p. 201° (dec.)-
OH
O— PO(OH)2
Mycobacterium tuberculosis var. hominis
Michael A. Macheboeuf, Georgette Levy and Marguerite
Faure, Compt. rend. 204 1843 (1937). (Occurred as a fatty
acid ester)
James Cason and R. J. Anderson, J. Biol. Chem. 126 527
(1938). (As a constituent of a polysaccharide)
35 D-Mannitol, CgHijOe, colorless prisms, m.p. 163° (166°) [aln"^
—0.49°. (C 1 in water. Addition of borax ^^ strong dex-
trorotation. )
CH2— CH— CH— CH— CH— CH.
OH OH OH OH OH OH
Aspergilli, penicillia, other fungi, many lichens, algae
and bacteria
For example: Mitizo Asano, Chunoshin Ukita and
Tomoyoshi Komai, Japanese Patent 180,442 (1949) describe
extraction of mannitol and ergosterol from Penicillium
mycelium. See W. Karrer's compilation (listed in the general
reference bibliography) for other references.
36 D-Volemitol, C^H^-O-, silky needles, m.p. 153.5° [a],r" +17.08°
(1.001 g. + 0.7 g. of Borax in 15 ml. of H.O).
CHo— CH— CH— CH— CH— CH— CH2
OH OH OH OH OH OH OH
Dermatocarpon miniatum (L.) Mann.
Yasuhiko Asahina and Motoyasu Kagitani, Ber. 67B 804
(1934).
Bengt Lindberg, Alfons Misiorny and Carl Axel Wacht-
meister. Acta Chem. Scand. 7 591 (1953). (A survey of the
occurrence of low molecular weight carbohydrate constituents
in lichens )
Pfizer Handbook of Microbial Metabolites
32
37 6-O-Acetylglucose, C8H14O7, minute colorless prisms, m.p, 133°,
[(x]d^° +48° (c 4.0 in water at equilibrium).
CHO
I
HCOH
1
HOCH
HCOH
I
HCOH
I
CH2OCOCH3
Bacillus megaterium
R. B. Dufe, D. M. Webley and V. C. Farmer, Nature 179
103 (1957).
38 D-Mannopyranosyl-1-meso-erythritol, C10H20O9, colorless crystals,
m.p. 160°, [a]v -36.7°.
CH2OH
-CH2
-CH— CH— CH2
1 I I
OH OH OH
Ustilago sp.
Besides this water-soluble compound the fungus pro-
duces 15 g. per liter of an oil, consisting of a mixture of
fatty acid esters of o-mannopyranosyl-l-meso-erythritol.
B. Boothroyd, J. A. Thorn and R. H. Haskins, Can. J.
Biochem. and Physiol. 34 10 (1956).
39 Umbilicin (3-yg-D-Galactopyranosido-D-arabitol), C11H22O10, color-
less crystals, m.p. 138°, [a]D"° —81° (c 2 in water).
CH2OH
HOCH
I
HC—
-0— CH
HCOH HCOH
I I
CH2OH HOCH
I
HOCH
I
HC
CH,OH
33
Alcohols, Glycols and Compounds Related to Sugars
Umbilicaria pustidata
Bengt Lindberg, Carl A. Wachtmeister and Borje Wickberg,
Acta Chem. Scand. 6 1052 (1952).
40 Trehalosamine, CjoHooOioN (Hydrochloride) white microcrys-
talMne powder, [a] d'' +176° (c 2.0 in water).
CH2OH
A streptomycete
A yield of about 5 g. per liter was obtained.
Frederico Arcamone and Franco Bizioli, Gazz. chim. ital.
87 896 (1957).
41 Leucrose (5-0-a-D-Glucopyranosyl-D-fructopyranose), C12H22O11,
colorless hygroscopic bars, m.p. 161-163° (anhydrous),
156-158° (monohydrate), [a]^'' -8.2'
c 4 in water).
CH2OH
■7.6° (<lhour,
CH2OH
Leuconostoc mesenteroides
Frank H. Stodola, E. S. Sharpe and H. J. Koepsell, J. Am.
Chem. Soc. 78 2514 (1956).
42 Kojibiose ( 2-0-a-D-Glucopyranosyl-D-glucose ) , CioHooOn, m.p.
(Octaacetate) 166°, [aU +150° (c 2.1 in chloroform).
Free sugar: [aU +136° (equil., c 0.5 in water).
CH2OH
Pfizer Handbook of Microbial Metabolites
34
Aspergillus niger
Stanley Peat, W. J. Whelan and Kathleen A. Hinson, Chem.
and Ind., 385 (1955).
A. Sato and K. Aso, Nature 180 984 (1957).
43 Trehalose (Mycose, a-D-Glucosido-a-D-glucoside), CioHooOu,
colorless, hygroscopic crystals, m.p. ~210° (dec.) (anhy-
drous), 97° (hydrate), [<x]t>-° (hydrate) +178° (in water).
CH2OH
Amanita muscaria, other mushrooms and molds, myco-
bacteria, yeasts and algae. First isolated from rye ergot
(Claviceps purpurea (Fr. ) Tul.).
Trehalose is present in young mushrooms, but as the
plants develop it is replaced by mannitol. It also occurs
in seaweeds and higher plants.
E. Bourquelot, Compt. rend. 108 568 (1889).
H. Bredereck, Ber. 63B 959 (1930). (Structure)
Bengt Lindberg, Acta Chem. Scand. 9 917 (1955).
44 Lactobionic Acid, CioHooOja, Calcium Salt : granular white pow-
der, [a],r' +25.1° (c 5.2 in water).
COOH
HCOH
- I
HOCH
HC
CH—
I
HCOH
I
HOCH
HOCH
HC
HCOH
I I
CH2OH CH2OH
Pseudomonas species, other oxidative bacteria (on lac-
tose)
A 77 '^f yield has been reported. Maltobionic acid was
prepared similarly from maltose.
Frank H. Stodola and Lewis B. Lockwood, J. Biol. Chem.
171 213 (1947).
35 Alcohols, Glycols and Compounds Related to Sugars
Lewis B. Lockwood and Frank H. Stodola, U. S. Patent
2,496,297(1950).
45 Hygromycin B, Ci.-.HosOioNo, amorphous powder, m.p. ^-'180°.
D-Talose has been shown to be one moiety of this anti-
biotic.
Streptomyces hygroscopicus
Robert L. Mann and W. W. Bromer, J. Am. Chem. Soc. 80
2715 (1958).
Paul F. Wiley and Max V. Sigal, Jr., ibid. 80 1010 (1958).
46 Grifolin, CieHo^Oo, fine colorless needles, m.p. 40°.
CHa OH
\ I
C=CH— CH.— CHj— C=CH— CH=CH— CH— C— CH.— CHs
/ I II
CHs CH3 OH CH3
Grifola confluens (=Polyporus confLuens)
Other components of the extract were mannitol, sterols,
a hemin-like substance, a compound C.SH14O (m.p. 145°)
and a compound Ci,r,H^,402 (m.p. 151°).
Y. Hirata and K. Nakanishi, /. Biol. Chem. 184 135 (1950).
47 Cetyl Alcohol, C16H34O, colorless crystals, m.p. 50°, Ud'^ 1.4283.
CHsICHzIhCHsOH
Amanita phalloides
Heinrich Wieland and Gustav Coutelle, Ann. 548 270
(1941).
48 Clavicepsin, CisH^^Oip,, colorless crystals, m.p. (anhydr. ) 198°,
[aln-" +142°.
A glucoside hydrolyzing to 1 mole of mannitol and 2
moles of glucose. The detailed structure was not deter-
mined.
Claviceps purpurea
F. Marino-Zuco and U. Pasquero, Gazz. chim. ital. 41 368
(1912).
49 Stearyl Alcohol, CigHayO, colorless leaflets, m.p. 59°.
CHslCHslifiCHoOH
Penicillium notatum
A yield of 0.13 g. was obtained from 300 g. of dry
mycelium.
Pfizer Handbook of Microbial Metabolites
36
A. Angeletti, G. Tappi and G. Biglino, Ann. chim. (Rome)
42 502 (1952).
50 d-2-Octadecanol, CigHgsO, colorless needles, m.p. 56°, [ctjo +5.7°
(in chloroform).
CHslCHalisCHCHa
I
OH
Mycobacterium tuberculosis var. hominis, M. avium,
M. phlei
Mary C. Panghorn and R. J. Anderson, /. Am. Chem. Soc.
58 10 (1936).
R. E. Reeves and R. J. Anderson, ibid. 59 858 (1937).
R. J. Anderson, J. A. Crowder, M. S. Newman and F. H.
Stodola, J. Biol. Chem. 113 637 (1936).
51 d-3-Octadecanol, CisHggO, colorless crystals, m.p. 56°.
CH3(CH2),4CHCH2CH3
OH
Corynebacterium diphtheriae
A. A. Kanchukh, Ukrain. Biokhim. Zhur. 26 186 (1954).
52 Kanamycin, C18H36O11N4, Sulfate: white prisms which decom-
pose over a wide range above 250°, [ajn"* +146° (c 1 in
0.1 N sulfuric acid).
CH2NH
6-Glucosamine<
Kanosamine
>2-Deoxystrep-
tamine
Streytomyces kanainyceticus
Tomio Takeuchi, Tokuro Hikiji, Kazuo Nitta, Seiro Yama-
zaki, Sadao Abe, Hisaro Takayama and Hamao Umezawa, /.
Antibiotics (Japan) lOA 107 (1957).
Hamao Umezawa, Mashiro Ueda, Kenji Maeda, Koki
37 Alcohols, Glycols and Compounds Related to Sugars
Yagishita, Shinichi Kondo, Yoshiro Okami, Ryozo Utahara,
Yasuke Osato, Kazuo Nitta and Tomio Takeuchi, ibid. lOA
181 (1957).
Kenji Maeda, Masahiro Ueda, Koki Yagishita, Shohei
Kawaji, Shinichi Kondo, Masao Murase, Tomio Takeuchi,
Yoshiro Okami and Hamao Umezawa, ibid. lOA 228 (1957).
M. J. Cron, D. L. Johnson, F. M. Palermiti, Y. Perron, H. D.
Taylor, D. F. Whitehead and I. R. Hooper, }. Am. Chem. Soc.
80 752 (1958).
M. J. Cron, O. B. Fardig, D. L. Johnson, D. F. Whitehead,
I. R. Hooper and R. U. Lemieux, ibid. 80 4115 (1958).
53 Kanamycin B, colorless crystals, m.p. dec. from 170°, [ajn^*
+ 135° (c 0.63 in water).
Acid hydrolysis yields 2-deoxystreptamine and kanosa-
mine, but no 6-glucosamine as from kanamycin. An un-
identified ninhydrin-positive compound was obtained in-
stead. Positive Schiff, Molisch, Elson-Morgan tests.
Streptomyces kanamyceticiis
H. Schmitz, O. B. Fardig, F. A. O'Herron, M. A. Rousche
and I. R. Hooper, /. Am. Chem. Soc. 80 2911 (1958).
54 Streptomycin, C01H39O12N7, m.p. (Reineckate) 164° dec. (He-
lianthate) 220-226° dec, [ajc (Hydrochloride) -84° (c
0.5 in water), [aU^"-^ (Trihydrochloride) -86.1° (c 1.0
in water), [a]u'^ (Sulfate) -79° (c 1.0 in water). Salts
are deliquescent.
NH— C— NH2
H2N— C— NH I
Streptobiosamine
Streptidine
Streptose
N-Methyl-L-glucosamine
Pfizer Handbook of Microbial Metabolites
38
Streptomyces griseus (Krainsky) Waksman et Henrici
S. bikiniensis, S. mashuensis
Albert Schatz, Elizabeth Bugie and Selman A. Waksman,
Proc. Soc. Exptl. Biol. Med. 55 66 (1944). (Isolation)
Selman A. Waksman, "Streptomycin, Its Nature and Appli-
cations," Williams and Wilkins Co., Baltimore, Md., 1949. (A
review )
Herbert E. Carter, R. K. Clark, Jr., S. R. Dickman, Y. H.
Loo, P. S. Skell and W. A. Strong, J. Biol. Chem. 160 337
(1945).
Frederick A. Kuehl, Jr., Robert L. Peck, Charles E. Hoffhine,
Jr., Robert P. Graber and Karl Folkers, J. Am. Chem. Soc. 68
1460 (1946).
Frederick A. Kuehl, Jr., Edwin H. Flynn, Norman G. Brink
and Karl Folkers, ibid. 68 2096, 2679 (1946). (Structure)
I. R. Hooper, L. H. Klemm, W. J. Polglase and M. L.
Wolfrom, ibid. 69 1052 (1947).
H. E. Carter, R. K. Clark, Jr., S. R. Dickman, Y. H. Loo,
P. S. Skell and W. A. Strong, Science 103 540 (1946).
E. P. Abraham and H. W. Florey, "Antibiotics," Oxford Uni-
versity Press, London, 1949 Vol. II chap. 41, pp. 1297-1309.
E. P. Abraham, ibid. chap. 42, pp. 1310-1326.
55 Hydroxystreptomycin (Reticulin) C2iH;j,,05:iN7, Helianthate: red-
brown crystals, m.p. : darkening at 200° (dec.), Trihydro-
chloride: [a]n-^ -91° (c 1.0 in water).
NH— C— NH,
39 Alcohols, Glycols and Compounds Related to Sugars
Streptomyces griseocarneus
Seigo Hosaya, Momoe Soeda, Nobuhiko Komatsu and Yoko
Sonoda, Japan. J. Exptl. Med. 20 327 (1949).
Robert G. Benedict, Frank H. Stodola, Odette L. Shotwell,
Anne Marie Borud and Lloyd A. Lindenfelser, Science 112 77
(1950).
Frank H. Stodola, Odette L. Shotwell, Anne Marie Borud,
Robert G. Benedict and Arthur C. Riley, Jr., /. Am. Chem. Soc.
73 2290 (1951). ( Structure )
56 Dihydrostreptomycin, C^iH4iOi2N7, non-deliquescent white pow-
der [a]D"' —94.5°. Hydrochloride and sulfate were used.
NH— C— NH2
H2N— C— NH
Streptomyces humidus
Sueo Tatsuoka, Tsunaharu Kusaka, Akira Miyake, Mi-
chitaka Inoue, Hiromu Hitomi, Yutaka Shiraishi, Hidesuke
Iwasaki and Masahiko Imanishi, Pharm. Bull. 5 343 (1957).
(Primary fermentation product)
Pfizer Handbook of Microbial Metabolites
40
57 Hygromycin A, C23H29O12N, amorphous (some crystalline deriva-
tives have been prepared), [aln"'^ —126° (c 1 in water).
Partial structure:
HO-
O
1
HC-
/ \— CH— C— C— NH
^ CH3
HOCH
HCOH
I
HC
c=o
CH3
Streptomyces hygroscopicus (Jensen) Waksman and
Henrici
R. L. Mann, R. M. Gale and F. R. Van Abeele, Antibiotics
and Chemotherapy 3 1279 (1953). (Isolation)
Robert L. Mann and D. O. Wolf, J. Am. Chem. Soc. 79 120
(1957). (Structure)
58 Homomycin, white powder, m.p. 105-109° (dec. >160°).
Homomycin has been shown to be the same as hygro-
mycin except that the homomycin amino sugar moiety is :
Streptomyces noboritoensis n. sp.
Yusuke Sumiki, Gotaku Nakamura, Makoto Kawasaki,
Satoru Yamashita, Kentaro Anzai, Kiyoshi Isono, Yoshiko
Serizawa, Yoko Tomiyama and Saburo Suzuki, J. Antibiotics
(Japan) 8A 170 (1955). (Isolation)
Mitsuo Namiki, Kiyoshi Isono, Kentaro Anzai and Saburo
Suzuki, ibid. lOA 36 (1957). (Structure)
41
Alcohols, Glycols and Compounds Related to Sugars
59 Paromomycin, C23H45O14N5, white amorphous solid, [ajn^^ +64°
(c 1.0 in water). Hydrochloride [ix]d~'' +56.5° (c 1.0 in
water).
2-Deoxystreptamme
Paromamine
Paromobiosamine
D-Ribose
Streptomyces rimosus forma paromomycinus
Paromomycin seems to be identical with catenuHn.
Theodore H. Haskell, James C. French and Quentin R. Bartz,
J. Am. Chem. Soc. 81 3480 (1959).
Ibid. Belgian Patent 547,976.
60 Neomycins. (Fradiomycins, Streptothricins, Neomins, Mycifra-
din, Nivemycins, Myacins)
Neomycin A is identical with neamine, a moiety of
neomycins B and C. Neomycins B and C are identical ex-
cept for the diaminohexose components.
Neomycin B ( Streptothricin B II), C23H46O12N6, amor-
phous hygroscopic white powder, no definite m.p., [ajn'^
+83° (in 0.2 N H0SO4).
C12H05O5N4— O— CsHeOlOHla— O— C6H70(OH)2(NH2)2
Neamine
(structure
unknown)
D-Ribose
Diaminohexose B
(structure unknown)
Neomycin C (Streptothricin B I), C23H46O12N6, amor-
phous, hygroscopic white powder, no definite m.p., [ajn""'
+ 121° (in 0.2 N H2SO4).
Pfizer Handbook of Microbial Metabolites 42
Also contains neamine. The disaccharide portion
(neobiosamine C) has been characterized, however, as:
CH2NH2
D-Ribose Neosamine C
Streptomyces fradiae, other Streptomyces spp.
Selman A. Waksman and Hubert A. Lechevalier, Science
109 305 (1949). (Isolation)
Byron E. Leach, William H. DeVries, Harrison A. Nelson,
William G. Jackson and John S. Evans, J. Am. Chem. Soc. 73
2797 (1951). (Isolation)
Jared H. Ford, Malcolm E. Bergy, A. A. Brooks, Edward R.
Garrett, Joseph Alberti, John R. Dyer and H. E. Carter, ibid.
77 5311 (1955).
Kenneth L. Rinehart, Jr., Peter W. K. Woo, Alexander D.
Argoudelis and Astrea M. Giesbrecht, ibid. 79 4567 (1957).
Kenneth L. Rinehart, Jr., Peter W. K. Woo and Alexander D.
Argoudelis, ibid. 79 4568 (1957).
Idem., ibid. 80 6461 (1958).
Kenneth L. Rinehart, Jr., and Peter W. K. Woo, ibid. 80
6463 (1958). (Structure)
61 Catenulin (Sulfate) [a]ir^ +51.9° (c 1 in water).
A substance resembling paromomycin. Acid hydrolysis
yields neamine.*
Streptomyces catenulensis
J. W. Davisson, I. A. Solomons and T. M. Lees, Antibiotics
and Chemotherapy 2 460 (1952).
62 Dextromycin, Helianthate: m.p. 227°, Hydrochloride: [a]u'^
+61° (c 1 acetone).
Similar to neomycin B.*
Streptomyces sp. resembling S. fradiae
Koichi Ogata and Koichi Nakazawa, J. Antibiotics (Japan)
3 440 (1950).
* Probably identical with paromomycin. (Private communication
from Drs. W. Celmer and C. Shaffner)
43 Alcohols, Glycols and Compounds Related to Sugars
Toyonari Araki, Akira Miyake, Yoshitamo Aramaki, Hiroshi
Kojima, Hajime Yokotani, Koichi Ogata and Koichi Nakazawa,
Ann. Repts. Takeda Research Lab. 13 1 (1954).
* Identical with neomycin B. See addendum.
63 Framycetin (Actilin, Soframycin, Antibiotic E.F. 185), Hydro-
chloride: white powder, [a]i. +57° (c 1.0 in water), m.p.
(picrate) 189° (dec).
Framycetin resembles neomycin and streptomycin in
some respects, but is distinct. Hydrolysis yields neamine,
a pentose, and a diaminohexose. Framycetin forms pep-
tide derivatives such as a reineckate and a picrate. The
molecular weight is about 1400-1500. No guanidine
tests were observed, and all the nitrogen is present as pri-
mary amine groups.
Streptomyces sp. resembling S. lavendulae
Louis Jacques Decaris, Ann. pharm. frang. II 44 (1953).
Maurice Marie Janot, Henry Penau, Digna van Stolk, Guy
Hagemann and Lucien Penasse, Bull. Soc. chim. France, 1458
(1954).
A. Lutz and M. A. Witz, Compt. rend. soc. biol. 149 1467
(1955).
A. Saito and C. P. Schaffner, Congr. intern, biochim..
Resumes communs., 3"^ Congr., Brussels, 1955, p. 98.
64 Hydroxymycin, probable empirical formula C._,r,H470i5N-,, white
powder, [a]ir" 63° ± 2° (c. 1.0 in water) (Sulfate) white
powder, [aic-" +51° (c 1.0 in water).
A basic antibiotic similar to streptomycin and neomy-
cin. Contains 6.2% total nitrogen and 6.0% amino nitro-
gen. It is water soluble and insoluble in most organic
solvents with a molecular weight of about 610. Hydroly-
sis yields a fragment called pseudoneamine and others
which show pentose and 2-aminohexose reactions.
An antifungal substance was produced in the same
culture.
Streptomyces paucisporogenes
M. M. Janot, H. Penau, G. Hagemann, H. Velu, J. Teillon
and G. Bouet, Ann. pharm. frang. 12 440 (1954).
G. Hagemann, G. Nomine and L. Penasse, Ann. pharm.
frang. 16 585 (1958).
H. Penau, G. Hagemann and H. Velu, Bull. soc. chim. biol.
41 761 (1959).
J. Bartos, Ann. pharm. frang. 16 596 (1958).
Pfizer Handbook of Microbial Metabolites
44
65 Mannosidostreptomycin (Streptomycin B), C27H49O17N7, color-
less crystals, m.p. (Anhydrous Reineckate) 178° dec.
(Trihydrochlorlde) 190-200° dec, [a]u~^ (Trlhydrochlo-
ride) -47° (c 1.35 in water).
CH2OH
NH NH
II II
H2N— C— NH NH— C— NH2
O^
Occurs together with streptomycin in some cultures.
Streptomyces griseus
Josef Fried and Homer E. Stavely, /. Am. Chem. Soc. 74
5461 (1952). (Structure)
66 Phthiocerol, C36H74O3, colorless plates, m.p. 71.5-73°, [(x]j>
-4.50° (c 11.48 in chloroform).
45 Alcohols, Glycols and Compounds Related to Sugars
It is claimed (in the most recent reference below) that
phthiocerol, as ordinarily isolated, is a mixture of the fol-
lowing two substances:
OCH3
I
CH3(CHo)ooCH— CHo— CH{CH2)4CH— CH— CH2CH3
OH OH CH3
and
OCH3
CHslCHsl^oCH— CH2— CH(CH2)4— CH— CH— CH2CH3
I I I
OH OH CH3
Mycobacterium tuberculosis (human, bovine and
avian )
In the wax of the mycobacteria phthiocerol is present
mainly as the dimycoceranate.
J. A. Hall, J. W. Lewis and N. Polgar, /. Chem. Soc, 3971
(1955).
Hans NoU, /. Biol. Chem. 224 149 (1957).
H. Demarteau-Ginsburg, E. Lederer, R. Ryhage, S. Stallberg-
Stenhagen and E. Stenhagen, Nature 183 1117 (1959).
Aliphatic Acids and Glycolipides
The metabolic origins of some of the acids in this section can
be deduced from the foregoing chapter. Among these are
pyruvic, glyceric, acetic, formic, propionic and lactic acids.
Many of the other simpler acids are recognizable as members
of the citric acid cycle and ancillary routes. The citric acid
cycle (tricarboxylic acid cycle or Krebs cycle) is outlined
below :
-' The Citric Acid Cycle
Enzymes :
1. Condensing enzyme
2. Aconitase
3. Isocitric dehydrogenase
4. Oxalosuccinic decarboxylase
5. Succinic dehydrogenase
6. Fumarase
7. Malic dehydrogenase
47
Aliphatic Acids and Glycolipides
CH3COCOOH
Pyruvic Acid
DPN®
DPNH^^ —
^.
Coenzyme A
Lipoic Acid, Thiamine Pyrophosphate
^'
CO2
+ H
CH3CO-C0A
Acetyl-CoA
CO— COOH t (T)
I ' /^ ^r^ I
CHj— COOH H:0 Co-A HO— C— COOH
CH2— COOH H.O CH,— COOH
J I
< ^^C— (
C— COOH
Oxaloacetic Acid
DPNH <-
+ H®
DPN®^
(Z)
HOCH— COOH
I
CH>— COOH
Malic Acid
H2O
®
HOOC— CH
Flavin H^
Flavin
HC— COOH
Fumaric Acid
®
CH,— COOH (2) CH— COOH
Citric Acid c;s-Aconitic Acid
H2O
CH2-
-COOH
CH— COOH
HO— CH— COOH
Isocitric Acid
^TPN®
(3)
J^TPNH + H®
CH2— COOH
1
CH— COOH
1
1
co-
®
-COOH
Oxalosuccinic Acid
CHo— COOH
ATP ADP CH2
CHo— COOH
CH2— COOH
Succinic Acid I- \ |
^xH.O CH2— C00h\c02 i CO— COOH a-Ketoglu-
CoA-(— ->^| VV,^::^^^ taricAcid
CH2 /^/^\ Coenzyme A
CO— CoA I \
DPNH DPN®
Succinyl-CoA -f-
H©
Pfizer Handbook of Microbial Metabolites
48
The net effect of the cycle is to oxidize pyruvic acid to carbon
dioxide and water :
CH3COCOOH + 50 ^ 3CO2 + 2HoO
Enzymes of the citric acid cycle occur widely among micro-
organisms, and it is likely that the cycle and variants of it are
equally ubiquitous. Its primary physiological function in micro-
organisms (if a primary function can be singled out) is less
clear, two possibilities being: (a) an energy source and (b) a
source of amino acid skeletons. Interruption of the cycle or im-
balances under certain conditions lead to accumulation of cer-
tain acids. Thus high yields of citric, isocitric, a-ketoglutaric,
fumaric and malic acids can be obtained in controlled fungal
fermentations.
It was mentioned in the preceding chapter that certain micro-
organisms are capable of growing on a medium containing ace-
tate as the sole carbon source, synthesizing all their carbo-
hydrate requirements from it. In some of these microorganisms,
at least, this ability may be due to possession of a pair of en-
zymes (malate synthetase and isocitritase ) which permit opera-
tion of a cycle ancillary to the citric acid cycle or replacement
of the steps from isocitric acid to malic acid and commonly
called the glyoxylic acid cycle:
HC— COOH
II
HOOC— CH —
Fumaric Acid
The Glyoxylic Acid Cycle
Acetyl CoA
CH2— COOH
■I
CH2— COOH OHC— COOH
Succinic Acid Glyoxylic Acid
HO— CH— COOH
CH— COOH
I
CH2— COOH
Isocitric Acid
HO— CH— COOH
I
CH2— COOH
Malic Acid
CO— COOH
CH2— COOH
Oxaloacetic Acid
CH2— COOH
I
HO— C— COOH
I
CH2— COOH
Citric Acid
49
Aliphatic Acids and Glycolipides
The origin of certain other acids can be deduced; for example,
itaconic acid by decarboxlration of aconitic, oxalic acid by
oxidation of glyoxyUc and epoxysuccinic by oxidation of fu-
maric.
CH— COOH CH2
II — CO2 II
C— COOH >C— COOH
CH2— COOH
Aconitic Acid
CHo— COOH
Itaconic Acid
OHC— COOH
Glyoxylic Acid
[O]
HOOC H
\ /
C=C
/ \
H COOH
Fumaric Acid
-* HOOC— COOH
Oxalic Acid
[O]
HOOC
H
.U
H '^' COOH
frans-Epoxysuccinic Acid
Certain higher fungi and some molds produce acids such as
caperatic, agaricic, rangiformic, mineoluteic, roccellic, and
spiculisporic, which appear to be essentially aldol condensation
products of various keto acids of the citric acid cycle with long
chain fatty acids.
CH3(CH2),3— CH— COOH
HO— C— COOH
CH2— COOH
Caperatic Acid
(one ccrboxyl group a
methyl ester)
CH3(CH2)i3— CH— COOH
I
CH— COOH
I
CH2— COOH
Rangiformic Acid
(one carboxyl group a
methyl ester)
CH3{CH2)i5— CH— COOH
I
HO— C— COOH
CH2— COOH
Agaricic Acid
CH3(CH2)9— CH C=0
HOOC— C— OH \
I \
CH O
COOH
Minioluteic Acid
Pfizer Handbook of Microbial Metabolites
50
CHalCHj),!— CH— COOH
I
CH— COOH
CH3
Roccellic Acid
CHalCHj),— CH— COOH
I
O C— COOH
/
o=c
\
CH2— CH2
Spiculisporic Acid
Lipide production by microorganisms varies widely, some
yeasts and molds producing up to 50% of their dry weight.
Yeasts were used for commercial submerged culture production
of fat during World War II in Germany.
It has been estimated that 80-90% of all fatty acids in plants
and higher animals occur as esters — triglycerides and phospho-
lipides. In microorganisms a high percentage of the lipides
seem to be bound in some way, perhaps as lipoproteins, liposac-
charides, sterol esters, etc., and a preliminary acid hydrolysis is
required before complete extraction.
The fatty acid contents of the fats produced by a few molds
and yeasts have been studied in detail, and several of these are
reproduced in the following table.
TABLE I
Componenf Faffy Ac/ds of Fofs Produced by Microorganisms
Asper-
gillus
niditlans^
Penicil-
lium
soppii.'^
Penicil-
lium
lilaci-
num^
Penicil-
lium
spinulo-
sum*
Yeast
Strain
No. 72^
Rhodo-
torula
sp.«
Torulop-
sis ipj
Free acidity (%
08
0.6
0.2
5.8
33
18
51.2
Component Acids
Myristic
Palmitic
0.7
20.9
15.9
1.4
1.2
40.3
17.0
0.2
2.4
0.3
22.0
7.6
0.9
3.3
45.2
20.0
0.3
0.4
0.1
32.3
9.4
1.4
3.4
38.6
13.4
1.4
18.0
11.9
1.4
3.8
43.3
21.1
0.3
0.2
0.1
25.6
5.9
5.1
1.3
54.5
5.7
0.7
1.1
1.1
29.8
8.8
1.4
1.8
40.1
11.2
4.8
1.0
0.3
7.9
3.8
Arachidic, Be-
henic, Ligno-
0.2
Hexadecenoic. . .
Oleic
7.6
21.5
49.7
Linolenic
Unsaturated C20. .
4.4
51
Aliphatic Acids and Glycolipides
Generally microorganism lipides have a higher free fatty
acid content than those of animals. Bacterial fats seem to have
received less quantitative study. cis-Vaccenic and lactobacillic
acids have been shown to be major constituents of the lipides of
lactobacilli,'* streptococci" and Agrobacterium tiimefaciens}'^
An analysis of the fatty acids of two strains of Mycobacterium
tuberculosis has been published:"
TABLE II
Higher Fatfy Acid Content (%) in the Phosphatides and Fats of Mycobacterium tuberculosis
H.,7 Rv and BCG
Phosphatide
Fat
H:,7Rv
BCG
H:,7Rv
BCG
20.0
3.0
13.8
5.7
3.7
13.0
28.0
12.8
20.4
3.0
8.6
12.3
14.0
13.0
19.2
10.4
0.7
1.1
2.7
20.0
80
24.5
34.0
10.0
3.1
II. " "
2 1
III. " "
1.5
III. Phthioic Acid
5.5
IV. " "
2.3
22 1
Oleic and Palmitic Acids
48.2
15.2
The waxes and fats in which the acid-fast mycobacteria and
corynebacteria abound have been investigated extensively, and
a variety of oxidized, methylated and branched chain fatty acids
and alcohols isolated and characterized. In the oxidized and
ij. Singh, T. K. Walker and M. L. Meara, Biochem. J. 61 85
(1955).
2 J. Singh, Sudha E. PhiHp and T. K. Walker, /. Set. Food and Agr.
8 697 (1957).
"J. Singh, Sudha Shah and T. K. Walker, Biochem. J. 62 222
(1956).
*I. Shimi, Ph.D. Thesis, Univ. of Manchester, 1955.
^ T. P. Hilditch and R. K. Shrivastava, Biochim. et Biophys. Acta
2 80 (1948).
« John Holmberg, Svensk Kem. Tidskr. 60 14 (1948).
" R. Reichert, Helv. Chim. Acta 28 484 (1945).
^ Klaus Hofmann and Sylvan M. Sax, /. Biol. Chem. 205 55
(1953).
9 Klaus Hofmann and Fred Tauslg, ibid. 213 415 (1955).
^"Idem., ibid. 213 425 (1955).
^^ Josef Pokorny, Natiirwissenschaften 10 241 (1958).
Pfizer Handbook of Microbial Metabolites 52
methylated acids the oxygen and methyl groups usually appear
in positions consistent with the acetate theory of fatty acid
biogenesis. These bacteria seem to be able also (in effect) to
couple two long chain fatty acids to form ketones and branched
chain acids.
Bacterial lipopolysaccharides are irritating pyrogens, relatively
toxic to higher animals. The polysaccharide component is the
carrier of serological effects, while the lipide moiety has an
affinity for the surface of erythrocytes and produces the toxic
and pyrogenic effect.^- The high molecular weight wax called
cord factor from mycobacteria is quite toxic (quantitatively
comparable to diphtheria toxin) and is believed by some to be
the principal factor responsible for the virulence of tuberculosis
pathogens. Some of the simpler liposaccharides are shown in
this section. References to those of higher molecular weight
are included in an appendix.
Phosphatides are widely distributed in nature, though gen-
erally in small quantities. They are difficult to handle intact,
and few have been well characterized. The metabolism, theories
of function and biosynthesis of phospholipides have been re-
viewed. ^^
For many years chemists speculated on the reason for the
predominance of compounds with an even number of carbon
atoms among natural fatty acids. The mystery was intensified
by such animal feeding experiments as those of Knoop and
Dakin," which showed that in mammalian metabolism stepwise
degradation of fatty acids and similar substances occurred two
carbon atoms at a time.
Microorganisms have been instrumental in the discovery of
the significance of acetate in the cataboUsm and in the biosyn-
thesis of fatty acids. The enzymatic methods, particularly those
of anaerobic microorganisms, may differ in detail from those of
higher animals. This work has been well reviewed. ^^
Great advances were made in the discovery of coenzyme A,^*^
^- O. Westphal, O. Liideritz, E. Eichenberger and E. Neter, Deut. Z.
Verdauungs-u. Stoffivechselkrankh. 15 170 (1955).
13 E. P. Kennedy, Ann. Rev. Biochem. 26 130 (1957).
1* H. D. Dakin, "Oxidations and Reductions in the Animal Body,"
Longmans, Green and Co., London, 1922.
'^^ H. A. Barker, "Bacterial Fermentations," John Wiley and Sons,
Inc., New York, N. Y., 1956, p. 30.
^® Fritz A. Lipmann, "Les Prix Nobel," Stockholm, 1954.
53
Aliphatic Acids and Glycolipides
the isolation of acetyl coenzyme A (from yeast), the demonstra-
tion that the acetyl group was attached to its sulfur atom in a
thioester linkage and that acetyl coenzyme A was an active
acetylating agent. ^' The enzymic steps in what must be a
very general scheme of fatty acid catabolism now can be written
as follows:^®
MgO
CoA— SH
Fatty Acids
ATP
AMP + Pyrophosphate
DPN®
H© +DPNH
— CH2— CH2— CH2— CO— S— CoA
Acyl Coenzyme A
acy dehydrogenase
— CH.— CH=CH— CO— S— CoA
/rans-a,/3-Dehydroacyl Coenzyme A
enolhydrase
— CH2— CH— CH2— CO— S— CoA
1
OH
I©
DPN
©.
L-/3-Hydroxyacyl Coenzyme A
H^ + DPNH
/3-hydroxyacyldehydrogenase
— CH,— CO— CH2— CO— S— CoA
/3-Ketoacyl Coenzyme A
CoA— SH ,
cleavage enzyme
— CH2— CO— S— CoA + CH3CO— S— CoA
At first this process was thought to be reversible or cyclic. It
has since been shown that a separate set of enzymes controls
fatty acid biosynthesis. The required enzymes and cofactors
for the synthetic process have been isolated, and in outline the
^"^ Feodor Lynen, Ernestine Reichert and Luistraud Rueff , Ann. 574
1 (1951).
^* Feodor Lynen, Ann. Rev. Biochem. 24 653 (1955).
Pfizer Handbook of Microbial Metabolites
54
process is at present believed to be represented by the scheme : "
Biotin
C02
CH3CO— S— CoA
ATP
ADP
COOH
CH2— CO— S— CoA
Malonyl Coenzyme A
CH3CO— S— CoA
COOH
CH3— CO— CH— CO— S— CoA + HS— CoA
TPNH (4H®)
several steps,
decarboxylase, hydrogenase
CH3— CH2— CH,— CO— S— CoA + CO, + H,0
The butyryl coenzyme A can then react with another molecule
of malonyl coenzyme A and the process repeats. There is a
statistical distribution peak at 14-18 carbon atom length chains.
Certain bacteria can couple chains of considerable length as,
for example, in corynomycolic acid produced by corynebacteria :
CH3(CH>)u— CH
OH
COOH
I
CH— (CH,),3CH3
Corynomycolic
Acid
oxidative decarboxylation
CH3(CH,)u— C— CH,— (CH,),3CH3 + CO.
O
This compound is formed by the coupling of two palmitic acid
molecules as shown by a labeling experiment.-" C^M-Labeled
13 Salih J. Wakil, Edward B. Titchener and David M. Gibson,
Biochim. et Biophys. Acta 29 225 (1958); Salih J. Wakil, J. Am.
Chem. Soc. 80 6465 (1958); David M. Gibson, Edward B. Titchener
and Salih J. Wakil, Biochim. et Biophys. Acta 30 376 (1958).
-"Mireille Gastambide-Odier, E. Lederer, Nature 184 1563 (1959).
55 Aliphatic Acids and Glycolipides
palmitic acid was incorporated into mycolic acid, and the prod-
uct degraded to show that the carboxyl group and the oxidized
C-atom Ij-to it in the corynomycolic acid were labeled. A similar
biosynthetic path was suggested for the higher molecular weight
mycolic acids produced by mycobacteria. Thus, condensation
of 2 moles of n-C-c and 2 moles of n-C,s acids would yield the
Css mycolic acids of cord factor. A C^f, acid is known to be pro-
duced by mycobacteria, and a C-.o acid, corynine, by corynebac-
teria.
The biotin requirement for enzymatic carboxylations is be-
coming generally recognized. It was in connection with his
studies in lipide metabolism that Lynen isolated and synthesized
a reaction product of biotin and carbon dioxide in which COo
had reacted at one of the nitrogen atoms to give an allophanic
acid type of intermediate, the side-chain carboxyl group perhaps
11 Hooc ;i
/^\ \ /^\
HN N— COOH N NH
II II
CH CH or CH CH
CH2 CH— (CH,),— COOH CH2 CH— (CH2)4— COOH
being bound to the protein apoenzyme by an amide bond.
An intermediate may be adenosine diphosphoryl biotin (from
ATP):
O OH OH O
II I I II ^
/C\ /P—O—P—O— Adenosine ^Cv /COO©
HN N ^ ^ HN' N +Adenosine-
I I + CO2 — > I I diphosphate
CH CH CH CH
Other suggestions concerning the detailed function of this
carboxylase cofactor were made.-'
The lecithins are formed by initial ATP phosphorylation of
one glycerol hydroxyl group followed by esterification of the re-
-^ F. Lynen, J. Knappe, E. Lorch, G. Jutting and E. Ringelmann,
Angew. Chem. 71 481 (1959).
Pfizer Handbook of Microbial Metabolites
56
maining two hydroxyls by fatty acids as their coenzyme A esters.
The phosphate group is then displaced by a choline phosphate
group contributed by a coenzyme, cytidine diphosphocholine :
O
II
CH2— O— C— R
O CH3
CH— O— C— R + CH3-
NHo
CH2
O
T
-0— P— OH
OH
Diglyceride
Phosphate
-N— CH2— CH2— O— P-
I© I
CH3 eo
o
T
-0— p— o-
OH
-CH2
Cytidine-5'-diphosphatecholme
/""N
O
/On
OH OH
CH2— O— C— R
O
CH— O— C— R
+ Cytidine Phosphate
CH2
O
T
CH3
-CH2— N— CH3
©I
CH3
-0— P— O— CH2
00
The mechanism for cephalin formation is probably similar.
67 Formic Acid, CHoOo, colorless liquid, b.p. 100.5°, n,,-" 1.3714.
HCOOH
Pseiidomonas forniicans n. sp., etc.
See the reference below for earlier work.
Irving P. Crawford, /. Bacteriol. 68 734 (1954).
68 Oxalic Acid, C.H0O4 (Dihydrate), colorless tablets, m.p. 101°.
HOOC— COOH
Aspergillus niger, Penicilliuni oxalicinn, Citromyces
spp., many other fungus species and most lichens.
It occurs as the calcium salt in most lichens and higher
fungi, but occasionally also as the free acid.
57 Aliphatic Acids and Glycolipides
Jackson W. Foster, "Chemical Activities of Fungi," Aca-
demic Press Inc., New York, N. Y., 1949, chap. 10, pp. 326-
350.
G. Walter, "Organic Acid Production by some Wood-Rotting
Basidiomycetes," Univ. Microfilms Pub. 10,417, 1955, 99 pp.
69 Acetic Acid, C0H4O0, colorless liquid, b.p. 118°, nc'" 1.3718.
CH3COOH
Saccharomyces cerevisiae, other yeasts. Present in
small quantities in many microorganisms.
Leland A. Underkofler and Richard J. Hickey, "Industrial
Fermentations," Chemical Publishing Co., Inc., New York,
N. Y., 1954, Vol. I, Ruse H. Vaughn, Acetic acid-vinegar, chap.
17, pp. 498-535.
70 Pyruvic Acid, C;iH403, colorless liquid, b.p. 165° (dec), nn^"
1.4138.
CH3COCOOH
Pseudomonas sac char ophila, etc.
Approximately 2 moles of pyruvic acid were produced
per mole of glucose.
Nathan Entner and Michael DoudorofF, /. Biol. Chem. 196
853 (1952).
71 Malonic Acid, C;5H404, colorless plates, m.p. 135°.
HOOC— CH.— COOH
PenicilliuTn funiculosum, P. islandicum Sopp, other
fungi
D-Mannitol was isolated from the same culture.
Takeo Yamamoto, J. Pharm. Soc. Japan 75 761 (1955).
72 Tartronic Acid, C3H4O5, colorless crystals, m.p. 163° (dec).
HOOC— CH— COOH
OH
Acetobacter acetosum, Gluconoacetobacter liquefaciens
The first organism also produced 2-keto-D-gluconic acid
and 5-keto-D-gluconic acid. The second organism also
produced acetaldehyde, formic acid, acetic acid, 5-keto-
gluconic acid, glycolic acids, other reducing acids, rubigi-
nol, rubiginic acid and 3,5-dihydroxy-l,4-pyrone.
D. Kulka, A. N. Hall and T. K. Walker, Nature 167 905
(1951).
Pfizer Handbook of Microbial Metabolites 58
Ko Aida, Toshio Kojima and Toshinobu Asai, /. Gen. and
Appl. Microbiol. 1 18 (1955).
73 yg-Nitropropionic Acid, C3H-,04N, colorless crystals, m.p. 65°.
O2N— CH2CH2COOH
Aspergillus flavus, A. oryzae
Milton T. Bush, Oscar Touster and Jean Early Brockman,
J. Biol. Chevr. 188 685 (1951).
Seiji Nakamura and Chuji Shimoda, /. Agr. Chem. Soc.
Japan 28 909 (1954).
H. Raistrick and A. Stossl, Biochem. J. 68 647 (1958).
See addendum for reference on biosynthesis.
74 Propionic Acid, CgHeOo, colorless liquid with sharp odor, b.p.
140.5°.
CH3CH2COOH
Amanita muscaria L., Propionibacteria, Clostridium
propionicum
Julius Zellner, Monatsh. 26 727 (1905).
Kenneth V. Thimann, "The Life of Bacteria," The Macmil-
lan Company, New York, 1955, pp. 429-440.
75 L(+)-Lactic Acid (d-Lactic Acid, Sarcolactic Acid), C^H^O.,,
colorless crystals, m.p. 52.8°, [a],/' +3.33° (c 5.022 in
water), hygroscopic, polymerizes.
CH3CHCOOH
OH
Lactobacilli, Rhizopus species, etc.
Yields of 90% or better have been reported.
Leland A. Underkofler and Richard J. Hickey, "Industrial
Fermentations," Chemical Publishing Co., Inc., New York,
N. Y., 1954 Vol. I, Ruse H. Vaughn, Acetic acid-vinegar, chap.
17, pp. 498-535; H. H. Shopmeyer, Lactic acid, chap. 12,
pp. 391-419.
76 l(— )-Glyceric Acid, C:^Hf;04, unstable, usually isolated as a salt.
Ca salt (dihydrate), m.p. 138°, [aW +13.3° (c 4.5 in
water).
COOH
HCOH
I
CH2OH
59 Aliphatic Acids and Glycolipides
We have observed (by paper chromatographic compari-
son with an authentic sample on several solvent systems)
the production of this acid by a wide variety of fungi. It
is always accompanied by gluconic acid.
n 2-Phosphoglyceric Acid, C;iH707P.
COOH
I
HC— OPO3H2
CH2OH
Yeast
O. Meyerhof and W. Kiessling, Biochem. Z. 276 239 (1935).
78 Fumaric Acid, C4H4O4, colorless crystals, m.p. 290° (subl.)
(dec).
HOOC H
\ /
c=c
/ \
H COOH
Rhizopus species, also Mucor, Cunnirighamella and Cir-
cinella species, Aspergillus and Penicillium species, Bole-
tus spp., Fusaria, etc.
Yields are about 59 Sr ■
Leland A. Underkofler and Richard J. Hickey, "Industrial
Fermentations," Chemical Publishing Co., Inc., New York,
N. Y., 1954 Vol. I, Ruse H. Vaughn, Acetic acid-vinegar, chap.
17, pp. 498-535; Jackson W. Foster, Fumaric acid, chap. 15,
pp. 470-487.
79 i-frflrjs-Ethylene Oxide x./S-Dicarboxylic Acid (Epoxy succinic
Acid), C4H4O-, colorless crystals, m.p. 185° (dec.) [<xW^
-117° (c 1 in water).
HOOC H
H O COOH
Aspergillus fumigatus, Monilia formosa, Penicillium
viniferum
Yields greater than 20 g. per liter have been obtained.
Andrew J. Moyer, U. S. Patent 2,674,561 (1950).
Pfizer Handbook of Microbial Metabolites 60
80 Succinic Acid, C4H(j04, colorless prisms, m.p. 185-187°.
HOOC— CH2— CH2— COOH
Mucor stolonifer, Aspergillus terreus, Ustilina vulgaris,
Penicillium aurantio-virens, Fusarium oxysporum, lichens,
etc.
Occurrence is wide, but yields are generally rather low.
Ve. S. Butkevich and M. V. Fedorov, Biochem. Z. 219 103
(1930).
Jackson W. Foster, "Chemical Activities of Fungi," Aca-
demic Press Inc., New York, N. Y., 1949, p. 373.
81 Z-Malic Acid, C4H6O5, colorless crystals, m.p. 99°, [ajn'" -1.43°
(c 21.65 in water).
HOOC— CH—CH>— COOH
OH
White aspergilli, clasterosporium spp., many other
fungi.
Yields are high in some cases.
Reinhold Schreyer, Biochem. Z. 240 295 (1931).
John L. Yuill, Chem. Ind. 55 155 (1936).
82 L(+)-Tartaric Acid, C4H6O6, colorless powder or crystals, m.p.
168-170° (dec), [aW +11.98° (c 20 in water).
COOH
I
HCOH
HCOH
I
COOH
Gibberella saubinetii, Acetobacter suboxydans
Citric and acetic acids were produced also.
Lyle E. Hessler and Ross A. Gortner, /. Biol. Chem. 119 193
(1937).
Jonas Kamlet, U. S. Patent 2,314,831 (1943).
83 Itaconic Acid, C-^Ht-O^, colorless crystals, m.p. 162-164°.
CH2=C— COOH
1
CH2— COOH
Aspergillus terreus, Ustilago zeae, Helicobasidium
monpa, other fungi
6 1 Aliphatic Acids and Glycolipides
Jasper H. Kane, Alexander C. Finlay and Philip F. Amann,
U. S. Patent 2.385.283 (1945).
Leland A. Undeikofler and Richard J. Hickey, "Industrial
Fermentations," Chemical Publishing Co., Inc., New York,
N. Y., 1954 Vol. I. Lewis B. Lockwood, Itaconic acid, chap. 16,
pp. 488-498.
Yields are high in the case of A. terreus. Ustilago zeae
is reported to produce 15 g. per liter as well as some
dianthrone and glycolipides.
R. H. Raskins, J. A. Thorn and B. Boothroyd, Can. J. Micro-
biol. 1 749 (1955).
84 fra??s-Ghitaconic Acid, C-,H,;04, colorless needles, m.p. 138°.
COOH
CH
CH
I
CHo
COOH
Aspergillus niger (on Z-xylose)
Shinichiro Baba and Kinichiro Sakaguchi, Bull. Agr. Chem.
Soc. (Japan) 18 93 (1942).
85 a-Ketoglutaric Acid, C-HfiO.,, colorless crystals, m.p. 115-116°.
O
II
HOOC— C— CH,— CHo— COOH
Pseudomonas fiuorescens
Harold J. Koepsell, Frank H. Stodola and Eugene S. Sharpe,
U. S. Patent 2,724,680 (1955).
Leland A. Underkofler and Richard J. Hickey, "Industrial
Fermentations," Chemical Publishing Co., Inc., New York,
N. Y., 1954 Vol. II, Lewis B. Lockwood, Ketogenic fermenta-
tion processes, chap. 1, pp. 18-19.
86 Dimethylpyruvic Acid, C^H^Og, leaflets, m.p. ~24°, b.p. 76-78°.
CHs O
\ II
CH— C— COOH
/
CHa
Pfizer Handbook of Microbial Metabolites 62
Aspergillus spp., Piricularia oryzae ( biotin-deficient
medium)
K. Ramachandran and V. Radha, Current Sci. (India) 24
50 (1955).
Hirohiko Katsuki, /. Am. Chem. Soc. 77 4686 (1955).
87 Otlier Keto-Acids:
Many of the transitory a-keto-acids present in cultures
of microorganisms can be isolated by means of intercep-
tors such as 2,4-dinitrophenylhydrazine. One recent pa-
per reported the following acids identified principally in
lactic and propionic bacteria cultures:
Glyoxylic Acid p-Hydroxyphenylpyruvic
Pyruvic Acid Acid
a-Ketoisovaleric Acid Hydroxypyruvic Acid
a-Ketoisocaproic Acid Oxalacetic Acid
a-Ketocaproic Acid a-Ketoglutaric Acid
Matti Kreula and Artturi I. Virtanen, Acta. Chem. Scand.
11 1431 (1957).
88 Glutaric Acid, C,r,Hs04, colorless needles, m.p. Q?"".
COOH
I
CH2
CH2
I
CH2
COOH
Aspergillus niger (on Z-xylose)
Shinichiro Baba and Kinlchiro Sakaguchi, Bull. Agr. Chem.
Soc. (Japan) 18 93 (1942).
89 Ita tartaric Acid, C^HgOfi, occurs as a gummy equilibrium mix-
ture of lactone and free acid. Characterized as the methyl
ester derivative.
COOH
HO— C— CH,OH
I
CHo
I
COOH
Aspergillus terreus mutant
Frank H. Stodola, M. Friedkin, Andrew J. Moyer and
Robert D. Coghill, J. Biol. Chem. 161 739 (1945).
63 Aliphatic Acids and Glycolipides
90 a-Methylbutyric Acid, C-.HjoOo, colorless crystals, m.p. 176°,
[a],r^ +17.6°.
CHaCH-CHCOOH
CH3
Peuicillium notatum
Donald J. Cram and Max Tishler, /. Am. Chem. Soc. 70
4238 (1948).
91 a,/i-DihydroxyisovaIeric Acid, C,-,H,o04, colorless syrup, [ccW^
-12.4° (c 2 in dilute HCl, pH 1 ) and + 10° (c 2 in water,
pH 5.5-6.5). Forms crystalline quinine salt.
CH3
\
C — CH— COOH
CH3 OH OH
A valine precursor isolated from a Neurospora crassa
mutant
John R. Sjolander, Karl Folkers, Edward A. Adelberg and
E. L. Tatum, ;. Am. Chem. Soc. 76 1085 (1954).
92 cis-Aconitic Acid, C,jH,;0,;, colorless crystals, m.p. 125°.
HC— COOH
II
C— COOH
I
CH2— COOH
Aspergillus niger
This acid presumably is present to some extent in all
organisms with the citric acid cycle.
Kinichiro Sakaguchi and Shinichiro Baba, Bull. Agr. Chem.
Soc. (Japan) 18 95 (1942). (Not isolated)
93 a«o-Isocitric Acid (Lactone), C,.H„Oe, m.p. 140-141° [aW""
+ 42.3° (c 4.83 in water).
O
/C.
COOH CHo
I " ^
J 1/
c — c
H COOH
Pfizer Handbook of Microbial Metabolites 64
Penicillium purpiirogeniim Stoll var. rubrisclerotium
Thorn.
Yields greater than 20% of the glucose substrate sup-
plied have been reported. Probably the isomer normal to
the mammalian citric acid cycle also occurs in some
microorganisms, but it has not been reported to accumu-
late.
Teruhiko Beppu, Shigeo Abe and Kinichiro Sakaguchi, Bull.
Agr. Chem. Soc. (Japan) 21 263 (1957).
94 tra ns-/3-Methylglutaconic Acid, C,jHs;04, colorless crystals, m.p.
131-134°. HOOC— CH=C— CH,— COOH
CH3
Ustilago sphaerogena
This substance is a component of ferrichrome A pig-
ment,* in which its monohydroxamate is complexed with
iron.
Thomas Emery and J. B. Neilands. (In press)
* See addendum.
95 Citric Acid, CgHsO- (occurs as monohydrate), colorless crystals
or white powder, m.p. (monohydrate) ~100°, (anhy-
drous) 153°. CH,— COOH
HO— C— COOH
I
CH2— COOH
Wide variety of fungi, e.g., Aspergillus niger.
Yields are high.
Leland AT Underkofler and Richard J. Hlckey, "Industrial Fer-
mentations," Chemical Publishing Co., Inc., New York, N. Y.,
1954 Vol. I; Marvin J. Johnson, The citric acid fermentation,
chap. 13, pp. 420-445.
96 Mevalonic Acid Lactone (Hiochic Acid, /^-Hydroxy-yg-methyl-
S-valerolactone), C,5Hi„0;{, colorless, hygroscopic crystals,
m.p. 27°, b.p. 90° (0.3 mm.). (Synthetic racemate. )
CH3
CHo I CH,.
I OH I
CH, C-O
65 Aliphatic Acids and Glycolipides
Yeasts (Isolated from Distillers' Dried Solubles).
Donald E. Wolf, Carl H. Hoffman. Paul E. Aldrich, Helen R.
Skeggs, Lemuel D. Wright and Karl Folkers, J. Am. Chem. Soc.
78 4499 (1956).
Helen R. Skeggs, Lemuel D. Wright, Emlen L. Cresson,
Gloria D. E. MacRae, Carl H. Hoffman, Donald E. Wolf and
Karl Folkers, /. Bad. 72 519 (1956).
Carl H. Hoffman, Arthur F. Wagner, Andrew N. Wilson,
Edward Walton, Clifford H. Shunk, Donald E. Wolf, Fred-
erick W. Holly and Karl Folkers, /. Am. Chem. Soc. 79 2316
(1957).
Clifford H. Shunk, Bruce O. Linn, Jesse W. Huff, James L.
Gilfillan, Helen R. Skeggs and Karl Folkers, ibid. 79 3294
(1957).
97 x.^-Dihydroxy/S-methylvaleric Acid, C6H10O4, colorless syrup,
[a]i,"' +3° (c 2.3 in water containing 1 equiv. of Ca(0H)2)
and -16.7° (c 2.3 in dilute HCl, pH 1 ). Forms crystalline
quinine salt.
CH3
CH3CH2— C— CH— COOH
! !
OH OH
A precursor of isoleucine isolated from a Neiirospora
crassa mutant.
John R. Sjolander, Karl Folkers, Edward A. Adelberg and
E. L. Tatum, J. Am. Chem. Soc. 76 1085 (1954).
98 2-Phospho-4-hydroxy-4-carboxyadipic Acid, C7H11O11P.
OPO3H2
HC— COOH
I
CHo
HO— C— COOH
CH,— COOH
Escherichia coli
W. W. Umbreit, J. Bacteriol. 66 74 (1953).
99 Lipoic Acid (6,8-Thioctic Acid), C8H14O0S2, pale yellow crystals,
m.p. 47°, [7W +10.4°.
CH2— CH2— CH— (CH,)4— COOH
I I
s s
Yeast, E. coli mutant
Pfizer Handbook of Microbial Metabolites 66
Lester J. Reed, Quentin F. Soper, Geo. H. F. Schnakenberg,
Stanley F. Kern, Harold Boaz and I. C. Gunsalus, /. Am. Chem.
Soc. 74 2383 (1952); Lester J. Reed, I. C. Gunsalus, G. H. F.
Schnakenberg, Quentin F. Soper, Harold E. Boaz, Stanley F.
Kern and Thomas V. Parke, ibid. 75 1267 (1953). (Isolation)
Edward Walton, Arthur F. Wagner, Louis H. Peterson, Fred-
erick W. Holly and Karl Folkers, ibid. 76 4748 (1954); Edward
Walton, Arthur F. Wagner, Frank W. Bachelor, Louis H.
Peterson, Frederick W. Holly and Karl Folkers, ibid. 77 5144
(1955). (Synthesis)
100 2-Decene-l,10-dioic Acid, CioHigO^, colorless crystals, m.p. 172°,
HOOC— CH=CH— (CH..)6— COOH
Penicillium notatum
Donald J. Cram and Max Tishler, /. Am. Chem.. Soc. 70
4238 (1948). (Isolation)
101 10-Undecynoic Acid, CnHigOs, colorless crystals, m.p. 39°.
HC=C— (CHoJs— COOH
Rhodotorula glutinis var. lusitanica
Undecenoic acid was isolated from the same culture.
Nagueira Prista, Anais. fac. farm. Porto 14 19 (1954).
102 10-Undecenoic Acid (10-Undecylenic Acid), Ci,Hj„0^., colorless
crystals, m.p. 24°, n,,'-* 1.4464.
CH2=CH(CHo)8COOH
Rhodotorula glutinis var. lusitanica
Nogueira Prista, Anais. fac. farm. Porto 14 19 (1954).
103 Myristic Acid, Ci4HoyOj, colorless soft leaflets, m.p. 54°.
CH3{CH,),oCOOH
Widely distributed, especially as its triglyceride.
104 D-^-Hydroxymyristic Acid, C14H2SO.S, colorless crystals, m.p. 73°,
[a]u'' -16° (c 2.0 in chloroform).
CH,3{CH>),oCHCH,COOH
OH
Escherichia coli
Obtained together with lauric, myristic and palmitic
acids from an acid hydrolysate of the phospholipide frac-
tion.
67
Aliphatic Acids and Glycolipides
Miyoshi Ikawa, J. B. Koepfli, S. G. Mudd and Carl Niemann,
]. Am. Chem. Soc. 75 1035 (1953).
105 Mineoluteic Acid, CnjH^c.O;, colorless needles, m.p. 171°, [a]-,4Gi^''
+ 108.1° (c 1.07 in acetone)
-c=o
CH;,(CH,)9— CH
HOOC— C— OH
CH
COOH
Penicillium minioluteum Dierckx
Spiculisporic acid is produced in the same culture.
John H. Birkinshaw and Harold Raistrick, Biochem. J. 28
828 (1934).
106 Palmitoleic Acid (Physetolic Acid, 9-Hexadecenoic Acid),
CigHsoO^' colorless crystals, m.p. 30-33°.
CH3(CHo)5CH=CH(CH.)7COOH
Yeast, Corynebacterium diphtheriae, Streptococcus
spp., Penicillium lilacinum occurs widely.
E. Chargaff, Z. phijsiol. Chem. 218 223 (1933).
Klaus Hofmann and Fred Tausig, /. Biol. Chem. 213 415
(1955).
J. Singh, Sudha Shah and T. K. Walker, Biochem. J. 62 222
(1956).
107 Pyolipic Acid, CigHaoOy, colorless, viscous oil.
-CH— CH.— COOH
HCOH
HCOH
HOCH
CH
(CH,)6
CHs
CHs
Pseudomonas pyocyanea
The yield was 1-2 g. per liter.
Sune Bergstrom, Hugo Theorell and Hans Davide, Arch.
Biochem. 10 165 (1946).
Pfizer Handbook of Microbial Metabolites 68
108 Palmitic Acid, CieHgoOo, soft white crystals, m.p. 62.5°.
CHslCHoluCOOH
Widely distributed, especially as esters.
109 Spiculisporic Acid, CiyHo^O^., colorless crystals, m.p. 145°, [3!]546i
-14.76° (in alcohol).
CH3(CHo)a— CH— COOH
O C— COOH
/
o=c
\
CH2— CH2
Penicillium spiculisporum Lehman, P. crateriforme
Gilman and Abbott and P. minioluteum Dierckx
P. W. Clutterbuck, H. Raistrick and M. L. Pintoul, Trans.
Roy. Soc. (London) B220 301 (1931). (Isolation and struc-
ture)
Albert E. Oxford and Harold Raistrick, Biochem. J. 28 1321
(1934). (Isolations)
no Roccellic Acid, C^jH-i.204, colorless crystals, m.p. 131°, [alo^®
+ 16.80°.
CH3(CHo)„— CH— COOH
CH— COOH
CH3
Roccella tinctoria (L.), R. viontagnei Bel., etc., also
Lecanora species
Yields 1-4%. Erythrin and i-erythritol also were pres-
ent.
G. Kennedy, J. Breen, J. Keane and T. J. Nolan, Sci. Proc.
Roy. Dublin Soc. 21 557 (1937).
in cis-Vaccenic Acid, Ci,sH;i402, soft white platelets, m.p. 43°.
CH3(CH,),CH=CH(CH2)9COOH
Lactobacillus arabinosus, L. casei, Agrobacterium
tumefaciens. Streptococcus spp.
Klaus Hofmann, Robert A. Lucas and Sylvan M. Sax, /. Biol.
Chem. 195 473 (1952).
Klaus Hofmann and Fred Tausig, ibid. 213 425 (1955).
69 Aliphatic Acids and Glycolipides
112 Lactarinic Acid ( 5-Ketostearic Acid), CisH340.{, colorless plates,
m.p. 87°.
O
CH3(CH,),o— C— (CHolsCOOH
Lactarius rufus Scopol.
A. K. Schneider and M. A. Spielman, /. Biol. Chem. 142 345
(1942).
113 Stearic Acid, CisHj^^Oo, colorless leaflets m.p. 69°.
CH3(CHo)i6COOH
Widely distributed.
114 Lactobacillic Acid (Phytomonic Acid), CigHggOs, colorless crys-
tals, m.p. 33.6-35°.
CHslCHola— CH CH— (CHzls— COOH
\ /
CH2
Lactobacillus arabinosus, L. casei, Agrobacterium
(Phytomonas) tumefaciens
Klaus Hofmann, Otto Jucker, William R. Miller, Alfred C.
Young, Jr. and Fred Tausig, J. Am. Chem. Soc. 76 1799 (1954).
Klaus Hofmann, Gino J. Marco and George A. Jeffrey, ibid.
80 5717(1958). (Structure)
115 Tuberculostearic Acid (MO-Methyloctadecanoic Acid), Ci^Hj^sO^,
colorless oil, m.p. 12.8-13.4°, n,r' 1.4514, [oiW' -0.045°.
CHslCHo);— CH— (CH-Js— COOH
I
CH3
Mycobacterium tuberculosis var. hominis
Franklin S. Prout, James Cason and A. W. Ingersoll, /. Am.
Chem. Soc. 70 298 (1948). (Synthesis)
116 Alternaric Acid, CoiHgoOs, colorless crystals, m.p. 138°.
O
CH3 OH OH CH2 O I
CH3— CH2— CH— CH— C— CH=CH— CH,— C— CHo— CHo— C— CH CHo
COOH
C CH
O ^ CH3
Alternaria solani Ell. and Mart., Jones and Grout
Pfizer Handbook of Microbial Metabolites 70
John Frederick Grove, /. Chem. Soc, 4059 (1952). (Isola-
tion)
J. R. Bartels-Keith and John Frederick Grove, Proc. Chem.
Soc, 398 (1959). (Structure)
117 Rangiformic Acid, Cm,H;jsO,;, colorless needles, m.p. 106°, [a]i,-*
+ 16.2°.
CH3(CH2),3— CH— COOH 1
CH — COOH j>Monomethyl ester
CH2— COOHj
Cladonia rangiformis Hoffm., C. viitis Sandst.
Masaru Aoki, J. Pharm. Soc. Japan 66A 52 (1946).
118 Caperatic Acid, C2iH3g07, colorless leaflets, m.p. 132°, [aW°
-3.85°.
CH3(CH2)i3— CH— COOH
I (one carboxyl group
HO — C — COOH exists as the methyl
j ester)
CHj— COOH
Parmelia caperata (L.), Nephromopsis stracheyi, f.
ectocarpisma Hue.
Protocetraric acid also was present.
Michizo Asano, Yukio Kameda and Osamu Tamemasa, /.
Pharm. Soc. Japan 61 203 (1944).
119 Ungulinic Acid, C^.^H.^sOt;, colorless microcrystalline needles,
m.p. 78-80°.
Tentative structure of hydrate (ordinarily a y-lactone) :
Ri— CH— COOH I Ri=C,6H3.3, R2=R3=H.
R2— C— COOH II R2=Ci6H33, Ri=R3=H.
R3— C— COOH Mi R3=Ci6H33, R,=R2=H.
I
OH
Polyporus betulinus
J. H. Birkinshaw, E. N. Morgan and W. P. K. Findlay,
Biochem. J. 50 509 (1952).
Sidonie Marcus, ibid. 50 516 (1952).
7 1 Aliphatic Acids and Glycolipides
120 Ajraricic Acid (Agaricin, Laricic Acid, Agaric Acid) C2i.H4„07,
colorless microcrystalline powder, m.p. 142° (dec), [^tlu^"
-9° (in dilute NaOH solution).
CH3(CH.)i5— CH— COOH
HO— C— COOH
CH2— COOH
Polyporus officinalis (=Fomes officinalis, Fomes laricis)
A yield of 189^ of the weight of the fruiting body has
been reported.
H. Thomas and J. Vogelsang, Ann. 357 145 (1907).
121 Ventosic Acid, C00H44O,., white amorphous powder, m.p. 183°. A
tetrahydroxybehenic acid.
Haematomma ventosum, other lichens
Thamnolic acid was isolated from the same source.
Yngve Johannes Solberg, Acta Chem. Scand. 11 1477
(1957).
122 Tetracosanoic Acid (Lignoceric Acid), C04H4SO0, colorless plates,
m.p. 87.5°.
CH3(CH,),,COOH
Mycobacterium tuberculosis, Phycomyces blakesleeanus,
Penicillium chrysogenum
Robert L. Peck and R. J. Anderson, /. Biol. Chem. 140 89
(1941).
Karl Bernhard and Hans Albrecht, Helv. Chim. Acta 31 977
(1948).
Yoshiro Abe, Proc. Fac. Erig. Keiogijuku Univ. 2 15 (1949).
(Chem. Abstr. 47 49491)
123 Pentacosanoic Acid, Co-.H.-.oOs, colorless crystals, m.p. 84°.
CH3(CHo)o3COOH
Mycobacterium tuberculosis var. homiriis
A. Aebi, J. Asselineau and E. Lederer, Bull. soc. chim. biol.
35 661 (1953).
124 Hexacosanoic Acid (Phthioic Acid, Cerotic Acid, Cerinic Acid),
CogHgoOo, colorless crystals, m.p. 88°.
CH3 (CH..)24COOH
Mycobacterium tuberculosis, Phycomyces blakesleeanus
Pfizer Handbook of Microbial Metabolites 72
Obtained together with palmitic, tuberculostearic and
mycoceranic acids.
R. J. Anderson, J. Biol. Chem. 83 505-519 (1929).
Karl Bernhard and Hans Albrecht, Helv. Chim. Acta 31 977
(1948).
Jean Asselineau, Compt. rend. 237 1804 (1953).
1 25 Mycolipenic Acid ( ( + )-2,4L,6L-Trimethyltetracos-2-enoic Acid ) ,
CotH^-^.Oo, low melting solid [a]i,-" +7.9° (c 25.2 in ether),
n^"' 1.'4600.
CH3(CH2)i7— CH— CH,— CH— CH=C— COOH
CH3 CH3 CH3
Mycobacterium tuberculosis var. hominis
J. D. Chanley and N. Polgar, /. Chem. Soc, 1003 (1954).
(Isolation)
D. J. Millin and N. Polgar, Proc. Chem. Soc, 122 (1957).
( Synthesis )
126 Csv-Phthienoic Acid (trans-2,4-Dimethyl-13-n-amyl-2-eicosenoic
Acid), CoyH^oOo, soft white crystals, m.p. 26° and 39°
( polymorphic ),"[ a] d'' +17.8° ±0.2°, n,,^' 1.4666.
Tentative structure :
CHACHoU
\
CH— (CH,)8— CH— CH=C— COOH
/ I 1
CH3(CH2)4 CH3 CH3
The author emphasizes the difference of this compound
from mycolipenic acid.
Mycobacterium tuberculosis var. hoviinis
James Cason, Hans-Ruedi Urscheler and C. Freeman Allen,
J. Org. Chem. 22 1284 (1957). (Structure) and earher papers
in this series.
127 Ustilagic Acids.
The corn smut fungus produces a group of related
glycolipides. As originally isolated, the properties of the
partially purified mixture were given as : CayH^o-eeOiy, color-
less, needle-like crystals, m.p. 144-147°, [x]rr' +7° (c 1.0
73 Aliphatic Acids and Glycolipides
in pyridine). Two of the component structures have been
characterized as shown:
H
OH
H
CH2OH
<^\
/
\ "
/
OR
OH
" U
Y
H
\
H
-o^
\o/
/\
N°"
H
4
CH2OH H OH
R = — OOC— CH— (CH2)io— CH-CHoOH (Ustilic Acid A)
OH
and
R = — OOC— CH— (CH2)i2— CH— CHoOH (Ustilic Acid B)
OH OH
Ustilago zeae, other Ustilaginales spp.
Yields of 12-33% of the glucose supplied were reported.
R. H. Haskins and J. A. Thorn, Can. J. Botany 29 585
(1951).
R. U. Lemieux, J. A. Thorn, Carol Brice and R. H. Haskins,
Can. J. Chem. 29 409 (1951). (Isolation)
R. U. Lemieux, ibid. 29 415 (1951).
R. U. Lemieux, J. A. Thorn and H. F. Bauer, ibid. 31 1054
(1953).
128 Bongkrekic Acid, C29H40OY, unstable, resinous, [ajo" +165° (c
2.0inNaHCd3).
The stabler hydrogenated compound, C29H54O7, was
given the following partial structure.
C2H5(±CH2)
HOOCl I
(C17H33 ± 2CH2)— CH2— C— CH2— CH— CH-COOH
HOOCj I I , ^ 1
OCH3 V
CH3,H
Pseudomonas cocovenenans (on a special copra-con-
taining medium)
Bongkrekic acid is a toxin and has antibiotic properties.
D. H. Nugteren and W. Berends, Rec. trav. chim. 76 13
(1957).
Pfizer Handbook of Microbial Metabolites
74
129 Mycoceranic Acid (Mycocerosic Acid), C.^He^O^, white solid,
m.p. 30°, [a],.-' -6.9° (c 16.8 in ether). "
CH3(CH2)2iCH— CK2— CH— CHo— CH~COOH
CH3 CH3 CH3
Mycobacterium tuberculosis
Occurs esterified with phthiocerol.
J. D. Chanley and N. Polgar, /. Chem. Soc, 1003, 1011
(1954).
130 Glycolipide from Pseiidomonas aeruginosa, C;{^H,5,|Oi4 (Monohy-
drate), colorless rectangular platelets, m.p. 86°, [aju —84°
(c 3.0 in chloroform).
Probable structure:
H
I
C —
HCOH
HCOH O
I
HOCH
CH
C O— CH— CH,— COO— CH— CH,— COOH
HCOH (CH.)
1 i
— HC CH3
i
HOCH
CH
(CH,)fi
CH3
CH3
CH3
Pseudomonas aeruginosa (three different strains)
F. G. Jarvis and M. J. Johnson, J. Am. Chem. Soc. 71 4124
(1949). (Isolation)
131 Corynomycolenic Acid, Co^Hij^O;^, colorless oil, ni/'' 1.4758.
Methyl ester: [a],-,4(ii"' +9.0 ±0.3°.
COOH
CH3(CH,)6CH=CH(CH,)7CHCH(CH,),3CH3
OH
Corynebacterium diphtheriae
J. Pudles and E. Lederer, Biochim. et Biophys. Acta 11 163
(1953).
75 Aliphatic Acids and Glycolipides
132 Corynomycolic Acid, Ch2H,5403, colorless crystals, m.p. 70°, [ajn
7.5°.
COOH
CH3(CH2)i4— CH— CH— (CHo),3CH3
I
OH
Corynebacterhim diphtheriae, C. ovis
E. Lederer, J. Pudles, S. Barbezat and J. J. Trillat, Bull. soc.
chim. France 93 (1952).
Anne Diara and Julia Pudles, Bull. soc. chim. biol. 41 481
(1959).
133 Fungal Cerebrins
A. C42H85O5N
CHslCHslisCH CH CH CH2OH
OH OH NH— C— CH(CHo)2iCH3
O OH
B. C42H85O6N
CH3(CH2)i3CH CH CH CHoOH
OH OH NH— C— CH— CH— (CHskCHs
II I I
O OH OH
PenicilliuTn spp., yeasts
Takeshi Oda, /. Pharm. Soc. Japan 72 136 (1952). (Isola-
tion); idem., ibid. 72 142 (1952). (Structure)
A. H. Cook, "The Chemistry and Biology of Yeasts," A. A.
Eddy, Aspects of the chemical composition of yeast, Academic
Press, Inc., New York, N. Y., 1958, p. 203.
134 Yeast Cerebrin, C44HsoO-,N, colorless crystals, m.p. 87-89°, [a]D
+31°.
Tentative structure:
CH3(CH2),3CH— CH— CH— CH.OH
! I I
OH OH NH— C— CH— (CHo)o3CH3
O OH
Yeasts
Pfizer Handbook of Microbial Metabolites
76
Fritz Reindel, A. Weichmann, S. Picard, Karl Luber and
Paul Turula, Ann. 544 116 (1940).
A. H. Cook, "The Chemistry and Biology of Yeasts," A. A.
Eddy, Aspects of the chetnical composition of yeast. Academic
Press, Inc., New York, N. Y., 1958, p. 203.
135 Lecithins and Cephalins
The lecithins and cephalins are widely occurring phos-
pholipides. They are generally oily or partially crystalline
materials with mixed fatty acids. Lecithin and Cephalin
Structures (R = various fatty acids).
a-Lecithin
CH2— O— R
CH— O— R
oe
CH2— O— P— O— CH2— CH2— N(CH3)3
II ■ ■ ■
O Choline
©
/3-Lecithin
CH2— O— R
OG
I
CH— O— P— O— CH2— CH2— N(CH3)3
II
O
CH2— O— R
©
The cephalins are similar except that the choline residue
is replaced by ethanolamine.
Yeast, Aspergillus sydoivi, etc.
F. M. Strong and W. H. Peterson, J. Am. Chem. Soc. 56 952
(1934).
D. W. Woolley, F. M. Strong, W. H. Peterson and E. A. Prill,
ibid. 57 2589 (1935).
L. F. Salisbury and R. J. Anderson, /. Biol. Chem. 112 541
(1936).
136 Dipalmitoleyl-a-lecithin, C40H76O8NP, semi-solid material, [ajn
+ 6.6°.
CH2— O— CO— (CHolv— CH=CH— (CH,),— CH3
CH— O— CO— (CH.JT— CH=CH— (CH,)5— CH3
O
II
CH2— O— P— O— CHo— CHo— N(CH3)3
I ©
oo
Yeast
77
Aliphatic Acids and Glycolipides
Donald J. Hanahan and Michael E. Jayko, J. Am. Chem.
Soc. 74 5070 (1952). (Isolation)
137 Corynine (Corynodic Acid), C.-2Hn,404, colorless crystals, m.p.
70°.
CHa— CH— (CHj);— CH— CH— CH— CH— CH— (CHaliT— CH— (CHJn— CHs
OH CHs OH CH3 CH.3 COOH CH3
Corynebacteriiim diphtheriae
Obtained from the saponification of the phospholipide
fraction.
Hideo Takahashi, J. Pharm. Soc. Japan 68 292 (1948).
138 A Mycolic Acid, CS4H174O4 (^SCH^), colorless microcrystals,
m.p. 56-58°, [all, +2° (c 2.446 in chloroform).
OH OH
CH3— (CH,)„— CH— CH— CH— CH— CH— COOH m + n ~ 28
(CHoJa R C24H49 R ■ ' C24H49
CH3
Mycobactermm tuberculosis human Canetti strain
This acid was isolated by chromatography from a sa-
ponification of the chloroform soluble wax.
Jean Asselineau, Bull. soc. chim. France 135 (1960).
139 Cord Factor, CisoHaoeOj^ ±10 CH2, nearly colorless wax, m.p.
43-45°, [a],, +40 ±5° (c 1.37 in chloroform).
OH
CH2O— CO— CH— CH— C6oHi2o(OH)
C24H49 H OH
H H
CO— CH— CH— CeuHi-olOH)
I
C24H49
Pfizer Handbook of Microbial Metabolites 78
Mycobacterium tuberculosis (six different virulent hu-
man and bovine strains as well as the BCG strain).
Hydrolysis yields 1 mole of trehalose and 2 moles of
mycolic acid.
H. Noll, H. Bloch, J. Asselineau and E. Lederer, Biochim. et
Biophys. Acta 20 299 (1956).
Tetronic Acids and Other Lactones
and Lactams
This chapter includes derivatives of tetronic acid as well as
some related lactones. Ascorbic acid is included in this section
because it is structurally similar to the tetronic acids, although
it might equally well have been placed with the sugar acids.
The tetronic acids appear to be condensation products of two
simple molecules. Ehrensvard and his collaborators have ob-
tained experimental confirmation of this in two cases.' By
labeled acetate studies on carlosic and carolic acids, they have
shown the B portions of the molecules as indicated below to be
HO
HO A| B C— CH2— CH2— CHa
O HOOC— CHo ' O
Tetronic Acid Carlosic Acid
B C— CH2— CH2— CH2— OH
O
Carolic Acid
^ Gosta Ehrensvard, "Chemical Society Symposia," Special Publica-
tion No. 12, The Chemical Society, London, 1958, p. 14.
Pfizer Handbook of Microbial Metabolites 80
composed of three acetate units, while the A part is probably
derived from another source related to carbohydrate biosynthe-
sis. It would seem as if in the case of carlosic acid the A portion
were derived from oxaloacetic acid, and in carolic acid from
lactic or pyruvic acids.
Inspecting other structures it appears (formally at least) that
in zymonic acid, isolated by Stodola from many yeasts, the A
portion could be from tartronate.
O
I / il
HO— C=^=C— CH3 HO— C=^C— C— CH3
I ! I I i I
HOOC— CH I C=0 CH \ C=0
y CH3— CH2— CH z
I "
CH3
Zymonic Acid Tenuazonic Acid
HOOC— C=4=C— CH3
I I
CH3-(CH2)i2— CH ! C=0
Lichesterinic Acid
There are other possibilities in this case, however. Tenuazonic
acid, a lactam similar to the tetronic acids, must surely be de-
rived from isoleucine and acetoacetate.* Lichesterinic acid
apparently is the result of a condensation between pyruvate and
3-oxypalmitate. Nephromopsic acid, which sometimes is found
with lichesterinic acid, may be a reduction product.
I
HOOC— CH CH— CH3 HO— C=[^CH
CH3— (CH2)i2— CH C=0 CH3— CH i C=-0
\o/^ ^Y
Nephromopsic Acid 7-Methyltetronic
Acid
OH
HOOC— CH— C— CH2COOH
I I
CH3— (CH2)i2— CH2 C=0
I
OH
Caperatic Acid
It is interesting to note the co-occurrence of nephromopsic acid
and caperatic acid, the former being (apparently) a condensa-
* See addendum.
8i
Tetronic Acids and Other Lactones and Lactams
don product of a C^r, fatty acid and pyruvate while the latter
seems to be the condensation product of a Ck, fatty acid with
oxaloacetate. Many other such apparent biosynthetic origins
can be detected.
The biosynthesis of penicillic acid has been studied.- At first
glance this would appear to be derived from acetate and
dimethylpyruvate, ^-methylglutaconate or a similar unit. It
was found that 2-C''*-mevalonic acid lactone was not incorporated
into the penicillic acid molecule when added to the growth me-
dium of Penicillium cyclophim Westling. However, CH;^C'^OOH
was incorporated with equal labeling at the sites shown:
HO
CH3O— C
CH3
=CH
CH3
CH2
X
C— C
c=o
o o
H
CHo
/
C— C— C=CH— COOH
OCH3
Penicillic Acid
With a relationship to the terpene biosynthetic route ruled out
and a similarity to the valine biogenetic pathway also unlikely,
the authors suggested a precursor of the orsellinic acid type,
perhaps the 4-methyl ether :t
CH3
COOH
OH
c
1
*CO
c
C— CO
?"' COOH
1* /
CO ^
CO
/
c
HO OH
Orsellinic Acid
CH3
-
CH3
1
0
lo]
*c
\/\ *
C CH— COOH
*C COOH
c
-CO,>
0 *C
C CH2
CH30
* *C COOH
CH3O c
H
H
_J
Penicillic Acid
- A. J. Birch, G. E. Blance and Herchel Smith, J. Chem. Soc, 4582
(1958).
t See addendum.
Pfizer Handbook of Microbial Metabolites
82
A somewhat similar aromatic ring cleavage has been proposed^
in the biosynthesis of patulin.
It is likely that the biosynthetic origins of the two recently re-
ported streptomycete antibiotics, acetomycin and 3-carboxy-2,4-
pentadienal lactol (PA-147) are mutually related.
CH3
I
CH-
CH
CH3
-C— CO— CH3
I
c=o
CH3CO— o o
Acetomycin
CH=
I
CH
/ \ /
HO O
C— CH=CH2
c=o
CH=
=C— CH=CH2
O
3-Carboxy-2,4-pentadienal Lactol
CH
c=o
HO
The biosynthesis of ascorbic acid in Aspergillus niger is
known to involve the following stages:*
000
II , II II
:ko c — c — c —
— — 0= — c
_ o^ o-^ II c
COOH CH2OH CH2OH CHoOH
D-Glucuronic L-Gulono- 2-Keto-L- L-Ascorbic
Acid lactone gulonolactone Acid
The glucuronic acid probably quite generally can arise from
glucose by a hexose interconversion of the type discussed earlier
in the section on sugars. In muscle tissue it may also come
from myoinositol.
•■' J. D. Bu'Lock and A. J. Ryan, Proc. Chem. Soc, 222 (1958).
*K. Sivarama Sastry and P. S. Sarma, Nature 179 44 (1957).
83
Tetronic Acids and Other Lactones and Lactams
MO y-Methyltetronic Acid, Cr.HfiOg, colorless crystals, m.p. 115°,
[a].-.«, -21° (c 0.526 in water).
HO
CH3
^o-^X
Penicillium charlesii G. Smith, P. felliitamnn
The yield of this and the following tetronic acids from
P. charlesii totaled l^% of the glucose consumed.
Percival Walter Clutterbuck, Harold Raistrick and Fritz
Reutter, Biochem. J. 29 1300 (1935).
V. C. Vora, /. Set. Ind. Research (India) 13B 504 (1954).
141 3-Carboxy-2,4-pentadienal Lactol (PA-147), CgHeOg, viscous oil
which polymerizes on standing at room temperature, [oi]n
0 ±2° (c2in CHCI3).
CH=CH2
CH=CH2
HC— =C
C C
O HO O
HO O
Streptomyces sp.
Hans Els, B. A. Sobin and W. D. Celmer, /. Am. Chem.
Soc. 80 878 (1958).
142 Zymonic Acid, CgHeO.-, isolated as the stable methyl ester, b.p.
118-123° (1 mm.), n,r" 1.4640.
HO— C=
HOOC— HC
<— CH3
I
c=o
Trichosporon capitatum, Hansenula subpelliculosa,
Kloeckera brevis, Sporobolomyces salmonicolor, Crypto-
coccus laurentii, Debaryomyces hansenii, Nematospora
coryli, Torula mellis
Pfizer Handbook of Microbial Metabolites 84
Frank H. Stodola, Odette L. Shotwell and Lewis B. Lock-
wood, /. Am. Chem. Soc. 74 5415 (1952).
Frank H. Stodola, "Chemical Transformations of Micro-
organisms," Squibb Lectures on Chemistry of Microbial Prod-
ucts, John Wiley and Sons, New York, N. Y., 1958, pp. 97-
102.
143 Ascorbic Acid (Vitamin C), CgHsOo, colorless crystals, m.p.
190-192°, [a]ir' +48° (c 1 in methanol).
HO— C C— OH
I I
CH,— CH— CH C=0
OH OH \^/
Serratia marcescens (on xylose), Aspergillus niger
(Up to 140 mg. per liter yields have been reported from
A. niger.)
M. Geiger-Huber and H. Galli, Helv. Chim. Acta 28 248
(1945).
Adelheid Galh, Ber. schweiz. botan. Ges. 56 113 (1946).
J. M. Van Lanen and F. W. Tanner, Jr., Vitamins arid Hor-
mones 6 163 (1948).
144 Penicillic Acid, CSH10O4, colorless crystals, m.p. 87° (anhy-
drous), 64° (hydrate).
CH3 CH3OV CH3
C
CH
C— C— C=CH— COOH
HO CH2 OCH3
Penicillium cyclopium Westling, P. piiberidum Bainier,
P. thomii, P. baarnense, Aspergillus ochraceus
John H. Birkinshaw, Albert E. Oxford and Harold Raistrick,
Biochem. J. 30 394 (1936). (Structure)
O. F. Black and C. L. Alsberg, 17. S. Dept. Agr., Bur. Plant
Ind. Bull. No. 199 (1910); Carl L. Alsberg and Otis F. Black,
Bur. Plant Ind. Bull. No. 270 (1913). (Isolation)
R. A. Raphael, J. Chem. Sac, 805 (1947). (Synthesis of
dihydropenicillic acid )
E. O. Karow, H. B. Woodruff and J. W. Foster, Arch.
Biochem. 5 279 (1944). (Isolations)
85
Tetronic Acids and Other Lactones and Lactams
145 Dehydrocarolic Acid, CgHsO^, colorless fine platelets, polymerizes
above 80°.
CH.
I
O
CH2
I
c
CH2 o
Penicillium cinerascens Biourge
Carlosic acid, spinulosin and gliotoxin also were pro-
duced.
A. Bracken and H. Raistrick, Biochem. J. 41 569 (1947).
146 Carolic Acid, C9Hig04, colorless needles, m.p. 132° [a]-,nn +84°
(c 0.50 in water).
CH,
CH2
I
O
CH,
\
CH3 o
p. charlesii G. Smith
Percival W. Clutterbuck, Walter N. Haworth, Harold Rai-
strick, Geo. Smith and Maurice Stacey, Biochem. J. 28 94
(1934).
147 Carolinic Acid, CyHioOg, colorless prisms, m.p. 123° (dec),
W]:a6i +60° (c 0.34 in water).
HO
C— CH2- CH2— COOH
CH3 o
Penicillium charlesii G. Smith
Pfizer Handbook of Microbial Metabolites 86
L. J. Haynes, J. R. Plimmer, and (in part) A. H. Stanners,
/. Chem. Soc, 4661 (1956). (Synthesis)
Percival W. Clutterbuck, Walter N. Haworth, Harold Rai-
strick, Geo. Smith and Maurice Stacey, Biochem. }. 28 94
(1934).
148 Garlic Acid, CioHioO,j, colorless needles, m.p. 176° (dec.) [a:]546i
-160° (c 0.28 in water).
CH2
o=c
^ CH,
P. charlesii G. Smith
Percival W. Clutterbuck, Walter N. Haworth, Harold Rai-
strick, Geo. Smith and Maurice Stacey, Biochem. J. 28 94
(1934). (Isolation)
149 Carlosic Acid, CjoHi^Oc, colorless needles, m.p. 181°, [a].:546]
-160° (c 0.21 in water).
O
HO C— CH2— CH2— CH3
HOOC— CH2 O
P. charlesii G. Smith
Percival W. Clutterbuck, Walter N. Haworth, Harold Rai-
strick, Geo. Smith and Maurice Stacey, Biochem. J. 28 94
(1934). (Isolation)
150 Acetomycin, Ci„Hi40-,, colorless rods, m.p. 115° (subl. 70°), [ajn
-167° (in ethanol).
CH3 CH3
I I
HC C— CO— CH3
I I
CH C
CH3— CO— o '-' o
Streptomyces ramulosus n. sp.
8?
Tetronic Acids and Other Lactones and Lactams
The yield was about 1 g. per hter.
L. Ettlinger, E. Gaumann, R. Hiitter, W. Keller-Schierlein,
F. Kradolfer, L. Neipp, V. Prelog and H. Zahner, Helv. Chim.
Acta 41 216 (1958). (Isolation)
151 Tenuazonic Acid, Ci^Hj-jO^N, straw-colored gum, b.p. 117°
(0.035 mm.), [a]54Gi'" -136 ±5° (c 0.2 in chloroform).
HO
O
II
C— CHa
CH
CHa— CHj— CH
\
CHa
Alternaria tenuis Auct.
Tenuazonic acid is one of several compounds isolated
from culture filtrates of this fungus. The other substances
(structures still unknown) were: Altenuic acids I, II and
III, altenusin, dehydroaltenusin and altertenuol. Altema-
riol and its methyl ether were isolated from the mycelium.
T. Rosett, R. H. Sankhala, C. E. Stickings, M. E. U. Taylor
and R. Thomas, Biochem. J. 67 390 (1957). (Isolation)
C. E. Stickings, ibid. 72 332 (1959). (Structure)
152 Terrestric Acid, C11H14O4, colorless crystals, m.p. 89°, [a]546i^°
+ 61.1° (c 0.53 in water).
CH2
CH3— CH,— CH
O
CH2
C
\
CHj O
Penicillium terrestre Jensen
John Howard Birkinshaw and Harold Raistrick, Biochem. J.
30 2194 (1936).
Pfizer Handbook of Microbial Metabolites 88
153 Viridicatic Acid (Ethylcarlosic Acid), CisHieOe, colorless plate-
lets, m.p. 174.5°, [a]n46i'° -105° (c 1.0 in ethanol).
HO CO— CH2— CH2— CH2— CH,— CHa
\ /
C c
I I
CH C
HOOC— CH2 ^ O
Penicillium viridicatum Westling
J. H. Birkinshaw and M. S. Samant, Biochem. J. 74 369
(1960).
154 Nephrosterinic Acid, C17H28O4, colorless leaflets, m.p. 96°, [<xW°
+ 10.81°.
HOOC CH2
\ /
CH C
I I
CH C
/ \o/\
CH3(CH2)io O
Nephromopsis endocrocea Asahina (=Cetraria en-
docrocea (Asahina) Sato)
Nephrosteranic acid, endocrocin and caperin were also
present.
Yasuhiko Asahina, Masaiti Yanagita and Y. Sakurai, Ber.
70B227 (1937).
155 Nephrosteranic Acid, C17H30O4, colorless plates, m.p. 95°.
HOOC CH3
CH CH
I 1
CH C
CH3(CH2)io ^ O
Nephromopsis endocrocea Asahina
Yasuhiko Asahina, Masaiti Yanagita and Y. Sakurai, Ber.
70B 227 (1937).
156 Z-Lichesterinic Acid, C19H32O4, colorless needles, m.p. 124°, [cc]v^^
-32.66°.
HOOC CH3
\ /
c— c
I I
CH C
CH3(CH2)i2 " O
Sg Tetronic Acids and Other Lactones and Lactams
Cetraria islandica f. tenuifolia, Nephromopsis stracheyi
f. ectocarpisma Hue.
Yasuhiko Asahina and Masaiti Yasue, Ber. 70B 1053 (1937).
Yukio Kameda, /. Pharm. Soc. Japan 61 266 (1941).
(German abstract)
157 d-Protolichesterinic Acid, C19H32O4, colorless leaflets, m.p. 107.5°,
[2W +12.1°.
HOOC CH2
\ X
CH C
I I
CH C
CH3(CH2)l2 O
Cetraria islandica Ach., Parmelia sinodensis Asahina,
Cladonia papillaria (Ehrh.) Hoffm.
Yasuhiko Asahina, /. Japan. Botan. 18 489 (1942).
The Z-isomer, m.p. 107.5°, [a]D'^^ -12.7°, has been iso-
lated from Cetraria crispa Nyl. (=C. tenuifolia Howe).
Y. Asahina and M. Asano, J. Pharm. Soc. Japan No. 539, 1
(1927).
Eugene E. van Tamelen and Shirley Rosenberg Bach, /. Am.
Chem. Soc. 80 3079 (1958). (Synthesis)
158 f-aZio-Protolichesterinic Acid, C19H32O4, colorless plates, m.p.
107°, [ocW^ -102°.
Cetraria islandica Ach. var. orientalis Asahina
Yasuhiko Asahina and Masaiti Yasue, Ber. 70B 1053 (1937).
159 Nephromopsic Acid, C19H34O4, colorless leaflets, m.p. 137°.
HOOC CH3
\ y
CH CH
I i
CH C
CH3(CHo)i2 '-' O
Nephromopsis stracheyi f. ectocarpisma Hue.
Occurs with usnic acid, Michesterinic acid, Z-proto-
lichesterinic acid and caperatic acid.
Michizo Asano and Tiaki Azumi, Ber. 68B 995 (1935).
Carotenes and Carotenoids
Carotene pigments are widely distributed throughout nature,
and many microorganism pigments are carotenoid. Their iso-
lation and characterization are often comphcated by the co-oc-
currence of closely related compounds, and in some cases by
poor stability. Many identifications have been made on the
basis of ultraviolet absorption spectra alone.
For these reasons, and because of dupHcations in nomencla-
ture, the literature dealing with microorganism carotenoids is
confused. The situation has been reviewed by T. W. Goodwin,^
and to augment the entries in this section some pertinent tables
and references from this book have been incorporated as an
appendix.
Carotenoids occur in both photosynthetic and non-photosyn-
thetic microorganisms, and their functions are not established
clearly. In fungi they may stimulate photokinetic responses
such as phototropic bending. In sarcina and staphylococcus
species there may be some protection of the cell from ultraviolet
light. In photosynthetic genera it has been suggested that
carotenoids may -serve as blue-light energy absorbers, as oxygen
carriers and in the prevention of chlorophyll-catalyzed photo-
oxidations.
The work that has been done on carotene biogenesis in micro-
organisms has been well summarized.- ^ It has been found* ^
^ T. W. Goodwin, "Comparative Biochemistry of Carotenoids,"
Chemical Publishing Co., Inc., New York, N. Y., 1954.
- G. E. W. Wolstenholme and Maeve O'Connor, "CIBA Foundation
Symposium on the Biosynthesis of Terpenes and Sterols," E. C. Grob,
The biosynthesis of carotenoids by microorganisms, Little, Brown
and Co., Boston, Mass., 1959, pp. 267-278.
3 T. W. Goodwin, ibid., pp. 279-294.
91
Carotenes and Carotenoids
that Mucor hiemalis uses acetate for the production of ^-caro-
tene. The product derived from C"-labeled acetate has been
partially degraded, and the following partial distribution pattern
demonstrated :
i3-carotene
o Carbon atom from the methyl group of acetate
• Carbon atom from the carboxyl group of acetate
Mevalonic acid is an effective carotene precursor in at least
certain microorganisms. ''■ '' In this connection it is noteworthy
that in Phyconiyces hlakesleeanus and in Mucor hiemalis the
production of sterols and carotenoids always runs proportion-
ally.* The scheme shown below has been proposed for the
mode of condensation. -
HOOC-
OH
\
OH
COOH
Leucine has been known for many years to have ketogenic
and carotenogenic properties to a greater extent than other
amino acids. The discovery of mevalonic acid facilitated an
*E. C. Grob and R. Butler, Helv. Chim. Acta 39 1975 (1956).
■^E. C. Grob, Chimia 10 73 (1956).
6 G. D. Braithwaite and T. W. Goodwin, Biochem. J. 66 31p (1957).
^E. C. Grob, Chimia 11 338 (1957).
* E. C. Grob, M. Bein and W. H. Schopfer, Bull. soc. chim. biol.
33 1236 (1951).
Pfizer Handbook of Microbial Metabolites
92
explanation of this effect, and this interesting work has been
reviewed.^' ^°
Some of the relationships thought to exist are :
CH,
CH3
\
o-Ketoglutarate
CH— CHr- CH— COOH <-
Glufamate
CH3
CoA— SH
NH2
Leucine
CO2
transaminase,
pyridoxal CH3
phosphate
CH— CH2— C— COOH
a-Ketoisocaproic Acid
CH3
o-ketoacylde-
hydrogenase,
thiamin
pyrophosphate
CH3
\
<
CH— CHo- C— S— CoA
Isovaleryl
Coenzyme A
acylde-
hydrogenase
flavin
flavin — H2
ADP ATP
O \ biotin f CH3 O
II v CO2 y \ II
HOOC— CH2— C=CH— C— S— CoA <-^^^ — ^— ^ C=CH— C— S— CoA
CH3
/3-Methylglutaconyl CoA
H2O
/3-methyl- /
glutaconyl CH3
carboxylase
/3,/3-Dimethylacrylyl CoA
(SenecioyI CoA)
/S-^methyl-
/^ glutaconase
CH3
HOOC— CH2—C—CH2—C—S— CoA
I
OH
^-Hydroxy-/3-methyl
glutaryl-CoA
" G. E. W. Wolstenholme and Maeve O'Connor, "CIBA Foundation
Symposium on the Biosynthesis of Terpenes and Sterols," M. J.
Coon, F. P. Kupiecki, E. E. Dekker, M. J. Schlesinger and Alice del
Campillo, The enzymic synthesis of branched-chain acids. Little,
Brown and Co., Boston, Mass., 1959, pp. 62-74.
^" Idem., ibid., Harry Rudney, The biosynthesis of P-hydroxy-fi-
methylglutaryl coenzyme A and its conversion to mevalonic acid,
pp. 75-94.
93
Carotenes and Carotenoids
Carotenes
Sterols, Triterpenes, etc.
cofactors
CH3
HOOC— CH2— C— CH2— CH2OH
I
OH
Mevalonic Acid
± TPNH
CH3
HOOC— CH2— C— CH2— CHO
I
OH
Mevaldic Acid
Y
± TPNH, DPNH
CH3 O
-> HOOC— CH2— C— CH2— C— S— CoA
condensing
enzyme
OH
/3-Hydroxy-/3-methyl-
glutaryl-CoA (HMG-CoA)
HMG
cleavage
enzyme
CH3— C— S— CoA
Acetyl-CoA
CH3— C— CHo— C— OH
Acetoacetic Acid
succinyl CoA
transferase
(ATP activation)
CH3— C— CH2— C— S— CoA + CoA— SH
Acetoacetyl CoA
Fatty Acids
The precursors of the carotenes are colorless, more reduced
compounds. These substances then are dehydrogenated in a
stepwise fashion, a process which requires light and oxygen.
Pfizer Handbook of Microbial Metabolites
94
Oxygen-containing carotenoids appear at an early stage in the
biosynthetic scheme. Based on the order of appearance in cul-
tures of Neurospora crassa, Grob has proposed* the following
partial pathway of carotenoid formation:
7-Carotene
Lycopersene has not been isolated from a natural source, but
this colorless polyene has been synthesized and seems to be a
logical early member of this sequence.
* See addendum.
95
Carotenes and Carotenoids
160 Azafrin (Escobedin), C27H;{s04, orange crystals, m.p. 213°,
h]iu
-75° (c 0.28 in alcohol), U.V. 428, 458 m^i in
chloroform.
COOH
161
Mycobacterium phlei
Mary A. Ingraham and Harry Steenbock, Biochem. J. 29
2553 (1935).
Richard Kuhn, Alfred Winterstein and Hubert Roth, Ber.
64A 333 (1931).
Torularhodin (May = Lusomycin), C:^7H4s02, red needles, m.p.
202° (vac.) (dec), U.V. 554, 515, (483) m/A in chloro-
form.
COOH
Rhodotorula rubra, R. sanniei
The yield from R. sanniei was 2900 y per gram of dry
cells. Also obtained were torulene (143 y per gram) and
^-carotene (10 y per gram) and traces of y-carotene and
lycopene.
Edgar Lederer, Bull. soc. chim. biol. 20 611 (1938).
Claude Fromageot and Joue Leon Tchang, Arch. Mikrobiol.
9 424 (1938).
L. Nogueira Prista, Congr. Luso-Espan. farm. 2 274 (1952).
(Chem. Abstr. 48 13807a)
R. Entschel and P. Karrer, Helv. Chim. Acta 42 466 (1959).
162 Astacin (3,4,3',4'-Tetraoxo-/3-carotene), C4,jH4s04, violet, metal-
loid needles, m.p. 240-243°, U.V. 500 m^x in carbon disul-
fide.
^^^
Mycobacterium laticola
Pfizer Handbook of Microbial Metabolites
96
H. F. Haas and L. D. Bushnell, /. Bacterial. 48 219 (1944).
(Isolation)
R. Kuhn, E. Lederer and A. Deutsch, Hoppe-Seylers Z. 220
229 (1933).
R. Kuhn and E. Lederer, Ber. 66 448 (1933).
163 Canthaxanthin (4,4'-Dioxo-;8-carotene) C40H52O2, red crystals,
m.p. 218°, U.V. 480 nifx, in benzene.
Cantharellus cinnaharinus, Cory neb acterium michi-
ganense
Francis Haxo, Botan. Gaz. 112 228 (1950). (Isolation)
S. Saperstein and M. P. Starr, Biochem. J. 57 273 (1954).
F. J. Petracek and L. Zechmeister, Arch. Biochem. and
Biophys. 61 137 (1956). (Structure)
C. K. Warren and B. C. L. Weedon, J. Chem. Soc, 3986
(1958). (Synthesis)
164 a-Carotene, C40H56, deep purple prisms, m.p. 187.5° (vac), [aW^
+ 385° (c 0.08 in benzene), U.V. 446, 473 m^^ in light
petroleum ether.
Dacromyces stillatus, Neurospora crassa (mutants),
Mycobacterium phlei, Phycomyces blakesleeanus, Rho-
dotorula rubra, Gymno sporangium juniperi-virginianae,
Puccinia coronifera, Aleuria aurantia, Cantharellus ci-
barius, Coleosporium senecionis, Penicillium sclerotiorum
Edgar Lederer, Bull. soc. chim. hiol 20 611 (1938).
Harry Willstaedt, Svensk. Kern. Tidskr. 49 318 (1937).
B. L. Smits and W. J. Peterson, Science 96 210 (1942).
J. Bonner, A. Sandoval, W. Tang and L. Zechmeister, Arch.
Biochem. 10 113 (1946).
T. W. Goodwin, Biochem. J. 53 538 (1953).
97
Carotenes and Carotenoids
165 ^-Carotene, C4,|H.r,fi dark violet prisms from benzene-methanol,
red leaflets from petroleum ether, m.p. 183° (vac.), U.V.
425, 450, 476 rufi in light petroleum ether.
^^^^^/'V^^^^^^/'^
Phycomyces blakesleeanus, Neurospora crassa, Rho-
dotorula rubra, R. sanniei, R. glutinis, Sporobolomyces
roseus, S. salmonicolor, Cantharellus cibarius, C. cinna-
barinus, Allomyces javanicus, Coleosporium senecionis,
Mitrula paludosa, Penicillium sclerotiorum, Fremella mes-
enterica, Puccinia coronifera, Pilobolus bleinii, Gymno-
sporangium juniperi-virginianae , Dacromyces stillatus,
Aleuria aurantia, Cryptococcus laurentii, C. luteolus, Mo-
nilia sitophila, Corynebacterium michiganense (mutants),
Mycobacterium phlei, Sarcina aurantiaca
For references see:
T. W. Goodwin, Ann. Rev. Biochem. 24 497 (1955).
Idem., "Carotenoids," Chemical Publishing Co., Inc., New
York, N. Y. 1954, p. 108 etc.
166 y-Carotene, C40H56, fine deep red crystals with a blue luster from
benzene-methanol, m.p.
in petroleum ether.
177.5°, U.V. 493, 462, 437 nifjL
Allomyces arbuscula, A. javanicus, A. macrocygna,
A. moniliformis, Puccinia coronifera, Phycomyces blakes-
leeanus, Neurospora crassa, Cantharellus cibarius, Coleo-
sporum senecionis, Dacromyces stillatus, Gymnosporan-
gium juniperi-virginianae, Cryptococcus laurentii, C. lute-
olus, Mycobacterium phlei, Chlorobium spp. Penicillium
sclerotiorum
For references see:
T. W. Goodwin, Ann. Rev. Biochem. 24 497 (1955).
Pfizer Handbook of Microbial Metabolites 98
Idem., "Carotenoids," Chemical Publishing Co., Inc., New
York, N. Y. 1954, p. 108 etc.
J. Bonner, A. Sandoval, W. Tang and L. Zechmeister, Arch.
Biochem. 10 113 (1946).
167 8-Carotene, C40H56, fine orange to red needles, m.p. 140.5°, U.V.
488, 456, 430, 280 m^u in isooctane.
Proposed structure:
Cantharellus cibarius, Neurospora crassa (mutants),
Staphylococcus aureus
Harry Willstaedt, Svensk Kem. Tidskr. 49 318 (1937).
Ben Sobin and Grant L. Stahly, /. Bacterial. 44 265 (1942).
J. W. Porter and M. M. Murphy, Arch. Biochem. and
Biophys. 32 21 (1951). (Isolation)
Francis Haxo, Biol. Bull. 103 268 (1952).
168 Lycopene ( Solanorubin, Rhodopurpurene ) C4oH,-g, brownish red
to carmine crystals, m.p. 174°, U.V. 446, 474, 506 m^^ in
petroleum ether.
Phycomyces Make slee anus, certain Cantharellus spp.,
Neurospora^ crassa. Micrococcus tetragenus (pink type),
Anthurus aserioformis, Allomyces javanicus, Rhodotorula
glutinis, R. rubra, R. sanniei, Corynebacterium michiga-
nense, C. diphtheriae, Mycobacterium phlei. Staphylococ-
cus aureus, Coleosporium senecionis, Sarcina aurantiaca
Harry Willstaedt, Svensk. Kem. Tidskr. 49 318 (1937).
Francis Haxo, Arch. Biochem. 20 400 (1949).
P. Karrer, C. H. Eugster and E. Tobler, Helv. Chim. Acta
33 1349 (1950). (Synthesis)
T. W. Goodwin, Ann. Rev. Biochem. 24 497 (1955).
Synnove Liaaen Jensen, Germaine Cohen-Bazire, T. O. M.
Nakayama and R. Y. Stanier, Biochim. et Biophys. Acta 29
477 (1958).
99
Carotenes and Carotenoids
169
Rhodopin, C4„H,:^60, violet-red needles, m.p. 168° (171°), U.V.
440, 470, 501 m^ in light petroleum.
Polystigma rubrum
Edgar Lederer, Bull. soc. chim. biol. 20 611 (1938).
Synnove Liaaen Jensen, Acta Chem. Scand. 13 842 (1959).
(Structure)
Paul Karrer and Ulrich Solmssen, Helv. Chim. Acta 18 25,
1306 (1935); 21 454 (1938).
170 Rubixanthin (3-Hydroxy-y-carotene), C40H56O, coppery red nee-
dles, m.p. 160°, U.V. 432, 462, 494 nifj, in hexane.
^^^
171
Staphylococcus aureus, Coleosporium senecionis. Mi-
crococcus tetragenus
E. Lederer, Bull. soc. chim. biol. 20 611 (1938).
Ben Sobin and Grant L. Stahly, J. Bacteriol. 44 265 (1942).
H. A. Reimann and C. M. Eklund, J. Bact. 42 605 (1941).
Richard Kuhn and Chrlstoph Grundmann, Ber. 67 339
(1934).
Cryptoxanthin (Cryptoxanthol, 3- or 4-Oxy-/?-carotene, C40H56O)
deep red prisms, m.p. 169° (vac), optically inactive, U.V.
425s, 450, 480 m/x in hexane.
^^^
Mycobacterium phlei, Dacromyces stillatus, Vibrio
adaptatus, Pseudomonas xanthochrus, P. aestumarina,
Rocella montagnei
Pfizer Handbook of Microbial Metabolites lOO
Richard Kuhn and Christoph Grundmann, Ber. 66 174
(1933).
Mary A. Ingraham and Harry Steenbock, Biochem. J. 29
2553 (1935).
F. P. Zscheile, J. W. White, B. W. Beadle and J. R. Roach,
Plant Physiol. 17 331 (1942).
T. R. Seshadry and S. S. Subramanian, Proc. Indian Acad.
Sci. 30A (1949).
172 Lycophyll (3,3'-Dihydroxylycopene), C40H56O2, purple crystals,
m.p. 179°, U.V. 444, 473, 504 m^ in petroleum ether.
HO—
Rho do spirillum ruhrum, Chromatium spp.
M. S. Barber, L. M. Jackson and B. C. L. Weedon, Proc.
Chem. Soc, 96 (1959). (Structure)
L. Zechmeister and L. V. Cholnoky, Ber. 69B 422 (1936).
173 Zeaxanthin (Zeaxanthol), C40H56O2, yellow crystals, m.p. 207°
(215°), optically inactive, U.V. 451, 476 m/x in petroleum
ether.
/OH
A
M' ' ' '
HO^ '
Mycobacterium phlei, Dacromyces stillatus, Staphylo-
coccus aureus, Pseudomonas xanthochrus, P. aestumar-
ina. Vibrio adaptatus
Erwln ChargafF and Joseph Dieryck, Naturwissenschaften
20 872 (1932).
Mary A. Ingraham and Harry Steenbock, Biochem. J. 29
2553 (1935).
Walter Steuer, Zentr. Bakteriol. Parasitenk. 167 210 (1956).
T. W. Goodwin, Biochem. J. 53 538 (1953).
lOI
Carotenes and Carotenoids
174 Lutein (Xanthophyll, Luteol), C40H56O2, yellow prisms, m.p.
190°, [alcd'" +165° (c 0.7 in benzene), U.V. 420, 446.5,
476 m^u, in petroleum ether.
Mycobacterium phlei, Staphylococcus aureus, Sarcina
hitea, Micrococcus lysodeikticus
Erwin Chargaff, Compt. rend. 197 946 (1933).
Mary A. Ingraham and Harry Steenbock, Biochem. J. 29
2553 (1935).
Tatsuo Ohta, J. Pharm. Soc. Japan 71 1319 (1951). (Isola-
tion)
A. R. Gilby and A. V. Few, Nature 182 55 (1958).
175 Neurosporene (6,7,6',7'-Tetrahydrolycopene), C40H60, yellow-or-
ange or yellow-brown crystals, m.p. 124°, U.V. 414, 438.5,
469 rrifj. in petroleum ether.
Neurospora crassa, Rhodotorula rubra, etc.
Neurosporene and hydroxylated neurosporenes are
probable intermediates in the biogenesis of other carote-
noids occurring in microorganisms.
J. Bonner, A. Sandoval, W. Tang and L. Zechmeister, Arch.
Biochem. 10 113 (1946).
Francis Haxo, ibid. 20 400 (1949).
L. Zechmeister and B. Kenneth Koe, /. Am. Chem. Soc. 76
2923 (1954).
Synnove Liaaen Jensen, Germaine Cohen-Bazire, T. O. M.
Nakayama and R. Y. Stanler, Biochim. et Biophys. Acta 29 477
(1958).
Pfizer Handbook of Microbial Metabolites
I02
176 7;-Carotene, C4,,H,j4, probably has not been entirely purified, U.V.
376 (380), 396 (404), 418 (424), 450.
Phycomyces blakesleeanus, Neurospora crassa (mu-
tants), Dacromyces stillatus
H. A. Nash and F. P. Zscheile, Arch. Biochem. 7 305
(1945).
T. W. Goodwin, "Carotenoids," Chemical Publishing Co.,
Inc., New York, N. Y. 1954, p. 108, etc.
G. MacKinney, C. O. Chichester and Patricia S. Wong,
Arch. Biochem. and Biophys. 53 480 (1954).
177 Phytoene (7,8,ll,12,12',ll',8',7'-Octahydrolycopene), C40H64,
colorless, viscous oil with a strong fluorescence in ultra-
violet light, U.V. 275s, 283, 295s in isooctane.
^^^/-^
Mycobacterium phlei, Rhodopseudomonas spheroides
(mutant), Rho do spirillum rubrum
J. W. Porter and F. P. Zscheile, Arch. Biochem. and Biophys.
10 537 (1946).
W. J. Rabourn and F. W. Quackenbush, Arch. Biochem. and
Biophijs. 61 111 (1956). (Structure)
T. W. Goodwin, and Malini Jamikorn, Biochem. J. 62 269
(1956).
178 Phytofluene (5,6,7,8,9,10,10',9',8',7',6',5'-Dodecahydrolycopene),
C4„Hfis, colorless, viscous oil with a strong fluorescence in
ultraviolet light, U.V. 332, 347, 367 m^u, in petroleum
ether.
Neurospora crassa, N. sitophila, Mycobacterium phlei,
Phycomyces blakesleeanus, etc.
I03
Carotenes and Carotenoids
Phytofluene probably occurs widely among microorgan-
isms. It is a probable precursor of many of the carotene
pigments.
L. Zechmeister and F. Haxo, Arch. Biochem. 11 539 (1946).
(Isolation from neurospora)
L. Zechmeister, Experientia 10 1 (1954). (Structure)
179 P-481,C4iH-,sO, U.V. 455, 482, 514 m^ in petroleum ether.
Tentative structure:
V^^^%^^/^^/^==^ /^
OCH3
Rho do spirillum rubriim, Chromatium spp.
M. S. Barber, L. M. Jackson and B. C. L. Weedon, Proc.
Chem. Soc, 96 (1959). (Structure)
Synnove Liaaen Jensen, Acta Chem. Scand. 12 1698 (1958).
180 Hydroxy-P-481 (May = Rhodovibrin), C41H5SO., U.V. 455, 482,
515 m/x in petroleum ether.
Tentative structure:
^^-"^^-^^
OH
Rho do spirillum rubrum, Chromatium, spp.
M. S. Barber, L. M. Jackson and B. C. L. Weedon, Proc,
Chem. Soc, 96 (1959).
Synnove Liaaen Jensen, Acta Chem. Scand. 12 1698 (1958).
181 Hydroxyspirilloxanthin (May = Bacteriopurpurin, Bacterioeryth-
rin) C4iH-„sOo, U.V. 489, 523 m^x in petroleum ether.
Tentative structure:
^^^^.^5^/^^^
HO
\l
OCH3
Rhodospirillum rubrum, Chromatium spp.
Pfizer Handbook of Microbial Metabolites 1 04
M. S. Barber, L. M. Jackson and B. C. L. Weedon, Proc.
Chem. Soc, 96 (1959).
182 Pigment R ( Spheroidenone ) , C41H58O2, red crystals, m.p. 155.5-
158°, U.V. 460 (455), 482 (4"87), 513 (516.5) rrifi in
light petroleum.
CH3O
I I
Rhodopseudomonas spheroides, other purple bacteria
C. B. Van Niel, Antonie Van Leeuwenhoek J. Microbiol.
Serol Jubilee Vol. Albert J. Kluyver 12 156 (1947). (Isola-
tion)
T. W. Goodwin, D. G. Land and M. E. Sissins, Biochem. J.
64 486 ( 1 956 ) . ( Structure )
183 Pigment Y, C41H60O, yellow unstable crystals, m.p. 116-135°
(dec). Stable in solution. U.V. 426.5, 452 (454), 484
(486) nifj. in petroleum ether.
CH3O I
^^^/^/^==^^^^^^^
Rhodopseudomonas spheroides, other purple bacteria
A hydroxylated pigment Y was produced in the same
fermentation, but could not be crystallized.
C. B. Van Niel, Antonie Van Leeuwenhoek J. Microbiol.
Serol. Jubilee Vol. Albert J. Kluyver 12 156 (1947). (Isola-
tion )
T. W. Goodwin, D. G. Land and M. E. Sissins, Biochem. J.
64 486(1956). (Structure)
Synnove Liaaen Jensen, Acta Chem. Scand. 12 1698 (1958).
184 Spirilloxanthin (Rhodoviolascin), C42H6„02, violet spindle-form
crystals, m.p. 218°, U.V. 464, 491, 524 m^x in petroleum
ether.
CH3O
\l
^/^=^-/W^'^/^^^/^^/^^/^-^
1 05 Carotenes and Carotenoids
Rhodospirillum rubrum, other purple bacteria, Neuro-
spora crassa (mutants), Chromatium spp.
P. Karrer and U. Solmssen, Helv. Chim. Acta 18 1306
(1935).
C. B. Van Niel and James H. C. Smith, Arch. Mikrobiol. 6
219 (1935). (Isolation)
A. Polgar, C. B. Van Niel and L. Zeehmeister, Arch.
Biochem. 5 243 (1944).
Synnove Liaaen Jensen, Germaine Cohen-Bazire, T. O. M.
Nakayama and R. Y. Stanier, Biochim. et Biophys. Acta 29
477 (1958). (Synthesis)
M. S. Barber, L. M. Jackson and B. C. L. Weedon, Proc.
Chem. Soc, 96 (1959).
185 Torulene, C42H60O2, dark red crystals, m.p. 185°, U.V. 460, 486,
519 m^ in petroleum ether.
Tentative structure:
OCH3
CH30
Rhodotorula rubra
Occurs together with y8-carotene, torularhodin and an
unstable, uncharacterized carotene.
Edgar Lederer, Bull. soc. chim. biol. 20 611 (1938).
J. Bonner, A. Sandoval, W. Tang and L. Zeehmeister, Arch.
Biochem. 10 113 (1946).
186 Sarcinaxanthin, yellow crystals, m.p. 149°, U.V. 415, 440, 469
m/x in petroleum ether.
About 3.4 mg. of this mono-hydroxy xanthophyll were
obtained from 385 g. of dried Sarcina lutea cells. It is
also produced by Flavobacterium marinotypicum and by
Staphylococcus citreus.
A closely related hydrocarbon, sarcinene, occurs in all
these species as well as in Flavobacterium sulfureum.
Yoshiharu Takeda and Tatuo Ota, Z. physiol. Chem. 268 1
(1941). (Isolation)
Doris P. Courington and T. W. Goodwin, J. Bacterial. 70
568 (1955).
Tatsuo Ohta, Toshio Miyazaki and Teruo Minomiya, Chem.
Pharm. Bull. 7 254 (1959).
Pfizer Handbook of Microbial Metabolites io6
187 Neurosporaxanthin, dark grayish purple leaflets, m.p. 192°
(vac), U.V. 472 m^ in hexane (486 m^ in benzene).
An uncharacterized carotenoid which gives yellow so-
lutions and a red color adsorbed on sucrose.
Neiirospora crassa
Marko Zalokar, Arch. Biochem. and Biophys. 70 568
(1957). (Isolation)
188 Leprotene (Leprotin), coppery red needles, m.p. 197°, U.V. 429,
452, 479 rriyu in petroleum ether.
The principal carotene of Mycobacterium phlei and
other mycobacteria. It contains no ionone rings and does
not function as a provitamin A.
Yoshiharu Takeda and Tatsuo Ohta, J. Biochem. Japan 36
535 (1944). (Isolation)
Tatsuo Ohta, /. Pharm. Soc. Japan 71 462 (1951).
189 Mycoxanthin, U.V. 385, 406, 430 m^ in petroleum ether.
A new yellow carotenoid with a relatively short chromo-
phore.
Mycobacterium phlei, M. marianurn, M. battaglini
Aldo Gaudiano, Atti. accad. nazl. Lincei, Rend., Classe set.
fis., mat. e nat. 21 308 (1956). (Chem. Abstr. 51 8876 f)
(Isolation)
Polyenes and Polyynes,
Excluding Polyene Macrolides
The polyenes of this section somewhat resemble crocetin,
bixin and the carotenes in their long systems of conjugated
double bonds with the resultant color and other physical prop-
erties, but they lack the isoprenoid structure.
The acetylenic compounds often occur in low yields and in
complex mixtures. While generally colorless, they are conspic-
uous by their strong and characteristic ultraviolet absorption
spectra. Many of them are unstable.
From the examples reported to date it seems that basidiomy-
cetes are the principal producers of such metabolites among
microorganisms, although such substances occur widely in
higher plants. That lower fungi are capable of forming poly-
enes is demonstrated, however, by the side-chains of metabolites
classified elsewhere, for example fumagillin, sorbicillin and
auroglaucin :
C— (CH=CH)o— CHs
C— (CH=CH)4— COOH
II
O
Fumagillin Sorbicillin
Pfizer Handbook of Microbial Metabolites 1 08
CH3(CH=CH)
OH
Auroglaucin
It is likely that both polyenes and polyynes are acetate-de-
rived. It has been demonstrated^ that nemotinic acid with 11
carbon atoms is formed from 6 moles of an acetic acid deriva-
tive, with head to tail Hnkage and elimination of the terminal
methyl group.
HC^C— C=C— CH=C=CH— CH— CHj— CH2— COOH
OH
Nemotinic Acid
CH3— C=C— C=C— CH=C=CH— CH— CH2— CHo— COOH
OH
Odyssic Acid
Odyssic acid was presumed to be formed similarly, but with
terminal methyl group retention.
In the examples available the acetylenic acids with an odd
number of carbon atoms terminate in an acetylenic bond. This
seems to indicate elimination of the terminal methyl group by
oxidation and decarboxylation. It is interesting to note that the
reverse process has been demonstrated in the conversion of
propynoic acid to acetylenedicarboxylic acid by a soil isolate.^
CO2 + HC^C— COOH -^ HOOC— C=C— COOH
The xyloside of nemotinic acid also has been isolated.^ When
isolated from a culture grown on glucose with l-C"-labeled
acetic acid added to the medium, labeling is found in the poly-
acetylenes but not in the xylose moiety. When isolated from
1 J. D. Bu'Lock and H. Gregory, Biochem. J. 72 322 (1959).
2 Akira Hanaoka, Tokuya Harada and Takeo Takizawa, /. Agr.
Chem. Soc. Japan 26 151 (1952).
3 J. D. Bu'Lock and H. Gregory, Experientia 15 420 (1959).
log Polyenes and Polyynes, Excluding Polyene Macrolides
HC=C— C^C— CH=C=CH— CH— CH2— CH2— COOH
a culture grown on ethanol with l-C^*-labeled acetic acid added
to the medium, labeling was found in the xylose as well as in
the acetylenic acid. It was assumed that in the latter case,
where the molecule was synthesized entirely from C2 units, the
xylose was produced by way of intermediates closely related to
glucose. Glucose itself acted as the xylose precursor, then, in
the first experiment. A closer analysis of the labeling pattern
of the xylose moiety led to the suggestion that the pentose was
formed from glucose by way of glucuronic acid followed by
decarboxylation.
Many of the acetylenic acids have antibiotic properties.
A review of polyacetylenes was published recently.*
About a dozen more compounds of this type are listed in the
addendum.
190 Agrocybin, C8H5O0N, unstable compound white crystals, darken-
ing in air, m.p. 130-140° (dec. explosively), U.V. 216,
224, 269, 286, 304, 325 m^u in 95% ethanol.
HOCH.— C=C— C^C— C=C— CONH2
Agrocyhe dura
Marjorie Anchel, J. Am. Chem. Soc. 74 1588 (1952).
J. D. Bu'Lock, E. R. H. Jones, G. H. Mansfield, J. W. Thomp-
son and M. C. Whiting, Chem. and Ind., 990 (1954). (Struc-
ture)
P. J. Ashworth, E. R. H. Jones, G. H. Mansfield, K. Schlogl,
J. M. Thompson, M. C. Whiting, /. Chem. Soc, 950 (1958).
(Synthesis)
191 Diatretyne 1, CsHjOgN, unstable crystals, m.p. 198° (dec. ex-
plosively), U.V. 223, 260, 275, 290, 309 m^ m 95% etha-
nol.
HOOC— CH=CH— C^C— C=C— CONH2
and
4E. R. H. Jones, Proc. Chem. Soc, 199-211 (1960).
Pfizer Handbook of Microbial Metabolites no
192 Diatretyne 2 (Nudic Acid B), C^HgOoN, short colorless needles,
m.p. 179^ (dec), U.V. 228, 238, 268, 283, 299, 322 iti/a
in 957c ethanol.
HOOC— CH=CH— C=C— C=C— C=N
Clitocybe diatreta
Marjorie Anchel, J. Am. Chem. Soc. 74 1588 (1952).
Idem., ibid. 75 4621 (1953).
Idem. Science 121 607 (1955). (Structure)
P. J. Ashworth, E. R. H. Jones, G. H. Mansfield, K. Schlogl,
J. M. Thompson and M. C. Whiting, J. Chem. Soc, 950 (1958).
(Synthesis)
193 trans-Non-2-ene-4,6,8-triyn-l-al, C9H4O, colorless needles, which
rapidly decompose in light at room temperature. U.V.
210.5 (220), 228, 240, 257, 271, 287, 306, 327 m/j, in
ethanol.
HC=C— C=C— C=C— CH=CH— CHO
Coprinus quadrifidus
Six related compounds occurred in the same culture.
E. R. H. Jones and J. S. Stephenson, /. Chem. Soc, 2197
(1959).
194 trans-Non-2-ene-4,6,8-triyn-l-ol, CgH^O, colorless crystals, decom-
posing at ordinary conditions, U.V. 233, 243, 255, 283,
300, 320 m,x in hexane.
HC=C— C^C— C=C— CH=CH— CHoOH
Coprinus quadrifidus
E. R. H. Jones and J. S. Stephenson, /. Chem. Soc, 2197
(1959).
195 (2d,3d)-Nona-4,6,8-triyn-l,2,3-triol, CjHsO.j, colorless crystals
(dec.) ~40°, [a],. +6° (c 0.82 in ethanol), U.V. 208, 254,
269.5, 286.5, 305 m^^ in ethanol.
HC=C— C=C— C^C— CHCHCH:OH
I I
OH OH
Coprinus quadrifidus
E. R. H. Jones and J. S. Stephenson, J. Chem. Soc, 2197
(1959).
Ill Polyenes and Polyynes, Excluding Polyene Macrolides
196 Biformin, highly unstable crystals.
Probably a straight-chain, nine carbon atom glycol, con-
taining two acetylenic and two ethylenic bonds in con-
jugation.
Polyporus bifonnis
A similar substance, biforminic acid, occurred in the
same culture.
William J. Robblns, Frederick Kavanagh and Annette
Hervey, Proc. Nat. Acad. Sci. 33 176 (1947).
Marjorie Anchel and Marvin P. Cohen, /. Biol. Chem. 208
319 (1954).
197 tra?2S-Dec-2-ene-4,6,8-triyn-l-al, CjoHuO, pale yellow needles, m.p.
108°, U.V. (225) (234.5), 245.5, 258 (272), 288, 306,
326, 350, m^ in hexane.
CH3— C^C— C=C— C=C— CH=CH— CHO
Pleurotus ulmarius
J. N. Gardner, E. R. H. Jones, P. R. Leeming and J. S.
Stephenson, J. Chem. Soc, 691 (1960).
198 Diatretyne-3 (traris-10-Hydroxydec-2-ene-4,6,8-triynoic Acid),
Ci„H«;03^ nearly colorless rods from ethyl acetate, rapidly
becoming coated with blue-green polymer, U.V. 253, 280,
297, 316, 339 m^.
HOCH2— C=C— C^C— C^C— CH=CH— COOH
Clitocybe diatreta
The author noted the similarity to the antibiotic prin-
ciple of the royal jelly of bees:
trans
HOCH,CH2CH2CH,CHoCHoCH2— CH=CH— COOH
Helen Flon and Marjorie Anchel, Arch. Biochem. and
Biophys. 78 111 (1958).
Marjorie Anchel, Arch. Biochem. and Biophys. 85 569
(1959).
199 Deca-trarzs-2,tra?is-8-diene-4,6-diyne-l,10-dioic Acid, Ci„Hg04,
amorphous powder, m.p. (dec.) ^200°, U.V. 216 (258),
267, 296, 315, 338 m^^ in ethanol.
HOOC— CH=CH— C^C— C=C— CH=CH— COOH
Polyporus anthracophilus
Pfizer Handbook of Microbial Metabolites 112
J. D. Bu'Lock, E. R. H. Jones and W. B. Turner, J. Chem.
Soc, 1607 (1957).
200 Marasin [(-)-Nona-3,4-diene-6,8-diyne-l-ol], CioHgO, unstable
oily substance, polymerized spontaneously, [<x]d^^ about
-325° (c 0.2).
HC^C— C=C— CH=C=CH— CH2— CH2— OH
Marasmius ramealis
Gerd Benz, Arkiv for Kemi 14 305 (1959).
201 trans-Dec-2-ene-4,6,8-triyn-l,10-diol, CjoHsO^, colorless needles,
(dec.) 138°, U.V. 205, 212, 231, 243.5, 259, 279, 290.5,
309.5, 330.5 m^ in ethanol.
HOCH2— C^C— C=C— C=C— CH=CH— CH2OH
Coprinus quadrifidus
E. R. H. Jones and J. S. Stephenson, /. Chem. Soc, 2197
(1959).
202 trans,trans-Matricaria Acid, CioHgOa, colorless plates, m.p. 175°
(dec), U.V. 245, 256, 310, 3"29 rri/x in ethanol.
CH3— CH=CH— C=C— C=C— CH=CH— COOH
Polyporiis anthracophilus
J. D. Bu'Lock, E. R. H. Jones and W. B. Turner, J. Chem.
Soc, 1607 (1957).
203 trans, trans-Matricarianol, CiyHi„0, colorless needles, m.p.
105.5°, U.V. 217.5, 231.5, 237, 247, 261, 276, 293, 312
m/x in ethanol.
CH3— jCH=CH— C=C— C=C— CH=CH— CH2OH
Polyporus anthracophilus
J. D. Bu'Lock, E. R. H. Jones and W. B. Turner, /. Chem.
Soc, 1607 (1957).
204 Deca-czs-24rans-8-diene-4,6-diyn-l-ol, CioHjoO, m.p. <20°, U.V.
213.5, 230, 237.5, 246.5, 261.5, 276.5, 293.5, 312.5 m^x.
CH3— CH=CH— C=C— C=C— CH=CH— CH2OH
Polyporus guttalatus
J. N. Gardner, E. R. H. Jones, P. R. Leeming and J. S.
Stephenson, /. Chem. Soc, 691 (1960).
113 Polyenes and Polyynes, Excluding Polyene Macrolides
205 10-Hydroxydec-trans-2-ene-4,6-diynoic Acid, C^^H^oO^, colorless
plates, m.p. 154.5°, U.V. 215, 222 (243) (225), 270,
285, 303 m;^ in ethanol.
HOCH2— CH.— CH,— C=C— C^C— CH=CH— COOH
Polyporus anthracophilus
J. D. Bu'Lock, E. R. H. Jones and W. B. Turner, /. Chem.
Soc, 1607 (1957).
206 Dimethyl Octa-trans-2,trans-6-dien-4-yne-I,8-dioate, CioHi„04, col-
orless plates, m.p. 117-119.5°, U.V. (205), 214 (240)
(278), 292, 307 m/x in ethanol.
CH3OOC— CH=CH— C=C— CH=CH— COOCH3
Polyporus anthracophilus
J. D. Bu'Lock, E. R. H. Jones and W. B. Turner, /. Chem.
Soc, 1607 (1957).
207 Undec-3,5,6-triene-8,10-diynoic Acid, CnHgOa.
HC^C— C=C— CH=C=CH— CH=CH— CH2— COOH
Drosophila semivestita
Marjorie Anchel, Science 126 1229 (1957).
208 Nemotin, CnHgOo, unstable except in solutions, [ajn^^ +380° (c
0.3 in ether), U.V. 207, 236, 248, 262, 276 m^x in water.
HC=C— C=C— CH=C=CH— CH— CH2— CH2— C=0
I o '
and
209 Nemotinic Acid, CnHioOg, unstable except in solutions, [ajn"
+320° (c 0.2 in ether), U.V. 208, 237, 249, 263, 277 m^x
in water.
CH^C— C=C— CH=C=CH— CH— CH2— CH2— COOH
I
OH
Porta corticola, P. tenuis and another unidentified ba-
sidiomycete
Yields of mixed acetylenes from one of the fungi were :
Pfizer Handbook of Microbial Metabolites
114
TABLE I
Compound
Concentration in
the medium
(mg. per liter)
Per cent of total
110
14
34
5
67.5
8.5
21
3
J. D. Bu'Lock, E. R. H. Jones and P. R. Leeming, /. Chem.
Soc, 4270 (1955). (Structure)
210 Methyl trarzs-10-Hydroxydec-2-ene-4,6,8-triyn-l-oate, CuHgOa,
needles (dec. -115°), U.V. 245, 256.5, 283, 301, 320.5,
343.5 rti/x in carbon tetrachloride.
HOCH,— C^C— C=C— C^C— CH=CH— COOCH3
Pleurotus ulmarius, Merulius lachrymans
J. N. Gardner, E. R. H. Jones, P. R. Leeming and J. S.
Stephenson, J. Chem. Soc, 691 (1960).
211 trans, trans-Matricaria Ester, CnHj„02, colorless needles, m.p.
62°, U.V. (234), 246, 258 (296), 314, 333 m^x in ethanol.
CH3— CH=CH— C^C— C=C— CH=CH— COOCH3
Polyporus anthracophilus
J. D. Bu'Lock, E. R. H. Jones and W. B. Turner, J. Chem.
Soc, 1607 (1957).
212 Methyl 10-Hydroxydec-trans-2-ene-4,6-diynoate, CnHioO.^, nearly
colorless oil, U.V. 215, 223 (243), 258, 273, 287, 305 m^
in ethanol.
HOCHo— CHo— CH.— C=C— C=C— CH=CH— COOCH3
Polyporus anthracophilus, Merulius lachrymans
J. D. Bu'Lock, E. R. H. Jones and W. B. Turner, J. Chem.
Soc, 1607 (1957).
213 Odyssin, Ci2H,„02, unstable except in solutions, [a]i,'° +360° (c
0.2 in ethanol), U.V. 210, 237.5, 250, 264, 280 m^.
CH3
and
-C=C— C=C— CH=C=CH— CH—CH,— CH2— C=0
I O '
115 Polyenes and Polyynes, Excluding Polyene Macrolides
214 Odyssic Acid, Ci2H,oO;i, unstable except in solutions, [aln^" +300°
(c 0.25 in etiianol), U.V. 211, 238, 250.5, 265, 280.5 m^x.
CHs— C=C— C=C— CH=C=CH— CH— CH,— CH.— COOH
OH
Poria corticola, P. tenuis
J. D. Bu'Lock, E. R. H. Jones and W. B. Turner, /. Chem.
Soc, 1607 (1957).
215 Dimethyl Deca-2,4,6-triyne-l,10-dioate, Ci2Hi„04, colorless nee-
dles, m.p. 45°, U.V. 209, 217, 226", 257, 272, 288, 307,
329 m^ in carbon tetrachloride.
CH3OOC— C=C— C=C— C=C— CH,— CHo— COOCH3
Merulius lachrymans
J. N. Gardner, E. R. H. Jones, P. R. Leeming and J. S.
Stephenson, /. Chem. Soc, 691 (1960).
216 Dimethyl Deca-trans-2,trar2S-8-diene-4,6-diyne-l,10-dioate,
Ci2H,„04, colorless plates, m.p. 104.5-107.5°, U.V. 216,
269, 298, 317, 339 m^ in ethanol.
CH3OOC— CH-=CH— C=C— C^C— CH=CH— COOCH3
Polyporus anthracophilus
J. D. Bu'Lock, E. R. H. Jones and W. B. Turner, J. Chem.
Soc, 1607 (1957).
217 Dimethyl Dec-trans-2-ene-4,6-diyne-l,10-dioate, C12H12O4, color-
less crystals, m.p. 56.5-58°, U.V. 214.5, 223 (243) (255),
270, 285, 303 m,x in ethanol.
CH3OOC— CH,— CH,— C^C— C=C— CH=CH— COOCH3
Polyporus anthracophilus
J. D. Bu'Lock, E. R. H. Jones and W. B. Turner, J. Chem.
Soc, 1607 (1957).
218 Mycomycin, C13H10O0, colorless needles, m.p. 75° (dec. explo-
sively), [a]rr' -130° (c 0.4 in ethanol), U.V. 256, 267,
281 rufx in diethyl ether.
HC=C— C^C— CH=C=CH— CH=CH— CH=CH— CH2— COOH
Nocardia acidophilus
Walter D. Celmer and I. A. Solomons, /. Am. Chem. Soc 74
1870, 3838 (1952). (Structure)
Edwin A. Johnson and Kenneth L. Burdon, /. Bacteriol. 54
281 (1947).
Pfizer Handbook of Microbial Metabolites 1 1 6
219 Corticrocin, C14H14O4, orange-red, amorphous powder or yellow
needles and prisms, m.p. subl. 270°, m. 317° (sealed
tube), U.V. 374, 393, 416 m^a in ethanol.
Corticeum croceumBies. (= Corticium sulfureum (Fr. )
Fr.)
Yields of about 4% of the mycorrhizal weight have
been reported.
Holger Erdtman, Acta Chem. Scand. 2 209 (1948).
(Isolation and Structure)
B. L. Shaw and M. C. Whiting, J. Chem. Soc, 3217 (1954).
(Synthesis)
B. C. L. Weedon, ibid. 4168 (1954). (Synthesis)
220 Nemotinic Acid Xyloside, CjsHisO^, [a],."' +237° (c 0.1 ethanol).
HC=C— C^C— CH=C=CH— CH— CHo— CHo— COOH
/ o^
OH >HO
HO
OH
Basidiomycete B-841
J. D. Bu'Lock and H. Gregory, Experientia 15 420 (1959).
22 1 Deca-trans-2-trarzs-8-diene-4,6-diynyl Deca-trans-2, trans-8-diene-
4,6-diynoate, CooHigOo, colorless crystals, m.p. 124-126°,
U.V. 213 (233"), 238.5, 246, 259, 277.5, 295, 314, 335
mfx in ethanol.
CH3— CH=CH— C=C— C^C— CH=CH— COO— CH2— CH=CH— C=C— C^C—
CH=CH— CH3
Polyporus anthracophilus
J. D. Bu'Lock, E. R. H. Jones and W. B. Turner, J. Chem.
Soc, 1607 (1957).
1 1 7 Polyenes and Polyynes, Excluding Polyene Macrolides
222 Methyl 10-(Deca-fra72S-2,frflns-8-diene-4,6-diyn-l-oyloxy)-dec-trans-
2-ene-4,6-diynoate, CoiHi^O,, colorless plates, m.p. 91-93°,
U.V. 223, 246.5, 259", 287, 305, 334 m^u in ethanol.
CHs— CH=CH— C=C— C=C— CH^CH— COO— CH2— CH2— CHo— C=C— C=C
— CH=CH— COOCH3
Polyporus anthracophilus
J. D. BuLock, E. R. H. Jones and W. B. Turner, 7. Chem.
Soc, 1607 (1957).
223 Cortisalin, C^iHoiiO;^, violet-red needles, m.p. dec. >290°, U.V.
(318),"345 (420), 443 (462) m^a in pyridine.
HO-Q-
Corticium salicinum Fries
A yield of 2.6 g. of crude material was obtained from
222 g. of fungal fruiting body.
Jarl Gripenberg, Acta Chem. Scand. 6 580 (1952).
D. Marshall and M. C. Whiting, /. Chem. Soc, 537 (1957).
( Synthesis )
224 Limocrocin, CosH^^OqN^, a yellow actinomycete pigment. Dark
red crystals from AcOH m.p. 316° (dec). Dimethyl ester
of perhydo-deriv., fine, colorless needles, m.p. 146-147°.
Partial structure:
O
\
HO— C\^v^^^?\^::r\^:;\^^;;\^~v^^:^v^ ^NHfCsHjONlCOOH
C
A demethylcrocetin derivative with the CsHjON probably a
heterobicycHc residue. Eq. wt. 225 (232).
Streptomyces limosus (Glycine-glycerol substrate)
Hans Brockmann and Hans-Ulrich May, Chem. Ber. 88 419
(1955).
Hans Brockmann and Gerhard Grothe, Chem. Ber. 86 1110
(1953).
Macrocyclic Lactones (Macrolides)
The macrolide (macrocyclic lactone) antibiotics are an in-
teresting new class of compounds elaborated by members of the
order actinomycetales and particularly by the genus strepto-
myces. The lactone moieties of these molecules resemble the
partially oxidized and alkylated aliphatic acids characteristic
of the related mycobacterium genus. A partial listing accord-
ing to Bergey's Manual of the members of the order actinomy-
cetales is shown below to clarify these relationships.
Order. . . Acfinomycefales*^
Families. . . Actino-
mycetaceae
Strepto-
mycefaceae
Myco- Actino-
bacteriaceae planaceae
Genera... Nocardia Sfreptomyces* Mycobacterium Actinoplanes
Actinomyces* Micromonospora Mycococcus Streptosporan-
Thermoactino- gium
myces
A resemblance- to the steroid glycosides, for example strophan-
thin and oleandrin shown below, also has been noted. ^
OH
Strophanthin
* In the vernacular usage streptomycete-streptomyces and actino-
mycete may indicate either order or genus, perhaps more commonly
the order.
1 R. B. Woodward, Festschr. Arthur Stoll, 524 (1957).
119
Macrocyclic Lactones (Macrolides)
OCOCH3
In this regard it is striking that the sugar L-oleandrose occurs
in both oleandrin and in the macroHde oleandomycin.
The macrolide antibiotics are most effective against gram-
positive bacteria. In the introduction to the section on steroids
and terpenoids, it was mentioned that no true steroids have
ever been detected conclusively in bacteria. It was noted also
that certain investigators exploring the utilization of mevalonic
acid by gram-positive bacteria (especially lactobacilli) found
that partially oxidized aliphatic substances with more than 15
carbon atoms were produced.- While these products were not
thoroughly characterized, the properties as described were rem-
iniscent of the lactone portions of the macrolides. It also has
been mentioned elsewhere that the general chemical structure
and metabolism of the actinomycetales seem to be more closely
related to that of the bacteria than to that of the fungi, which
they resemble superficially. From these premises, it is tempting
to speculate that the macrolide antibiotics may interfere in some
way with a primitive kind of hormonal or steroid metabolism
in gram-positive bacteria. In this connection it should be
noted, however, that the sugar portions of most of the known
macrolide antibiotics are essential to their antibacterial activity.
Tylosin and lankamycin may be exceptions.
Several of the many macrocyclic lactones which have been
isolated from streptomycete cultures have been well character-
ized structurally. Complete structures have been reported for
picromycin, methymycin, neomethymycin, erythromycin, eryth-
romycin B, erythromycin C, carbomycin (Magnamycin), carbo-
mycin B, oleandomycin and pimaricin. A considerable amount
of information has been reported concerning the structures of
narbomycin, the foromacidins (spiramycins) and the pentaenes
lagosin and fiUpin.*
The few cases available for comparison fall into a general
pattern. This involves the lactone of a long chain aliphatic
- E. Kodlcek, Abstracts of the Gordon Conference on Vitamins
and Metabolism, 1958.
* See addendum.
Pfizer Handbook of Microbial Metabolites 120
acid, quite evidently acetate-derived, in conjugation with one or
more sugar-like moieties. These sugars are uncommon ones,
and one of them is usually an amino-sugar, desosamine being
particularly prevalent so far. Several of the incompletely char-
acterized macrolides, especially those of the polyene type, have
been reported to contain no nitrogen, however. Among these
are lagosin, fungichromin, A-246, miamycin and filipin. One
macrolide, celesticetin,* contains sulfur. Lankamycin also con-
tains no nitrogen.
Of all the macroHdes the biosynthesis of erythromycin has
been investigated most thoroughly. One of the questions to be
answered was whether the erythronolide moiety is derived from
acetate or from propionate. A labeling and degradation study
wdth C^*-containing precursors has shown that propionate or its
biological equivalent is the true precursor.^ Propionate-C-1 was
incorporated only into the "methylene" carbon atoms, while
propionate C-2 was incorporated largely into the tertiary carbon
atoms and not at all into the carbon-bound methyl groups. Ad-
ditional evidence against the acetate hypothesis was the fact
that C^Mabeled formate or C^*-methyl methionine did not label
the terminal three carbon atom subunit of erythronolide.
A previous study* had shown that C"-l-labeled propionate
caused labehng of erythronolide, but not of the sugars desosa-
mine and cladinose. The reverse was true when the labeled
precursor was C'*-methyl methionine.^
Other evidence which has been published suggests or is con-
sistent with derivation of erythronolide from propionate."
A notice has been pubhshed that a labehng study on the
biogenesis of erythromycin is in progress with the use of pro-
pionic acid-l-C"-H^'
It remains to be seen whether or not some of the less highly
^ John W. Corcoran, Toshi Kaneda and John C. Butte, /. Biol.
Chem. 235 pc29 (1960).
* Z. Vanek, J. Majer, A. Babicky, J. Liebster, K. Veres and L.
Dolezilova, Abstr. IVth Intern. Congr. Biochem., Vienna, 1958; cf.
Angew. Chem. 71 40 (1959).
^ Z. Vanek, J. Majer, J. Liebster, K. Veres and L. Dolezilova,
Symposium on Antibiotics, Prague, 1959.
^ V. Musilek and V. Sevcik, Naturwissenschaften 45 86 215 (1958);
idem.. Symposium on Antibiotics, Prague, 1959.
^ H. Grisebach, H. Achenbach and U. C. Grisebach, Naturwissen-
schaften 47 206 (1960).
* See entry 923 for non-macrolide structure.
121
Macrocyclic Lactones (Macrolides)
branched lactones are derived in whole or in part from acetate.
It is obvious that in each case many modifications of the mac-
rolide moiety have occurred from the simplest intermediate
ring which could be envisaged. These include complete or
partial reduction of carbonyl groups, dehydration of the corre-
sponding secondary alcohols, epoxidation or reduction of carbon-
carbon double bonds, oxidation of tertiary carbon atoms, cleav-
age of epoxides to glycols, etc. Yet, despite the confusing detail,
the fundamental pattern of oxidation and reduction remains
apparent, just as it does in many of the metaboUtes of the myco-
bacteria and corynebacteria.
It wall be interesting to see how much of the information con-
cerning the biogenesis of the macrolides can be transposed to
metabolites of the mycobacteria and corynebacteria and vice
versa.
In the cases of picromycin, methymycin, erythromycin, nar-
bomycin and oleandomycin it is possible to follow the course of
alternate oxidation throughout the lactone rings wdth remark-
able regularity, the hypothetical intermediate being, apparently,
a single continuous chain, unbranched except for the methyl
groups. In the cases of carbomycin and pimaricin, anomalies
occur. These could be explained by a junction of shorter
chains, perhaps as shown below, in a manner similar to the for-
mation of corynomycolic acid by the coupling of 2 moles of pal-
mitic acid:
Pimaricin
OCOCH3
Lactone Portion of Carbomycin
Another suggestion has been made in the case of carbomycin,^
namely that a protocarbomycin may occur which later rear-
ranges by a glycol-aldehyde shift:
Pfizer Handbook of Microbial Metabolites
122
C— O— H
^ C-O-H
I
c=o
1
H
CH3 O OCOCH3
Proposed Precursor of the Proposed Glycol-aldehyde
Lactone Portion of Corbomycin Rearrangement at 7,8-Positions
Such a precursor is the more plausible because it would have an
1 8-membered carbon atom chain and a C-19 carbon skeleton,
the same as that of the known tuberculostearic acid, even in-
cluding the stereochemistry of the branching methyl group.
Streptomyces species produce many antifungal antibiotics
which have in common chains of conjugated olefinic bonds. By
means of the ultraviolet absorption spectra it is possible to clas-
sify them according to the length of the conjugated chain.
Generally these substances are rather intractable with low solu-
bilities and indefinite melting points.
A structure has been proposed for pimaricin, a tetraene.
Whether or not this structure proves to be entirely correct, there
is evidence from several sources that at least certain of these
substances are macrocyclic lactones.
So many of these compounds have been reported lately that
any listing is likely to be incomplete. The following table must
include most of them, however, grouped by number of conju-
gated olefinic bonds.
TABLE I
Tetraene
Hexaene
Pentaene
Heptaene
Nystatin (Fungicidin)
Fradicin
Eurocidin
Amphotericin B
Rimocidin
Flavacid
Fungichromatin
Candidin
Pimaricin
Mediocidin
Fungichromin
Candicidin
Amphotericin A
Endomycin B (Helixin B)
Filipin
Candimycin
Protocidin
PA- 153
Ayfactin
Chromin
Pentamycin
Ascosin
Antimycoin
Trichomycin
Sistomycosin
PA- 150
Endomycin A (Helixin A)
Antibiotic 1968
Etruscomycin
PA- 166
Tennecetin
Flavofungin
123
Polyene Macrolides
Various other substances, e.g. the etamycin, valinomycin and
actinomycin types of antibiotics, could be classed as macrolides
since they all contain large rings in which lactone groups par-
ticipate.
a. POLYENE MACROLIDES
225 Flavofungin, C^„H4s09 Dihydrate.
A polyene macrolide containing 7 acetylatable hydroxyl
groups, 5 hydrogenatable carbon-carbon double bonds of
which at least 4 are conjugated, contains no alicyclic ring,
has at least 2 and probably 3 C — CH^. Ozonolysis indi-
cates a CH;^(C,jHii) group. The most important struc-
tural elements are:
— CH=C-
<=CH-
CH3 CH3
-(CH=CH)3— C=0, CH3(C6H„)
O
CloHi3(OH)7
Shown to be distinct from pimaricin, nystatin, amphoteri-
cin-B, fungichromin, lagosin, filipin and fumagillin.
A streptomycete
R. Bognar, Angew. Chem. 72 139 (1960).
226 Pimaricin ( Myprozine ) , C34H49O14N, colorless crystals, m.p.
200° (dec), U.V. 279, 290, 303, 318 m^ in methanol.
Proposed structure:
CH2OH
I
OH O O CHOH
Streptomyces natalensis n. sp.
A. P. Struyk, I. Hoette, G. Drost, J. M. Waisvisz, T. Van Eek
and J. C. Hoogerheide, "Antibiotics Annual 1957-1958," Med-
ical Encyclopedia, Inc., New York, p. 878.
James B. Patrick, Richard P. Williams and John S. Webb,
J. Am. Chem. Soc. 80 6689 (1958). (Structure)
Pfizer Handbook of Microbial Metabolites 1 24
227 PA-166, C35H53O14N (proposed), colorless powder, m.p. gradual
dec. up to 260°, [a]n'' +275° (c 0.2 in pyridine).
An amphoteric tetraene. U.V. maxima: 291, 304, 319
in aqueous methanol. Positive ninhydrin, 2,4-DNPH and
Fehling's tests. Three C-methyl groups.
Streptomyces n. sp.
B. K. Koe, F. W. Tanner, Jr., K. V. Rao, B. A. Sobin and
W. D. Celmer, "Antibiotics Annual 1957-1958," Medical En-
cyclopedia, Inc., New York, p. 897.
228 Etruscomycin, CagH^TOi^N, white crystals, [a]D^° +296° (c 1 in
pyridine ) .
A tetraene antibiotic. I.R. peaks at: 2.91, 3.38, 5.83,
6.30, 9.44, 9.55, 11.85;x. U.V. peaks at: 290, 300, 316 m^x.
Streptomyces lucensis n. sp.
F. Arcamone, C. Bertazzoli, G. Canevazzi, A. DiMarco, M.
Ghione and A. Grein, Giorn. Microbiol. 4 119 (1957).
229 Lagosin (Antibiotic A-246), C41H66-70O14. m.p. ^235° (dec),
[a]ir" -160° (c 0.2 in methanol).
An antifungal pentaene macrolide antibiotic with the
following partial structure : *
n— CsHnCHOH
I
O— CO— CH— c— c— c— c— c— c— c— c— c— c—
I
CH3— CH— CH— (CH=CH)4— CH=C CH C—
> C6H30-34O9
OH CH3 OH OH
Streptomyces sp.
M. L. Dhar, V. Thaller and M. C. Whiting, Proc. Chem. Soc,
148 (1958)._
M. L. Dhar, V. Thaller, M. C. Whiting, Ragnar Ryhage,
Stina Stalberg-Stenhagen and Einar Stenhagen, ibid., 154
(1959). (Structure)
S. Ball, Christine J. Bessell and Aileen Mortimer, J. Gen.
Microbiol. 17 96 (1957). (Isolation)
230 Nystatin (Fungicidin, Mycostatin) C46H77O19N (tentative), yel-
low powder, m.p. dec. above 160°, but no definite m.p.,
[aln'^ +10° (in glacial acetic acid).
An amphoteric tetraene. U.V. maxima at: 280, 291,
304, 318 m/A. Contains a mycosamine moiety:
NH2
HO I OH
O:
HO CH3
* See addendum.
125 Polyene Macrolides
Streptomyces noursei
Elizabeth L. Hazen and Rachel Brown, Proc. Soc. Expl.
Biol. Med. 76 93 (1951).
James D. Dutcher, Gerald Boyack and Sidney Fox, "Anti-
biotics Annual 1953-1954," Medical Encyclopedia, Inc., New
York, p. 191.
David R. Walter, James D. Dutcher and O. Wintersteiner,
;. Am. Chem. Soc. 79 5076 (1957). (Structure)
231 Rimocidin (Sulfate heptahydrate), large fragile plates, m.p.
^151° (dec.), [aW (sulfate) +75° (c 1 in methanol).
An amphoteric tetraene. U.V. maxima at: 279, 291,
304, 318 m/x. Analysis (hydrated sulfate): C 57.65, H
7.82, N 1.81, S 2.03.
Streptomyces rimosus
J. W. Davlsson, F. W. Tanner, Jr., A. C. Finlay and I. A.
Solomons, Antibiotics and Chemotherapy 1 289 (1951).
232 Protocidin, m.p. dec. from 120°.
A polyene antifungal agent. U.V. maxima 277, 290,
303 and 318 mpi. Reduces KMn04. Green Fehling. Neg-
ative biuret, Sakaguchi, Molisch, ninhydrin, anthrone,
FeCL.
Streptomyces sp.
The yield was about 100 mg. per liter.
Jean Marie Sakimoto, J. Antibiotics (Japan) lOA 128
(1957).
233 Amphotericin-A, m.p. gradual dec. above 153°, [(x]o^^"^ +32° (in
acid dimethylformamide).
An amphoteric tetraene. U.V. maxima: 291, 305, 320
mix. Analysis: C 60.32, H 8.39, N 1.72.
Streptomyces sp.
J. Vandeputte, J. L. Wachtel and E. T. Stiller, "Antibiotics
Annual 1955-1956," Medical Encyclopedia, Inc., New York,
p. 587.
234 Sistomycosin, bufp or light yellow microcrystals, m.p. --'230°
(browning from 130°).
A neutral tetraene. U.V. maxima: 218, 292.5, 306,
320.5 m^ in aqueous solution. Positive Benedict and
Molisch tests.
Streptomyces viridosporus n. sp.
J. Ehrlich, M. Knudsen and Q. Bartz, Canadian Patent
514,894 (1955).
235 Endomycin A (Helixin A), yellow-brown powder.
An acidic tetraene. U.V. maxima at 292, 301, 319 mix.
Streptom.yces hygroscopicus (S. endus)
A yield of 11.7 g. of mixed endomycins from about 15
liters of broth has been reported.
Pfizer Handbook of Microbial Metabolites 126
L. C. Vining and W. A. Taber, Can. ]. Chem. 35 1461
(1957).
David Gottlieb, P. K. Bhattacharyya, H. E. Carter and H. W.
Anderson, Phytopathology 41 393 (1951). (Isolation)
Curt Leben, G. J. Stessel and G. W. Keitt, Mycologia 44 159
(1952).
R. R. Smeby, Curt Leben, G. W. Keitt and F. M. Strong,
Phytopathology 42 506 (1952).
236 Tennecetin, yellow amorphous powder.
A tetraene antibiotic. U.V. absorption peaks at 288,
300-302, and 315-318 m^.
Streptomyces chattanoogensis
James Burns and D. Frank Holtman, Antibiotics and Chem-
otherapy 9 398 (1959).
237 Antimycoin, organic acid, U.V. maxima: 291, 304—305, 318
mjx in ethanol. Similar to fungicidin. (A tetraene)
Streptomyces aureus Waksman and Curtis
Carl P. Schaffner, Irwin D. Steinman, Robert S. Safferman
and Hubert Lechevalier, "Antibiotics Annual 1957-1958,"
Medical Encyclopedia, Inc., New York, pp. 5869-5873.
Frederick Raubitscheck, Robert F. Acker and Selman A.
Waksman Antibiotics and Chemotherapy 2 179 (1952).
238 Filipin, C:^2H-,40io, fine yellow needles, m.p. 195-205° (dec.) (s.
147°), [a],," -148.3° (c 0.89 in methanol).
A neutral pentaene. U.V. maxima at 322, 338, 355 m^.
Contains 7-8 acetylatable non-vicinal hydroxyl groups and
3-4 C— CH. groups.
Possible partial structure : *
CH3 OH OH
-t I I I
CH3— C— C— C=C— (C=C)4— c— c — c
OH I C
o I
o=c— C— C— C— C— C— C— C— C— OH
n— CsHu— C— OH
Streptomyces fdipinensis n. sp.
Geo. B. Whitfield, Thomas D. Brock, Alfred Ammann,
David Gottlieb and Herbert E. Carter, ]. Am. Chem. Soc. 77
4799 (1955). (Isolation)
Alfred Ammann, David Gottlieb, Thomas D. Brock, Her-
* See addendum.
127 Polyene Macrolides
bert E. Carter and George B. Whitfield, Phytopathology 45 559
(1955).
Belig Berkoz and Carl Djerassi, Proc. Chem. Soc, 316
(1959). (Structure)
239 Fungichromin, C;{.-,H,i,,0,;!, pale yellow crystals, m.p. 205-210°.
A pentaene. U.V. maxima: 322.5, 338.5, 356.5 m^.
The following moiety has been obtained by alkaline hy-
drolysis followed by periodate oxidation:
OHC— C=CH(CH=CH)4— CHO
CH:,
Streptomyces cellidosae
A similar substance, fungichromatin, occurred in the
same culture.
Alfred A. Tytell, Frank J. McCarthy, W. P. Fisher, Wil-
liam A. Balhofer and Jesse Charney, "Antibiotics Annual
1954-1955," Medical Encyclopedia, Inc., New York, p. 716.
Arthur C. Cope and Herbert E. Johnson, /. Am. Chem. Soc.
80 1504 (1958).
240 PA-153, C:i7H,;,Oi4N (proposed), colorless powder, m.p. gradual
dec. up to 260° ( triethylamine salt dec. 126-129°), [x]^-^
-f398° (c 0.2 in pyridine).
An amphoteric pentaene. U.V. maxima: 303, 317,
332, 349 in aqueous methanol. Positive ninhydrin, 2,4-
DNPH and Fehlings tests. Three C-methyl groups.
Streptomyces n. sp.
B. K. Koe, F. W. Tanner, Jr., K. V. Rao, B. A. Sobin and
W. D. Celmer, "Antibiotics Annual 1957-1958," Medical En-
cyclopedia, Inc., New York, p. 897.
241 Pentamycin, pale yellow needles, m.p. 237° (dec).
An antifungal pentaene antibiotic resembling filipin in
some properties. U.V. maxima at: 322, 338, 356 m^.
Contains only C, H, O.
About 60 g. of fairly pure material were obtained from
100 liters of culture (mycelium).
Streptomyces penticus
Sumio Umezawa and Yoshiaki Tanaka, /. Antibiotics (Ja-
pan) llA 26 (1958).
242 Eurocidin.
A pentaene. U.V. maxima: 318, 333, 351 m^x.
Pfizer Handbook of Microbial Metabolites 128
Streptomyces alboreticuli n. sp.
Yashiro Okami, Ryazo Utahara, Shashiro Nakamura and
Hamao Umezawa, J. Antibiotics (Japan) 7A 98 (1954).
Ryozo Utahara, Yashiro Okami, Shashiro Nakamura and
Hamao Umezawa, ibid. 7A 120 (1954).
243 Fradicin, C3„H3404N4, pale greenish yellow crystals, m.p. dark-
ens without melting 180-300°, [alo'' +65° (c 1 dioxane).
Weakly basic hexaene. U.V. maxima: 290-295. Two
methoxyls.
Streptomyces fradiae
E. Augustus Swart, Antonio H. Romano and Selman A.
Waksman, Proc. Soc. Exptl. Biol. Med. 73 376 (1950).
Richard J. Hickey and Phil Harter Hidy, Science 113 361
(1951).
244 Flavacid, pale yellow microcrystalline powder, m.p. 102-105°
(dec).
A weakly acidic hexaene. U.V. maxima: 340, 360,
380 mix. A tetraene with peaks at 293, 306 and 324 is
also present.
A streptomycete resembling S. fiaviis
Isao Takahashi, /. Antibiotics (Japan) 6A 117 (1953).
L. C. Vining and W. A. Taber, Can. J. Chem. 35 1461
(1957).
245 Mediocidin, yellow amorphous powder.
A hexaene. U.V. maxima: 340, 357, 378 m/x. A
tetraene, probably identical with that in the flavacid com-
plex, is also present. U.V. maxima: 293, 306, 324.
Streptomyces mediocidicus, n. sp.
Ryazo Utahara, Yoshiro Okami, Shashiro Nakamura and
Hamao Umezawa, J. Antibiotics (Japan) 7A 120 (1954).
L. C. Vining and W. A. Taber, Can. J. Chem. 35 1461
(1957).
246 Endomycin B (Helixin B), yellow-brown powder.
An acidic hexaene. For U.V. spectrum see first refer-
ence below.
Streptomyces hygroscopicus (S. endus)
L. C. Vining and W. A. Taber, Can. J. Chem. 35 1461
(1957).
David Gottlieb, P. K. Bhattacharyya, H. E. Carter and H. W.
Anderson, Phytopathology 41 393 (1951). (Isolation)
Curt Leben, G. J. Stessel and G. W. Keitt, Mycologia 44 159
(1952).
R. R. Smeby, Curt Leben, G. W. Keitt and F. M. Strong,
Phytopathology 42 506 (1952).
129 Polyene Macrolides
247 Helixins.
A complex of three or four compounds. Helixin B is
identical with endomycin B.
Streptomyces sp.
Curt Leben, G. J. Stessel and G. W. Keitt, Mycologia 44 159
(1952).
248 Amphotericin-B, doHy^OooN (tentative) deep yellow prisms or
needles from dimethylformamide, m.p: gradual dec. above
170°, [ajp +333° (in acid dimethylformamide).
An amphoteric heptaene, U.V. maxima at: 364, 383,
408 m^. Contains a mycosamine moiety:
HO V"' OH
HO CH3
Streptomyces nodosiis
J. Vandeputte, J. L. Wachtel and E. T. Stiller, "Antibiotics
Annual 1955-1956," Medical Encyclopedia, Inc., New York,
p. 587. (Isolation)
David R. Walters, James D. Dutcher and O. Wintersteiner,
J. Am. Chem. Soc. 79 5076 (1957). (Structure)
249 Zaomycin, m.p. 242-246° (dec).
An amphoteric antibiotic said to resemble amphotericin.
Positive ninhydrin, Millon, biuret, FeClo tests. Negative
Fehling and Liebermann reactions.
Streptomycin zaomyceticus
Yorio Hinuma, J. Antibiotics (Japan) 7A 134 (1954).
250 PA-150, Cr,4H820i8N2 (proposed), yellow powder, m.p. gradual
dec. up to 260°, [ajrr' +294° (c 0.2 in pyridine).
An amphoteric heptaene. U.V. maxima: 340, 358,
377, 397 m^ in aqueous methanol. Positive 2,4-DNPH
and Fehlings tests. Four C-methyl groups.
Streptomyces n. sp.
B. K. Koe, F. W. Tanner, Jr., K. V. Rao, B. A. Sobin and
W. D. Celmer, "Antibiotics Annual 1957-1958," Medical En-
cyclopedia, Inc., New York, p. 897.
251 Trichomycin, yellow powder, m.p. 155° (dec).
A heptaene. U.V. maxima: 286, 346, 364, 384, 405
rufx. May be a mixture of two heptaenes.
Streptomyces hachijoensis n. sp.
Pfizer Handbook of Microbial Metabolites 130
Seigo Hosoya, Nobuhiko Komatsu, Momoe Soeda and Yoko
Sonoda, Japan J. Exptl. Med. 22 505 (1952).
Seigo Hosoya, Nobuhiko Komatsu, Momoe Soeda, Tatsuro
Yuwaguchi and Yoko Sonoda, 7. Antibiotics (Japan) 5 564
(1952).
252 Candidin, yellow powder.
Acidic heptaene. U.V. maxima: (Na salt) 234, 282,
345, 360, 383, 405 m^i in aqueous solution. The free acid
lacks the 345 peak. Contains nitrogen and gives positive
ketone tests.
Streptomyces viridofiavus
Willard A. Taber, Leo C. Vining and Selman A. Waksman,
Antibiotics and Chemotherapy 4 455 (1954).
Leo C. Vining, Willard A. Taber and Francis J. Gregory,
"Antibiotics Annual 1954— 1955, ' Medical Encyclopedia, Inc.,
New York, p. 980.
Candicidins.
Heptaenes. U.V. maxima:
253 Candicidin A: 360, 380, 403 m/x.
254 Candicidin B: 362, 381, 404 m^.
255 Candicidin C: 358, 379, 402 m/x.
Streptomyces griseus, other Streptomyces spp.
Hubert A. Lechevalier, R. F. Acker, C. T. Corke, C. M.
Haenseler and S. A. Waksman, Mycologia 45 155 (1953).
256 Ascosin, yellow-orange powder.
A weakly acidic heptaene. U.V. maxima: 234, 288,
340, 357, 376, 398 m/x in methanol.
Streptomyces canescus
Richard J. Hickey, Cyril J. Corum, Phil H. Hidy, I. Ray
Cohen, Urs F. B. Nager and Eleonore Kropp, Antibiotics and
Chemotherapy 2 472 (1952).
Isadore R. Cohen, U. S. Patent 2,723,216, (1955).
h. OTHER MACROLIDES
257 Nitrosporin, C^oH^eOfiNo, colorless crystals, m.p. 130-140°
(dec). Crystals brown on exposure to air.
A basic substance, apparently a macrolide.
Streptomyces nitrosporeus
Hamao Umezawa and Tomio Takeuchi, /. Antibiotics (Ja-
pan) 5 270 (1952).
131
Other Macrolides
258 Celesticetin I, amphoteric, crystaUine and dextrorotatory,
Co4H3^.4„Ot,N2S (suggested empirical formula). Oxalate
and Salicylate water soluble. Oxalate m.p. 149-154°;
Salicylate m.p. 139° (tabular monoclinic crystals).
Erythromycin-hke. (See entry 923, however)
Positive tests — FeCla, Molisch, Ekkert
White ppt. — Bro water, Millon's Reagent, HgCL
Negative tests — AgNOg, PbAc, Benedict, ninhydrin, io-
doform, nitroprusside (becomes + after standing several
days in 6 N hydrochloric acid)
No immediate reaction with Br^ — CCI4.
Streptomyces caelestis
Herman Hoeksema, Glen F. Crum, William H. DeVries,
Antibiotics Annual 2 837-841 (1954-1955). (Isolation and
purification )
259 Amaromycin, C^.-.H^^OyN (proposed), colorless prisms, m.p.
164.5°, [a]n'' +6.19° (c 1 in ethanol).
Basic substance, analysis: C 63.66, H 8.73, N 3.0.
Negative FeCl-^, biuret, ninhydrin, Sakaguchi, Schiff.
Positive Tollens, Fehlings. Precipitated by Reinecke's
salt. Probably a macrolide.
Streptomyces flavochromogenes
Toju Hata, Yashimoto Sano, Hideo Tatsuta, Ryazo Suga-
wara, Akihiro Matsumae and Kokichi Kanamori, /. Antibiotics
(Japan) 8A 9 (1955).
260
261
PA-133 A, C2r,H430eN, colorless amorphous solid, [a]n'' +39.6°
(c 0.5 in methanol).
A macrolide antibiotic.
Streptoviyces sp.
K. Murai, B. A. Sobin, W. D. Celmer and F. W. Tanner,
Antibiotics and Chemotherapy 9 485 (1959).
Methymycin, C05H43O7N, colorless prisms
1 Q70 rnn'io\ [1 23
197° (203°), [a],,-' +61'
, needles, m.p. 195—
(in methanol).
Desosamine
Pfizer Handbook of Microbial Metabolites
132
A streptomycete
Carl Djerassi and John A. Zderic, J. Am. Chem. Soc. 78
2907 (1956). (Structure)
Milton N. Donin, Joseph Pagano, James D. Dutcher and
Clara M. McKee, "Antibiotics Annual 1953-1954," Medical
Encyclopedia, Inc., New York, p. 179. (Isolation)
262 Neomethymycin, Co,-,H4..07N, colorless crystals, m.p. 156°, [aln^^
+93° (in chloroform).
XH3
-P.
OH N— CH3
CH3
CH3
CH3
O
CH3
Desosamine
OH
CH3 CH3
Same streptomycete which produces Methymycin
Carl Djerassi and O. Halpern, J. Am. Chem. Soc. 79 2022
(1957). (Structure)
J. Vandeputte, unpublished. (Isolation)
263 Picromycin, C25H4:^07N, colorless crystals, m.p. 169.5°, [alo^"
-33.5° (c 2.07 in chloroform).
(D
Picrocin
esosamine)
CH3
CH3— N
CH3
CH3
— o'
CH3
CHa
O
OH
/
HO CH3
CH3
Streptomyces felleus n. sp.
Hans Brockmann and Rudolf Oster, Chem. Ber. 90 605
(1957). (Partial structure)
R. Anliker and K. Gubler, Helv. Chim. Acta 40 119 (1957).
(Structure)
Hans Brockmann and Willfried Henkel, Chem,. Ber. 84 284
(1951). (Isolation)
Ibid., Naturwissenschaften 37 138 (1950). (Isolation)
133 Other Macrolides
264 PA-133-B, Cor.Hj-OioN, colorless crystals, m.p. 99.8-101°, [ajn''
+ 22.5° (c 0.5 in methanol).
A macrolide antibiotic.
Streptoviyces sp.
K. Mural, B. A. Sobin, W. D. Celmer and F. W. Tanner,
Antibiotics and Chemotherapy 9 485 (1959).
265 Griseomycin (Lomycln) (Hydrochloride) C25H4g08NCl, white
powder, m.p. 76-80° (dec), [a]n'' +32° (c 1 in chloro-
form).
Precipitated by Reinecke salt, bromine water, picric
acid. Thought to be a macrolide.
Streptomyces griseolus
P. J. Van Dijck, H. P. Van de Voorde and P. DeSomer, Anti-
biotics and Chemotherapy 3 1243 (1953).
Ibid. Belgian Patent 522,647 (1954).
266 Proactinomycin A, C27H47OSN (proposed), colorless crystals,
m.p. 168°.
267 Proactinomycin B, Co^H4c,OsN (proposed), colorless crystals,
m.p. 83-87°.
268 Proactinomycin C, C24H41O6N (proposed), amorphous.
Basic substances, precipitated by Reineckes salt, picric
or flavianic acids, etc. Probably macrolides.
Nocardia gardneri
A. D. Gardner and E. Chain, Brit. J. Exptl. Path. 23 123
(1942).
R. Q. Marston, ibid. 30 398 (1949). (Isolation)
Antimycins (Antipiriculins)*
269 Antimycin A^, C28H40O9N2, colorless crystals, m.p. 149-150°,
[ix]t>'^' +76 (c 1 in chloroform).
270 Antimycin Aoa, Cor,H3609N2, colorless crystals, m.p. 143-149°,
271 Antimycin A^^ (may be isomeric with A2a), colorless crystals,
m.p. 168°.
272 Antimycin A3 (Blastmycin), C20H3BO9N2, colorless crystals, m.p.
170.5-171.5°, [x]rr'= +64.3° (c 1 in chloroform).
* The antimycins might also be classified as depslpeptldes (pepto-
hdes).
Pfizer Handbook of Microbial Metabolites 134
273 Antimycin A4, oily.
CHj
O
O CH3
NH OH \ /
/ CH CH
OHC ^ V r^ ^^ R = n— CeHia in Ai.
CH3 ^ '\ R = n — C4H9 in A3.
O
At least seven streptomyces species produce antimy-
cins, including S. kitazawaensis Harada et Tanaka nov.
sp. and S. blastmyceticus. The former organism also pro-
duces carzinocidin. Blastmycin is identical with anti-
mycin A;(. Virosin is probably a mixture of antimycin
components. Certain antimycin-producing cultures also
contain actinomycin B.
Wen-chik Liu and F. M. Strong, J. Am. Chem. Soc. 81 4387
(1959).
Wen-chik Liu, E. E. Van Tamelen and F. M. Strong, ibid.
82 1652 (1960). (Degradations, etc.)
F. M. Strong, J. P. Dickie, M. E. Loomans, E. E. Van
Tamelen and R. S. Dewey, ibid. 82 1513 (1960). (Structure)
Bryant R. Dunshee, Curt Leben, G. W. Keitt and F. M.
Strong, ibid. 71 2436 (1949). (Isolation)
Yoshio Sakagami, Setsuo Takeuchi, Hiroshi Yonehara,
Heiichi Sakai and Matso Takashima, J. Antibiotics (Japan)
9A 1 (1956).
Kiyoshi Nakayama, Fukusaburo Okamoto and Yujiro
Harada, ibid. 9A 63 (1956).
Yujiro Harada, Keizo Uzu and Masaru Asai, ibid. IIA 32
(1958).
Hiroshi Yonehara and Setsuo Takeuchi, ibid. IIA 122
(1958). (Proposed structure)
Kiyoshi Watanabe, Tsutomo Tanaka, Keiko Fukuhara,
Norisama Miyairi, Hiroshi Yonehara and Hamao Umezawa,
ibid. lOA 39 (1957).
F. M. Strong, "Topics in Microbial Chemistry" (Squibb
Lectures on the Chemistry of Microbial Products), John Wiley
and Sons, Inc., New York, 1956, pp. 1-44. (A review to that
date)
135
Other Macrolides
274
Naibomycin, C^-sH^oOyN, colorless crystals,
[ai- +68.5° (c 1.35 in chloroform).
m.p. 113.5-115°,
f CH3 CH3
Desosamine
1 .OH
CH3 0
0
CH3 1
II CH
CH3
CH3
0 0
1
0 CHo
1
CH3 CH3
Streptomyces narboensis n. sp.
R. Corbaz, L. Ettlinger, E. Gaumann, W. Keller-Schierlein,
F. Kradolfer, E. Kyburz, L. Neipp, V. Prelog, P. Reusser, and
H. Zahner. Helv. Chim. Acta 38 935 (1955).
R. Anliker, D. D. Dvornik, K. Gubler, H. Heusser and V.
Prelog, ibid. 39 1785 (1956).
V. Prelog, A. M. Gold, G. Talbot and A. Zamojskl. (To be
published)
275 Leucomycin, C:i3,;^s;H54.p,jO,,_,;{N, colorless crystals, m.p. 124-
125.5°, [air,-" -67.1° (c 1 in ethanol).
Leucomycin appears to be a macrolide antibiotic*
Streptomyces kitasatoensis n. sp.
Toju Hata, Yoshimoto Sano, Natsuo Ohki, Yasuhiku Yoko-
yama, Akihiro Matsumae and Shinya Ito, /. Antibiotics (Ja-
pan) 6A 87 (1953).
Yoshimoto Sano, Tadashi Hoshi and Toju Hata, ibid. 7A
88 (1954).
Yoshimoto Sano, ibid. 7A 93 (1954).
* See addendum.
Pfizer Handbook of Microbial Metabolites
136
276 Oleandomycin (PA-105), Ca^.H^iOjoN, colorless prisms, m.p. 110'
(dec), [a]i)"^ —65° (c 1 in methanol).
Oleandrose
f CH3 CH3 1
\ /
N OCH3 _
1 OH 1 OH
Desosamine-
Xy Xy
CH3 0 0 CH3
CH3 1 CH3
CH3 ^^
CH2 .^ OH 0 \
^o^CVx °
0 1. '.. CH3
CH3 CHa
Streptomyces antibioticus
B. A. Sobin, A. R. English and W. D. Celmer, 'Antibiotics
Annual 1954-1955," Medical Encyclopedia, Inc., New York,
p. 827.
W. D. Celmer, H. Els and K. Murai, "Antibiotics Annual
1957-1958," Medical Encyclopedia, Inc., New York, p. 476.
Hans Els, Walter D. Celmer and Kotaro Murai, J. Am.
Chem. Soc. 80 3777 (1958).
W. D. Celmer, "Antibiotics Annual 1958-1959," Medical
Encyclopedia, Inc., New York, p. 277. (Biochemical correla-
tions )
F. A. Hochstein, H. Els, W. D. Celmer, B. L. Shapiro and
R. B. Woodward, /. Am. Chem. Soc. 82 3225 (1960). (Struc-
ture)
277 Erythromycin C, C;^,;H,;-,0]3N, white needles, m.p. 121-125°.
Erythromycin C differs from erythromycin only in the
neutral sugar moiety, so that the following partial struc-
ture can be written:
Desosamine
O O— C7H13O3
OH CH3
OH O O
OH
CH3 CH3 CH3
137
Other Macrolides
Streptoviyces erythreus
Paul F. Wiley, Richard Gale, C. W. Pettinga and Koert
Gerzon, /. Am. Chetn. Soc. 79 6074 (1957). (Structure and
isolation)
278 Erytliromycin B, CinHcyOj.^N, colorless crystals, m.p. 198°, [alo"^
-78° (c 2 in ethanol).
Desosamine '
Cladinose
CHs Cms CHs
Streptomyces erythreus
Paul F. Wiley, Max V. Sigal, Jr., Allidene Weaver, Rosema-
rie Monahan and Koert Gerzon, /. Am. Chem. Soc. 79 6070
(1957). (Structure)
C. W. Pettinga, W. M. Stark and F. R. Van Abeele, ibid. 76
569 (1954). (Isolation)
279 Erythromycin (Ilotycin, Erythrocin), CojHgyOiaN, white needles,
m.p. 136-140°, [aW -78° (c 1.99 in alcohol).
Desosamine"
Cladinose
Erythronolide
Streptomyces erythreus
R. K. Clark, Jr. Antibiotics and Chemotherapy 3 663
(1953). (Isolation)
Paul F. Wiley, Koert Gerzon, Edwin H. Flynn, Max V.
Sigal, Jr., Allidene Weaver, U. Carol Quarck, Robert R. Chau-
Pfizer Handbook of Microbial Metabolites
138
vette and Rosemarie Monahan, J. Am. Chem. Soc. 79 6062
(1957). (Structure)
280 PA-108, C,.isH6:hOi4N, colorless solid, m.p. 121-123°, [^W -36.8°
(c 1 in chloroform).
A macrolide antibiotic.
Streptoviyces sp.
K. Murai, B. A. Sobin, W. D. Celmer and F. W. Tanner,
Antibiotics and Chemotherapy, 9 485 (1959).
281 PA-148, C3sH6r,Oi-,N, colorless amorphous solid, m.p. 115-118°,
[a]v-^ -69.3° (c 0.5 in methanol).
A macrolide antibiotic.
Streptomyces sp.
K. Murai, B. A. Sobin, W. D. Celmer and F. W. Tanner,
Antibiotics and Chemotherapy, 9 485 (1959).
282 Carbomycin B, C4.Hf570i-,N, colorless plates, m.p. 141-144°
(dec), Hydro'chloride 164-166° (dec), [oc],,-' -35° (c 2.0
in chloroform).
CH3
OCOCH2CH(CH3)2
CH3
Isovaleryl
Mycarose
CH
Streptomyces halstedii
F. A. Hochstein and Kotaro Murai, /. Am. Chem. Soc. 76
5080 (1954). (Isolation)
R. B. Woodward, Angexv. Chem. 69 50 (1957). (Struc-
ture)
283 Carbomycin (Magnamycin), C42H(;70,,jN, colorless laths, m.p.
212-214° (dec), [aW -58.6° (c 1 in chloroform).
Carimbose
CHO CH
J /O
CH3
OCOCH2CH(CH3)2
CH3
Isovaleryl
Mycarose
OH
N(CH3)2
OCOCH3
Mycaminose
139 Other Macrolides
Streptomyces halstedii, S. alboreticuli
R. B. Woodward, Angew. Chem. 69 50 (1957). (Structure)
Richard L. Wagner, F. A. Hochstein, Kotaro Murai, N. Mes-
sina and Peter B. Regna, J. Am. Chem. Soc. 75 4684 (1953).
(Isolation)
284 Tertiomycin A, C4oH490ieN, white needles, m.p. 215-217° (s.
208") (dec.)" [a],/' -49° (c 1 in chloroform) [aW^ -47°
(c 1.0 in ethanol).
A macrolide antibiotic. Carbomycin produced also by
S. alboreticuli.
Streptomyces euroddicus, S. alboreticuli
Teisuke Osato, Masahiro Ueda, Setsuko Fukuyama, Koki
Yagishita, Yoshiro Okami and Hamao Umezawa, /. Antibiotics
(Japan) 8A 105 (1955).
285 Tertiomycin B, C4;5H7iOi7N (proposed), white needles, m.p.
97°, [a]n" -56° (c 1 in ethanol).
A macrolide antibiotic.
Streptomyces euroddicus
The same organism produces eurocidin, tertiomycin A
and azomycin.
Teisuke Osato, Koki Yagishita and Hamao Umezawa, /. An-
tibiotics (Japan) 8A 161 (1955).
Akira Miyoke, Hidesuke Iwasaki and Torao Tawewaka, J.
Antibiotics (Japan) 12A 59 (1959).
286 Foromacidin A (Spiramycin I): C4gH780i5N2, colorless powder,
m.p. 134-138°, [a]„ -81° (c 0.34 in methanol).
287 Foromacidin B (Spiramycin II): C47H;^nOi6No, colorless pow-
der, m.p. 130-132°, [a]D -83° (c 0.82 in ethanol).
288 Foromacidin C (Spiramycin III): C4,sHs20i6N2, colorless pow-
der, m.p. 124-128°, [a]D -79° (c 1.19 in ethanol).
289 Foromacidin D: Equiv. Wt. 452, colorless powder, m.p. 135—
140°, [alo -75° (c 0.81 in ethanol).
Two streptomycetes
R. Corbaz, L. Ettlinger, E. Gaumann, W. Keller-Schierlein,
F. Kradolfer, E. Kyburz, L. Neipp, V. Prelog, A. Wettstein and
H. Zahner, Helv. Chim. Acta 39 304 (1956).
The foromacidins (or spiramycins) are apparently
macrolide antibiotics. On degradation they yield three
sugars typical of this class.
Pfizer Handbook of Microbial Metabolites
140
Spiramycins
[1
II
C«H780,5N2
C47H80O16N2
C48H82O16N2
HO j"'
Neosp
i
ramycins
1:
C38H66O12N2
C40H68O,3N2 +
C41H70O13N2
OH
CHj OH
My ca rose
C7HMO4
(CHaliN
Foro(
:idins
{I
CaoHsiOuN
C32H53O12N +
C33H55O12N
CH3 OH
CsHnOzN
Raymond Paul and Serge TchelitchefF, Bull. soc. chim.
France 442, 734 (1957).
Idem., ibid., 150 (1960).
290 Tylosin, C45H-9O17N, colorless crystals, m.p. 128-132°, [ajn'"
—46° (c 2 in methanol).
A macrolide antibiotic, containing the sugars mycarose
and mycaminose. Also has an a, /?, y, 8-unsaturated car-
bonyl system.
Streptomyces fradiae
R. L. Hamill, M. E. Haney, Martha C. Stamper and Paul
Wiley, Abstr. Atlantic City Meeting, Am. Chem. Soc, Septem-
ber, 1959. (To be published)
J. M. McGuire, W. S. Boniece, W. A. Daily, C. E. Higgens,
M. M. Hoehn, W. M. Stark, W. B. Sutton, J. Westhead and
R. N. Wolfe- (To be published)
291 Angolamycin, C49_5oHs7_9iOisN, colorless crystals, m.p. 165—
168°, [aln'^ -64° (c 1.3 in chloroform).
A macrolide antibiotic apparently similar to carbomy-
cin, but with characteristic sugars.
Streptoviyces eurythermus
R. Corbaz, L. Ettlinger, E. Gaumann, W. Keller-Schierlein,
L. Neipp, V. Prelog, P. Reusser and H. Zahner, Helv. Chim.
Acta 38 1202 (1955).
292 Miamycin, colorless crystals, m.p. 221° (dec), [a]i)^^
1.0 in 0.02 N hydrochloric acid).
18° (c
^41 Other Macrolides
A macrolide antibiotic. Analysis: C 61.4, 6i;5, H 8.7
8.6. Mol. wt. ~609.
Streptomyces ambofaciens
H. Schmitz, M. Misiek, B. Heinemann, J. Lein and I. R.
Hooper, Antibiotics and Chemotherapy 7 37 (1957).
8
Alicyclic Compounds Other Than
Terpenoids and Steroids
This section contains non-terpenoid, non-steroid alicyclics of
diverse biosynthetic origin. Many of these, especially the strep-
tomycete products, were antibiotic isolates.
Included here are some of the intermediates in the biosyn-
thetic route from carbohydrates to aromatic amino acids and to
certain other aromatic compounds. Part of this sequence,
worked out largely by Tatum, Davis, Sprinson and collabora-
tors,^' -' ^ is reproduced below in brief outline only since it has
been widely reviewed and publicized. (P indicates phosphoryla-
tion ) :
CHoOP
I
c=o
HO— C— H
H— C— OH
H— C— OH
H— C— OH
CH2OP
Sedoheptulose
1, /-Diphosphate
COOH
I
C— O— P
CH.
Phosphoenol-
pyruvic Acid
+
HC=0
HC—OH
HC -OH
CH2— O— P
Erythrose
Phosphate
COOH
c=o
CH.2
HO— C— H
H— C— OH
H— C—OH
CH2-O— P
2-Keto-3-deoxy-
D-araboheptonic
Acid
^ Bernard D. Davis, Inlermediates in ammo acid biosynthesis. Ad-
vances in Enzymology 16 247-312 (1955). (A review)
^ Alton Meister, "Biochemistry of the Amino Acids," Academic
Press, Inc., New York, 1957, pp. 346-349.
■'' P. Pi. Srinivasan, Masayuki Katagiri and David B. Sprinson,
}. Biol. Chem. 2.'M 713 (1959); P. R. Srinivasan and David B. Sprin-
son, ibid. 234 716 (1959).
143
Alicylic Compounds (Non-terpenoid)
COOH
COOH"
c=o
c=o
1
CH,
1
CH,
1
HO— C— H
HO— C— H
. 1
c=o
1
-^ 1
H— C— OH
1
H— C— OH
1
1
c=o
1
CH,— O— P
1
CHj _
Aldol-like
conden- HO
sation
Dehydroquinic
Acid
i
Quinic Acid
COOH
OH
HO
Dehydroshikimic
Acid
COOH
r\/
COOH
HO
HO
3,4-Dihydroxy benzoic
Acid
Prephenic
Acid
i
COOH
r\/
CHoCOCOOH
NHo
Anthranilic
Acid
Phenyipyruvic
Acid
Phenylalanine
Tyrosine
Tryptophan
Homogentisic Acid
p-Aminobenzoic Acid
p-Hydroxybenzoic Acid
Microorganisms were the principal tools in this work, es-
pecially the mold Neiirospora crassa and the bacteria Esch-
erichia coli and Aerobacter aerogenes mutated so that the bio-
synthesis of aromatic amino acids was blocked at various points.
These mutants accumulated intermediates in the sequence prior
to the blocks, and these substances could then be isolated. Also
when such mutants (auxotrophs) were supplied with the critical
substance whose biosynthesis was blocked, the microorganisms
were capable of completing the sequence to the aromatic acids.
This route from carbohydrates to certain types of aromatic
substances has been established as quite general in metabolism.
Biosynthesis of the chlorinated cyclopentane, caldariomycin.
Pfizer Handbook of Microbial Metabolites
144
has been studied.'' ^-Ketoadipic acid and S-chlorolevulinic acid
were found to be intermediates. The sequence shown here,
then, probably represents at least part of the biogenetic scheme
for this metabolite.
COOH
I
OH CH2
I I
o=c c=o
CHo— CH2
/3-Ketoadipic Acid
5-Chlorolevulinic Acid
Caidariomycin
Palitantin appears to be an interesting example of an un-
aromatized acetate derivative. Its origin is revealed by the 14-
carbon atoms, the uneven-numbered side-chains and the pattern
of oxidation and unsaturation.
The cycloheximides also seem to be acetate derivatives, al-
though apparently no study of their biosynthesis has been pub-
lished.
Without having made a detailed analysis of the experimental
work it would seem that the proposed structures for the glau-
conic acids are unique if not improbable.
293 Caidariomycin,- CgHsOoClo, colorless needles, m.p. 121°, [a]r,46i^''
+59.2° (c 0.338 in water).
CI
CI
HCOH
I
-CH2
HOCH
CH2—
Caldariomyces fumago
* Paul D. Shaw, Jonathon R. Beckwith and Lowell P. Hager, /. Biol.
Chem. 234 2560 (1959).
145 Alicylic Compounds (Non-terpenoid)
Percival W. Clutterbuck, Sudhir L. Mukhopadhyay, Al-
bert E. Oxford and Harold Raistrick, Biochem. }. 34 664
(1940).
294 Sarkomycin, CyHsO.^, oil ( dihydro-derivative ) , m.p. 99° with sub-
limation, [a]i."'' +66.7° (in water).
COOH
Streptomyces erythrochromogenes
A yield of about 5 g. from 2 liters of broth has been
reported.
Hamao Umezawa, Tadashi Yamamato, Tomio Takeushi,
Teisuke Osato, Yashiro Okami, Seizaburo Yamaoka, Tomoharu
Okuda, Kazuo Nitta, Koki Yagishita, Ryazo Utahara and
Sumio Umezawa, Antibiotics and Chemotherapy 4 514 (1954).
(Isolation)
I. R. Hooper, L. C. Cheney, M. J. Cron, O. B. Fardlg, D. A.
Johnson, D. L. Johnson, F. M. Palermiti, H. Schmitz and
W. B. Wheatley, ibid. 5 585 (1955). (Structure)
M. M. Shemyakin, L. A. Shchukina, E. I. Vinogradova,
M. N. Kolosov, R. G. Vdovina, M. G. Karapetyan, V. Ya.
Rodionov, G. A. Ravdel, Yu. B. Shvetsov, E. M. Bamdas, E. S.
Chaman, K. M. Ermolaev and E. P. Semkin, Zhiir. Obschchei
Khim. 27 742 (1957). (Synthesis of dihydrosarkomycin)
295 Terrain, CsHioOs, m.p. 127°, [a]546i'° +185° (c 1 in water).
Aspergillus terreus Thom, Penicillium raistrickii
Harold Raistrick and Geo. Smith, Biochem. J. 29 606
(1935). (Isolation)
D. H. R. Barton and E. Miller, J. Chem. Soc, 1028 (1955).
(Structure)
Pfizer Handbook of Microbial Metabolites 146
296 5-Dehydroshikimic Acid, CyHj^Or,, colorless prisms, m.p. 150-
152°, [aju'^ -57° (in ethanol).
COOH
HO I OH
O
H
Escherichia coli mutants
Ivan I. Salamon and Bernard D. Davis, J. Am. Chem. Soc.
75 5567 (1953).
297 Shikimic Acid, C7H10O5, colorless crystals, m.p. 184°, [alc^"
-246° (in water).
COOH
Escherichia coli
Yields of about 0.5 g. per liter have been reported.
P. R. Srinivasan, Harold T. Shigeura, Milton Sprescher,
David B. Sprinson and Bernard D. Davis, /. Biol. Chem. 220
477 (1956).
298 5-Dehydroquinic Acid, C^HioOg, colorless crystals, m.p. 140-
142°.
COOH
Escherichia coli
Ulrich Weiss, Bernard D. Davis and Elizabeth S. Mingioli,
J. Am. Chem. Soc. 75 5572 (1953).
147 Alicylic Compounds (Non-terpenoid)
299 Dihydroshikimic Acid, C^Hi^O-,, colorless prisms, m.p. 135°,
[a],;--' -63° (c 10 in water).
COOH
Lactobacillus pastoriamis var. quinicus
A 96% yield was reported.
J. G. Carr, A. PoUard, G. C. Whiting and A. H. Williams,
Biochem. J. 66 283 (1957).
300 Cordycepic Acid, CyHjoOe, colorless needles, m.p. 168°, [aln'''
+6.8° (in water).
COOH
Cordyceps siriensis (Berkeley) Saccardo
The yield was 7% of the weight of the dried and de-
fatted mycelium.
R. Chatterjee, K. S. Srinivasan and P. C. Maiti, /. Am.
Pharm. Assoc. 46 114 (1957).
301 Prephenic Acid, CiyHioOe, unstable in aqueous solution, iso-
lated as the barium salt.
HOOC CH2COCOOH
Mutants of Escherichia coli and Neurospora crassa
Ulrich Weiss, Charles Gilvarg, Elizabeth S. Mingioli and
Bernard D. Davis, Science 119 774 (1954).
Pfizer Handbook of Microbial Metabolites 148
302 Frequentin, C14H20O4, colorless needles, m.p. 128°, [aln^^ +68°
(0.5 in chloroform).
Probably similar to palitantin in structure.
Penicillium freqiientans Westling, P. cyclopium
P. J. Curtis, H. G. Hemming and W. K. Smith, Nature 167
557(1951).
303 Palitantin, C14H22O4, colorless needles, m.p. 163°, [a]546i"^ +4.4°
(c 0.8 in chloroform).
O
HOCH2 II
OH
CH CH r
- \ / \ z"^-^--
CH CH
OH
CH2
/ \
CH3 CH2
Penicillium palitans Westling, P. frequentans, P. cy-
clopium
John Howard Birkinshaw and Harold Raistrick, Biochem. J.
30 801 (1936).
P. J. Curtis, H. G. Hemming and W. K. Smith, Nature 167
557 (1951).
A. Bracken, Anna Pocker and H. Raistrick, Biochem. J. 57
587 (1954).
K. Bawden, B. Lythgoe and D. J. S. Marsden, /. Chem. Soc,
1162 (1959). (Structure)
304 B-73, CigHieOoNo, colorless plates, m.p. 275°, [aln"' +3.43° (c
0.4 in dimethylformamide).
Negative ferric chloride test, non-fluorescent under U.V.
light, soluble in aqueous sodium hydroxide.
Streptomyces albulus
Non-antibiotic compound isolated from a broth contain-
ing cyclpheximide, 4-acetoxycycloheximide, C-73, and
fungicidin.
K. Rao, Abstracts, 134th Meeting of the American Chemical
Society, Chicago, September 1958.
305 C-73, C15H1-O4N, pale yellow needles, m.p. 199°, [a]i,^^ +5.06°
(c 0.4 in dimethylformamide).
Green ferric chloride test, bright yellow fluorescence in
U.V. light, soluble in sodium hydroxide solution.
Streptomyces albulus
This antibiotically inert compound was isolated from a
culture containing cycloheximide and stereoisomers, 4-
acetoxycycloheximide, fungicidin, E-73 and B-73.
149 Alicylic Compounds (Non-terpenoid)
K. Rao, Abstracts, 134th Meeting of the American Chemical
Society, Chicago, September 1958.
306 Actiphenol, C15H17O4N, colorless crystals, m.p. 199°.
An actidione-producing streptomycete (ETH 7796).
R. J. Highet and V. Prelog, Helv. Chim. Acta 42 1523
(1959).
307 Inactone, C15H21O4N, colorless needles, m.p. 116°, [cxW^ —55°
(c 2 in water).
Streptomyces griseus
Raymond Paul and Serge Tchelitcheff, Bull. soc. chim.
France 1316 (1955).
308 Cycloheximide (Actidione, Naramycin A), C15H03O4N, colorless
crystals, m.p. 119.5-121°, [aU''' -3.4° (c 9^47 in ethanol).
O
CH— CH,— ( NH
H
o
Streptomyces griseus, S. noursei
Byron E. Leach, Jared H. Ford and Alma J. Whiffen, /. Am.
Chem. Soc. 69 474 (1947).
Jared H. Ford and Byron E. Leach, ibid. 70 1223 (1948).
Pfizer Handbook of Microbial Metabolites 150
Edmund C. Kornfeld, Reuben G. Jones and Thomas V.
Parke, ibid. 71 150 (1949). (Structure)
Tomoharu Okuda, Chem. Pharm. Bull. (Japan) 7 659
(1959). (Stereochemistry)
309 Cycloheximide Diasterioisomer, Ci-,H^,304N, colorless rectangu-
lar plates, m.p. 100-105°, [a]u'' +12°.
The crystal form differed from that of cycloheximide,
and a mixture with authentic cycloheximide melted at
85-95°.
Streptomyces albidus
Cycloheximide, 4-acetoxycycloheximide, two antibioti-
cally inert compounds B-73 and C-73 and fungicidin were
isolated from the same culture.
K. Rao. Abstracts. 134th Meeting of the American Chemical
Society, Chicago, September 1958.
310 Naramycin B, Ci-,H^:^04N, colorless plates, m.p. 109°, [ajn^'^
+50.2° (c 2.0 in methanol).
0
OH
/
CH-
-CH2— / NH
\
0
Streptomyces sp.
A stereoisomer of cycloheximide.
Tomoharu Okuda, Makato Suzuki, Yoshiyuki Egawa and
Kokichi Ashino, Chem. Pharm. Bull. (Japan) 6 328 (1958).
(Isolation)
Tomoharu Okuda, ibid. 7 659 (1959). (Stereochemistry)
311 Streptovitacin A, Ci5H2sOr,N, colorless crystals, m.p. 156-159°.
OH
O
CH3 Y CH— CH2 /^
o
Streptomyces griseus
T. E. Eble, M. E. Bergy, C. M. Large, R. R. Herr and W. G.
Jackson, "Antibiotics Annual 1958-1959," Medical Encyclope-
dia, Inc., New York, p. 555. (Isolation)
151 Alicylic Compounds (Non-terpenoid)
Ross R. Herr, /. Am. Chem. Soc. 81 2595 (1959). (Struc-
ture)
312 Streptovitacin B, Ci5Ho;50-,N, colorless crystals, m.p. 124-128°.
OH
CH3
0
II
CH-
-CH
0
\
/
Y
NH
y^
\^
v
A
HO
CHs
0
Streptomyces griseiis
T. E. Eble, M. E. Bergy, C. M. Large, R. R. Herr and W. G.
Jackson, "Antibiotics Annual 1958-1959," Medical Encyclope-
dia, Inc., New York, p. 555. (Isolation)
Ross R. Herr, /. Am. Chem. Soc. 81 2595 (1959). (Struc-
ture)
313 Streptovitacin C^, Ci-,H^;^05N, colorless crystals, m.p. 91-96°.
OH
O I o
HO j CH— CH2 X
CH3 °
Streptomyces griseiis
Ross R. Herr, /. Am. Chem. Soc. 81 2595 (1959). (Struc-
ture)
314 Streptovitacin D, Ci-.H^.-^O-.N, colorless crystals, m.p. 67-69°.
A ring-hydroxylated cycloheximide of unknown struc-
ture.
Streptomyces griseus
Ross R. Herr, J. Am. Chem. Soc. 81 2595 (1959).
315 Streptimidone, Ci,;H2304N, colorless crystals, m.p. 72°.
O
CH3 CH3 O OH ^
I I II I r<
CHi^CH— C=CH— CH— C— CH2— CH— CHo— < N
H
o
A streptomycete
Pfizer Handbook of Microbial Metabolites 152
Roger P. Frohardt, Henry W. Dion, Zbigniew L. Jukabow-
ski, Albert Ryder, James C. French and Quentin R. Bartz,
/. Am. Chem. Soc. 81 5500 (1959).
E. E. Van Tamelen and V. Haarstad, J. Am. Chem. Soc. 82
2974 (1960). (Revised structure)
316 3-[2-(3,5-Dimethyl-5-acetoxy-2-oxocyclohexyl)-2-hydroxyethyl] glu-
tarimide (4-Acetoxycycloheximide, E-73), CiyHssOgN, col-
orless crystals, m.p. 140°, [<x]d~^ —8.8° (c 1.0 in methanol.)
Streptomyces alhulus
Two diastereoisomers of cycloheximide were isolated
from the same broth. Fungicidin and two unknown com-
pounds also were isolated.
Koppaka V. Rao and Walter P. Cullen, J. Am. Chem. Soc.
82 1127 (1960). (Isolation)
Koppaka V. Rao, ibid. 82 1129 (1960). (Structure)
317 Glauconic Acids.
Glauconic Acid I, CigHoyO^, colorless crystals, m.p.
202°, optically inactive.
Proposed structure:
CH3 r ' CH2CH2CH3
/ — V^"^
o o
and
Glauconic Acid II, CisHooOe, colorless crystals, m.p.
186°, optically inactive.
Proposed structure:
3
\
CH3 ^"' CH2CH2CH3
/^\
O O ?
/ \C"^
o o
153
Alicylic Compounds (Non-terpenoid)
Penicillium glaucum, P. purpurogenum
Nadine Wijkman, Ann. 485 61 (1931). (Isolation)
Kurt Kraft, ibid. 530 20 (1937). (Structure)
Matao Takashima, Akira Kitajima and Kenichi Otsuka,
Nippon Nogei-kagaku Kaishi 29 25 (1955). (Isolation from
P. purpurogenum) (Chem. Abstr. 52 20379d)
318 Fumagillin (Amebacilin, Fumidil) C26H34O7, colorless or pale
yellow crystals, m.p. 189-194° (dec), [aln"' -26.6° (c
0.25 in methanol).
CH2
O CH3
-CH— CH2— CH=C
CH3
CH3
OCH3
O
I
o=c-
Aspergillus fumigatus Fres.
J. Landquist, /. Chem. Soc, 4237 (1956).
J. McNally and D. Tarbell, /. Am. Chem. Soc. 80 3676
(1958).
D. Chapman and D. Tarbell, ibid. 80 3679 (1958).
A. Cross and D. Tarbell, ibid. 80 3682 (1958).
R. Carman, D. D. Chapman, N. J. McCorkindale, D. S.
TarbeU, F. H. L. Varino, R. L. West and D. L. Wilson, /. Am.
Chem. Soc. 81 3151 (1959).
D. S. TarbeU, R. M. Carman, D. D. Chapman, K. R. Huff-
man and N. J. McCorkindale, J. Am. Chem. Soc. 82 1005
(1960). (Structure)
T. E. Eble and F. R. Hanson, Antibiotics and Chemotherapy
1 54 (1951). (Isolation)
9
Terpenoids and Steroids
Ergosterol is the principal fungal sterol. It was named for its
occurrence in ergot, and it has been isolated from a wide variety
of other fungi as well as from lichens. It has been reported to
be the only sterol in certain molds, ^ but it is often accompanied
by related compounds. It has been identified also in algae.
Some yeasts produce several per cent of their dry cell weight in
ergosterol. Yeasts which produce large quantities of fat do not
necessarily produce a higher proportion of ergosterol.
There have been few reports of the isolation or detection of
sterols in bacteria, and there is doubt as to whether bacteria
produce sterols. A critical historical review of this question has
been published.- Mevalonic acid is an acetate-replacing factor
in lactobacilli, and a labeling study ■ with paper chromatography
and spectral work on the labeled non-saponifiable lipides showed
the presence of non-steroid, hydroxylated and unsaturated com-
pounds with more than 15 carbon atoms. It may be that sim-
pler substances of this sort replace sterols in bacteria. An
artificial requirement for vitamin D2 can be induced in some
bacteria. The resulting inhibition of growth can be reversed by
vitamins D2, D., or suprasterol, but not by 7-dehydroergosterol
nor by cholesterol.'^
Yeasts and higher fungi produce squalene and Co- to C;^! com-
pounds, some of which have been shown to be precursors of
cholesterol in mammalian metabolism. Some higher fungi and
many lichens produce triterpenes or close derivatives.
Since the availability of isotopes, which permit the tracing of
small quantities of material, much of the biosynthetic route to
Joseph V. Fiore, Arch. Biochem. 16 161 (1948).
2 Audrey Fiertel and Harold P. Klein, J. Bacteriol. 78 738 (1959).
•'* E. Kodicek, Abstracts of the Gordon Conference on Vitamins and
Metabolism, 1958.
1 55 Terpenoids and Steroids
the principal mammalian sterol, cholesterol, has been worked
out. Good reviews of this work are available.' Many of the
proved intermediates in this route have been isolated from fungi,
and evidently the biogenesis of ergosterol and the triterpenes is
quite similar to that of cholesterol up to the later stages. '
The conversion of acetate to mevalonate follows the
course : " '^'^
CHsCO— S— CoA + CHaCOCHjCO— S— CoA -^
Acetyl CoA Acetoacetyl CoA
CH3
CH3 "I
1
CoA— S— COCH2— C— CH2— COOH -^
1
OHC— CHo— C—CHo— COOH
1
OH
OH
3-Methyl-3-oxyglutaryl CoA
(Hydroxymethylglutaryl CoA,
HMG-CoA)
Mevoldic Acid
CH3
HOCHo— CH2— C— CH2— COOH
OH
Mevalonic Acid
In the light of the newer knowledge concerning the role of
malonyl CoA in fatty acid biosynthesis there may eventually be
some minor modifications in this scheme. It should be men-
tioned that mevalonic acid has been shown to be an irreversible
intermediate in the biosynthesis of terpenoids.' "• °
Isopentenyl pyrophosphate, a further intermediate in the bio-
* Louis F. Fieser and Mary Fleser, "Steroids," Reinhold Publishing
Corp., New York, 1959, pp. 403-420.
•'^ Pierre Crabbe, Record of Chemical Progress 20 189 (1959).
''J. W. Cornforth, R. H. Cornforth, A. Pelter, M. G. Horning and
G. Popjak, Tetrahedron 5 311 (1959).
^^G. E. W. Wolstenholme and Maeve O'Conner (Eds.), "CIBA
Foundation Symposium on the Biosynthesis of Terpenes and
Sterols," Harry Rudney, The biosynthesis of P-hydroxy-fi-methyl-
glutaryl coezyme A and its conversion to mevalonic acid. Little,
Brown and Co., Boston, 1959, pp. 75-94.
■ A. J. Birch, R. J. English, R. A. Massy-Westropp and Herchel
Smith, Proc. Chem. Soc, 233 (1957).
^Idem., J. Chem. Soc, 369 (1958).
^J. Fishman, E. R. H. Jones, G. Lowe and M. C. Whiting, Proc.
Chem. Soc, 127 (1959).
Pfizer Handbook of Microbial Metabolites
156
synthetic process, apparently arises from phosphorylated meva-
lonic acid by a concerted decarboxylation with elimination of
the C-3-hydroxyl group, since it has been shown that no proto-
nation of the carbon chain occurs during decarboxylation/°
CH3
HOCH2— CH2— C— CH2— COOH
I
OH
Mevalonic Acid
Mevalonic
Acid
Mevalonic
Acid
5-Monophosphate 5-Pyrophosphate
Mevalonic
Acid
3-Phosphate-
5-Pyrophosphate
00 CH3 O '
T T I ^--N II ^Q
HO— P— O— P— O— CH2— CH2— C— CH2— C— O ^
I
OH OH
OH
HO— P— O— P— OH
I i
o o
Mevalonic Acid Dipyrophosphate
00 ^ CH3
T T I
HO— P— O— P— O— CH2— CH2— C=CH2
I I
OH OH
Isopentenyl Pyrophosphate
Since both y,y-dimethylallyl pyrophosphate^^ and farnesyl
pyrophosphate^^ have been Isolated, it is possible to envisage a
continuation :
H3O6P2O— CH2
H3O6P2O
e
CH,
®<
Isopentenyl
Pyrophosphate
N
CH2— OP2O6H3
\
Dimethylallyl
Pyrophosphate
Isopentenyl
Pyrophosphate
^° A. de Waard, A. H. Phillips and Konrad Bloch, /. Am. Chem.
Soc. 81 2913 (1959).
11 B. W. Agranoff, H. Eggerer, U. Henning and F. Lynen, 7- Am.
Chem. Soc. 81 1254 (1959).
^2 F. Lynen, H. Eggerer, U. Henning and Ingrid Kessel, Angew.
Chem. 70 738 (1958).
157
Terpenoids and Steroids
CHj— OP2O6H3"
CH2— OP2O6H3
Farnesyl Pyrophosphate
Two moles of farnesyl pyrophosphate then unite head-to-head
in what, deuterium experiments indicate/^- " is probably a re-
ductive process to form squalene.* All trans-squalene is formed,
and this is the only isomer which can cyclize to triterpenes and
steroids. ^^
The significance of the stereoisomer has been considered, and
a generalized scheme devised for the various modes of cycliza-
tion of squalene, supported by the current theories of conforma-
tional analysis and ionic cyclization.^*^' "• ^®
Squalene can cyclize with no skeletal rearrangement to form
compounds such as the lichen substance, zeorin. It also can
rearrange to the lanostane skeleton found so frequently among
the steroids of the higher fungi. Lanosterol itself, a known
intermediate in the biosynthetic route to cholesterol, has been
found in yeast, as has squalene.
13 H. Rilling, T. T. Tchen and Konrad Bloch, Proc. Nat. Acad. Sci.
44 163 (1958).
'* H. C. Rilling and Konrad Bloch, }. Biol. Chem. 234 1424 (1959).
* See addendum for a recent modification of this scheme.
15 Robert G. Langdon and Konrad Bloch, ibid. 200 135 (1953).
^^ L. Ruzicka, A. Eschenmoser and H. Heusser, Experientia 9 362
(1953).
1^ A. Eschenmoser, L. Ruzicka, O. Jeger and D. Arigoni, Helv.
Chim. Acta 38 1890 (1955).
1® Alexander Todd, "Perspectives in Organic Chemistry," L. Ru-
zicka, Bedeutung der theoretischen organischen Chemie fi'ir die
Chemie der Terpenverbindungen, Interscience Publishers, Inc., New
York, 1956, pp. 265-315; L. Ruzicka, Proc. Chem. Soc, 341-360
(1959); Faraday Lecture, History of the isoprene rule.
Pfizer Handbook of Microbial Metabolites
158
It is likely that the cyclization of squalene to form such struc-
tures occurs by a concerted mechanism which proceeds from
ring to ring until complete and that this all occurs on one
enzyme surface. Thus, isolation of intermediates between
squalene and an initial cyclization product such as the one
shown is improbable. The cyclization is oxygen-initiated, ex-
plaining the frequent occurrence of the 3-hydroxyl groups in
natural steroids.
HO / \ HO
Proposed initial cyclization
product of the Squalene —>■ Lanosterol
route
Lanosterol
Transformation of the proposed tetracyclic precursor to lano-
sterol involves two 1,2-methyl group migrations (14-^ 13 and
8 ^ 14) as shown by tracer experiments." ^^
Eburicoic acid has the lanostane skeleton, but with a methyl-
ene group attached to carbon atom 24 of the side-chain. Simi-
larly, ergosterol has a methyl group in this position. Labeling
CHo
HOOC
Ergosterol
CH3 CH3
Eburicoic Acid
^'■' R. K. Maudgal, T. T. Tchen and Konrad Bloch, J. Am. Chem.
Soc. 80 2589 (1958).
159
Terpenoids and Steroids
experiments-'- -' -- ~-^ have shown that this "extra" carbon atom
is not derived from acetate, but is furnished by formate and,
more efficiently, by methionine.
Progressing along the biosynthetic route from squalene to
ergosterol (and cholesterol), it is obvious that lanosterol must
lose the two methyl groups at C-4 and one at C-14. These are
probably removed oxidatively, and eventually some of the inter-
mediates may be isolated. Zymosterol has been considered as
an intermediate in the biosynthesis of cholesterol; but while it
occurs together with ergosterol in yeasts, it has been found-** that
squalene, but not zymosterol, is converted to ergosterol by yeast
homogenates.
The biogenesis of the interesting diterpenoids gibberellic acid,
rosenonolactone and trichothecin has been studied. In the case
of gibbereUic acid-* studies with CH:^C"OOH and with C-2-la-
CH3COOH
beled m-evalonate gave the labeling pattern shown. A precursor
was inferred, and the followdng deductions made: (a) The
methyl carbon atom attached to ring A is derived specifically
from position 2 of mevalonic acid lactone, (b) The carboxyl
carbon atom is derived specifically from position 9 of the pre-
cursor, (c) The phyllocladene ring system of gibberellic acid
is formed by migration of C-6 to C-18.
Rosenonolactone, rosololactone and trichothecin are all pro-
duced by the fungus Trichothecium roseum.
2" George J. Alexander, Allen M. Gold and Erwin Schwenk, ibid. 79
2967 (1957).
21 William G. Dauben and John H. Richards, ibid. 78 5329 (1956).
2- William G. Dauben, Yoshio Ban and John H. Richards, ibid. 79
968 (1957).
2^ William G. Dauben, Gerhard J. Fonken and George A. Boswell,
ibid. 79 1000 (1957).
2* A. J. Birch, R. W. Rickards and Herchel Smith, Proc. Chem.
Soc, 192 (1958).
Pfizer Handbook of Microbial Metabolites
1 60
19 17
COOH
O^
o
CH3— CH=CH— coo
Rosenonolactone
Rosololactone
Trichothedn
The carbon skeleton of rosenonolactone'' is apparently derived
from the same kind of precursor as gibberellic acid, but in a
simpler way. All that is required is the migration of a methyl
group from C-12 to C-13 in the same manner as in the biosyn-
thesis of steroids.
The carbon skeleton of trichothecin^" can be derived from a
sesquiterpenoid intermediate by way of two 1,2-methyl group
shifts :
-O
2-C'^-Me-
valonate
Proposed sesquiter-
penoid intermediate
CH— COO
Trichothecin
319
When labeled acetate was used in this study, 95% of the
activity appeared in the crotonic acid moiety. These results,
considered together, are another confirmation of the irreversibil-
ity of the acetate-mevalonate process.
A symposium has been published thoroughly reviewing cur-
rent research on the biosynthesis of terpenes and sterols.^^
Lactaroviolin, C15H14O, red-violet crystals, m.p. 53°.
OHC
-=G. E. W. Wolstenholme and Maeve O'Conner (Eds.), "CIBA
Foundation Symposium on the Biosynthesis of Terpenes and Sterols,"
Little, Brown and Co., Boston, 1959.
i6i Terpenoids and Steroids
Lactaiius deliciosiis L.
Harry Willstaedt and B. Zetterberg, Svensk Kem. Tidskr. 58
306 (1946).
PI. A. Plattner, E. Heilbronner, R. W. Schmid. R. Sandrin
and A. Furst, Chem. and Ind., 1202 (1954). (Structure)
E. Heilbronner and R. W. Schmid, Helv. Chim. Acta 37
2018 (1954).
320 Lactarazulene, C15H16, blue liquid, b.p. 155-160° (2.5-3 mm.).
Lactariiis deliciosiis L.
Occurs together with iactaroviolin (q.v. ) and a green
321 crystalline compound, Verdazulene, C15H16, m.p. 90°.
Frantisek Sorm, Vera Benesova and Vlastimil Herout, Chem.
Listij 47 1856 (1953). (Structure)
Gibberellins and Gibberellenic Acid
Although gibberellic acid is the gibberellin produced in
highest yield by Gibberella fujikuroi, three minor gibber-
eUins are produced also, and the crude mixture is com-
monly isolated. The minor gibberellins are called A■^, A2
and A4, gibberelhc acid being A3. (It also has been called
gibberellin X.) Their structures are similar to those of
gibberellic acid.
Gibberellin A^ has been found in plants as well as in
fungi. All of the four gibberellins show plant hormone
activity. A fifth, inactive, compound called gibberellenic
acid has been isolated recently. It may be an artifact.
A structure for gibberellic acid was advanced in 1956
by an English group. Structure work has continued in
Japan, where the gibberellins were originally isolated, and
recently structures for all the gibberellins have been pub-
Ushed which differ somewhat from the one first advanced
in England. Even more recently a third set of structures,
complete with stereochemistry, has been proposed by the
English school. It is these structures which are shown
here.
Pfizer Handbook of Microbial Metabolites 162
322 Gibberellenic Acid, CjoHo^Op,, colorless crystals, m.p. 185° (dec).
Strong U.V. absorption at 253 lU/x (e = 19,200).
COOH
Fusarium moniliforme
Koert Gerzon, Harold L. Bird, Jr. and Don O. Woolf, Jr.,
Experientia 13 487 (1957).
323 Gibberellic Acid (Gibberellln A;., Gibberellln X), C19H22O6, col-
orless crystals, m.p. 235° (dec), [a]r,-" +92°.
Proposed complete stereochemical structure:
HO
P. J. Curtis and B. E. Cross, Chem. and Ind., 1066 (1954).
(Isolation)
B. E. Cross, John Frederick Grove, J. MacMillan and T. P. C.
Mulholland, Chem. and Ind., 954 (1956). (Structure)
Brian E. Cross, /. Chem. Soc, 4670 (1954).
Nobutaka Takahashi, Yasuo Seta, Hiroshi Kitamura and
Yusuke Sumiki, Bull. Agr. Chem. Soc. (Japan) 23 405 (1959).
Hiroshi Kitamura, Yasuo Seta, Nobutaka Takahashi, Akira
Kawarada_and Yusuke Sumiki, ibid. 23 408 (1959).
Yasuo Seta, Nobutaka Takahashi, Akira Kawarada, Hiroshi
Kitamura and Yusuke Sumiki, ibid. 23 412 (1959).
Nobutaka Takahashi, Yasuo Seta, Hiroshi Kitamura, Akira
Kawarada and Yusuke Sumiki, ibid. 23 493 (1959).
Yasuo Seta, Nobutaka Takahashi, Hiroshi Kitamura, Ma-
koto Takai, Sahuro Tamura and Yusuke Sumiki, ibid. 23 499
(1959).
Nobutaka Takahashi, Yasuo Seta, Hiroshi Kitamura and
Yusuke Sumiki, ibid. 23 509 (1959).
B. E. Cross, J. F. Grove, P. McCloskey and T. P. C. Mulhol-
land, Chem. and Ind., 1345 (1959); B. E. Cross, John Fred-
erick Grove, J. MacMillan, J. S. Moffatt, T. P. C. Mulholland
and J. C. Seaton, Proc. Chem. Soc, 302 (1959).
1 63
Terpenoids and Steroids
324 Gibberellin A4, C19H04O-,, colorless crystals, m.p. 222° (dec),
[a]u'° -20.8° (c 0.34 in methanol).
CH3 COOH \
Gibberella fujikuroi (Saw.) Wollenweber
Nobutaka Takahashi, Yasuo Seta, Hiroshi Kitamura and
Yusuke Sumiki, Bull. Agr. Chem. Soc. (Japan) 21 396
(1957). (Isolation of Gibberellin A,)
See other references under Gibberellin Ai for structure
work.
325 Gibberellin A^ C19H24O6, colorless crystals, m.p. 255-258°
(dec), [a]D-'+36°.
CH3 COOH \
CH2
Gibberella fujikuroi (Saw.) Wollenweber
Nobutaka Takahashi, Hiroshi Kitamura, Akira Kawarada,
Yasuo Seta, Makato Takai, Suburo Tamura and Yusuke Su-
miki, Bull. Agr. Chem. Soc. (Japan) 19 267 (1955). (Isola-
tion of gibberellins and their properties)
Nobutaka Takahashi, Yasuo Seta, Hiroshi Kitamura and
Yusuke Sumiki, ibid. 23 405 (1959).
Hiroshi Kitamura, Yasuo Seta, Nobutaka Takahashi, Akira
Kawarada and Yusuke Sumiki, ibid. 23 408 (1959). (Struc-
tures of the gibberellins)
Nobutaka Takahashi, Yasuo Seta, Hiroshi Kitamura, Akira
Kawarada and Yusuke Sumiki, ibid. 23 493 (1959). (Struc-
tures of the gibberellins).
Yasuo Seta, Nobutaka Takahashi, Hiroshi Kitamura, Ma-
kato Tokai, Saburo Tamura and Yusuke Sumiki, ibid. 23 499
(1959). (Structures of the gibberellins)
Nobutaka Takahashi, Yasuo Seta, Hiroshi Kitamura and
Yusuke Sumiki, ibid. 23 509 (1959). (Structures of the
gibberellins )
Pfizer Handbook o£ Microbial Metabolites
164
B. E. Cross, John Frederick Grove, J. MacMillan, J. S. Mof-
fatt, T. P. C. Mulholland and J. C. Seaton, Proc. Chem. Soc,
302(1959). (Above structure)
326 Gibberellin Ao, CisHoeOg, colorless crystals, m.p. 235-237°
(dec), [a]D +11.7°.
Gibberella fujikuroi (Saw.) Wollenw^eber
See references under Gibberellin Ai.
327 Trichothecin, C19H24O5, colorless needles, m.p. 118°, [cjId^
+44° (c 1.0 in chloroform).
CH2-^
X
CH3
o— c— c=c
II H H
o
Trichotheciiim roseum (Link)
G. G. Freeman and R. I. Morrison, Nature 162 30 (1948).
G. G. Freeman, J. E. Gill and W. S. Waring, J. Chem. Soc,
1105 (1959). (Structure)
J. Fishman, E. R. H. Jones, G. Lowe and M. C. Whiting,
Proc. Chem. Soc, 127 (1959). (Structure)
328 Rosenonolactone, C00H28O3, white prisms, m.p. 208°, [aln^^
— 116° (c 2.0 in chloroform).
Trichotheciiim roseum (Link)
About 6 g. of dry mycelium were obtained from a Uter
of culture solution, and from this about 0.2 g. of rosenono-
lactone was extracted.
Alexander Robertson, W. R. Smithies and Eric Tittensor, /.
Chem. Soc, 879 (1949). (Isolation)
165 Terpenoids and Steroids
Adelaide Harris, Alexander Robertson and W. B. Whalley,
ibid., 1799 (1958). (Structure)
329 9-Deoxorosenonolactone, CooH;io02, colorless crystals, m.p. 115°,
[a]D +57° (in chloroform).
Trichothecium roseum (Link)
W. B. Whalley, B. Green, D. Arigoni, J. J. Britt and Carl
Djerassi, /. Am. Chem. Soc. 81 5520 (1959).
330 Rosololactone, C00H30O3, white crystals, m.p. 186°, [ajn^^ +6.3°
(c 2.3 in chloroform).
COOH
Trichothecium roseum (Link)
Rosololactone is a minor product of this fermentation.
It occurs in the mycelium together with rosenonolactone
and mannitol.
Alexander Robertson, W. R. Smithies and Eric Tittensor, J.
Chem. Soc, 879 (1949). (Isolation)
Adelaide Harris, Alexander Robertson and W. B. Whalley,
ibid., 1807 (1958). (Structure)
331 Zymosterol, C27H44O, colorless crystals, m.p. 110°, [ajo +49°.
HO
Zymosterol is second to ergosterol in abundance in
yeast fat.
Pfizer Handbook of Microbial Metabolites i66
Ida Smedley-MacLean, Biochem. J. 22 22 (1928). (Isola-
tion)
332 Hyposterol, tentatively C27H40O or C27H44O, colorless unstable
crystals, m.p. 100-102°, [y.]u-° +12.5° (in chloroform).
Structure unknown. May be a C^s sterol.
Yeasts
Heinrich Wieland and G. A. C. Gaugh, Ann. 482 36 (1930).
133 Anasterol, C27H44O, colorless crystals, m.p. 157-159°, [a]D^^
—8.1° (in chloroform).
Structure unknown. May be a C2S sterol.
Yeasts
Heinrich Wieland and G. A. C. Gaugh, Ann. 482 36 (1930).
334 14-Dehydroergosterol, C08H42O, colorless needles, m.p. 198-
201°, [a]D -396° (in carbon tetrachloride).
^
/
HO
Aspergillus niger
Ergosterol was isolated from the same culture.
D. H. R. Barton and T. Bruun, J. Chem. Soc, 2728 (1951).
335 24(28)-Dehydroergosterol (5,7,22,24(28)-Ergostatetraen-3-^-ol),
C2SH42O, colorless crystals (Monohydrate), m.p. 118-120°,
[aln'' -78° (1% in chloroform).
Probable -structure :
HO
Yeasts
Under appropriate growth conditions, yields of this
sterol equal those of ergosterol.
1 67 Terpenoids and Steroids
O. N. Breivek, J. L. Owades and R. F. Light, J. Org. Chem.
19 1734 (1954).
336 Ergosterol, C0SH44O, colorless crystals, m.p. 165°, [a],^^ —130°
(in chloroform).
HO
Ergosterol is the most abundant sterol of yeasts and
molds. It occurs widely and was isolated first from ergot
(Claviceps purpurea) . It also occurs in lichens and has
been detected in Euglena spp. There is much literature,
one recent example being:
Akira Saito, /. Fermentation Technol. (Japan) 31 140
(1953).
Yields as high as 2-2.7% of dry cell weight have been
reported, by using Saccharomyces carlsbergensis. Ergos-
terol is reported to be the only sterol occurring in several
species of Fusaria. It occurs as the palmitate in Peni-
cillium spp. and in Aspergillus fumigatus.
Albert E. Oxford and Harold Raistrick, Biochem. J. 27 1176
(1933).
P. Wieland and V. Prelog, Helv. Chim. Acta 30 1028 (1947).
Joseph V. Flore, Arch. Biochem. 16 161 (1948).
337 Pyrocalciferol, C2SH44O, colorless needles, m.p. 93-95°, [alo^"
+502° (in alcohol).
HO
Penicillium notatum
A yield of 12 mg. was obtained from 450 g. of dry
mycelium.
Pfizer Handbook of Microbial Metabolites
1 68
A. Angeletti, G. Tappi and G. Biglino, Ann. Chim. (Rome)
42 502 (1952).
J. CasteUs, E. R. H. Jones, G. D. Meakins and R. W. J. Wil-
liams, J. Chem. Soc, 1159 (1959). (Structure)
338 Ergosta-7,22-dien-3-one, C08H44O, m.p. 184-187°, [a]u +6° (in
chloroform ) .
/^
/
Fomes fomentarius
H. R. Arthur, T. G. Halsall and R. D. Smith, /. Chem. Soc,
2603 (1958).
339 Ergosterol Peroxide, C28H44O3, colorless crystals, m.p. 178°, [ajn
-36°.
Aspergillus fumigatus (mycelium)
P. Wieland and V. Prelog, Helv. Chim. Acta 30 1028 (1947).
340 Episterol (A''^**"^''-Ergostadien-3/3-ol), CosH4qO, colorless crystals,
m.p. 150°, [(x]d —5° (in chloroform).
HO
Yeasts
1 69
Terpenoids and Steroids
Heinrich Wieland, Fridolf Rath and Horst Hesse, Ann. 548
34 (1941).
341 5,6-Dihydroergosterol (A'"--Ergostadien-3/?-ol), C2sH4(;0, color-
less crystals, m.p. 176°, [a]i)-° '^ —19° (in chloroform).
HO
Yeasts, Claviceps purpurea
Heinrich Wieland and Willi Benend, Ann. 554 1 (1943).
D. H. R. Barton and J. D. Cox, /. Chem. Soc, 1354 (1948).
342 Fecosterol (A^'^**^^*'-Ergostadien-3^-ol), C28H46O, colorless crys-
tals, m.p. 161-163°, [alo'' -f 42° (in chloroform).
C^
HO
Yeasts
Heinrich Wieland, Fridolf Rath and Horst Hesse, Ann. 548
34 (1941).
D. H. R. Barton and J. D. Cox, /. Chem. Soc, 214 (1949).
343 Ascosterol (A^^^"'-Ergostadien-3^-ol), C28H46O, colorless crystals,
m.p. 146°, [aW^ +45° (in chloro'form).
HO
Yeasts
Pfizer Handbook of Microbial Metabolites
170
Heinrich Wieland, Fridolf Rath and Horst Hesse, Ann. 548
34 (1951).
344 Cerevisterol (A' ---Ergostadiene-3;3,5a,6/3-triol), Co,sH4,.03, color-
less crystals, m.p. 256-259°, [a]n -83° (c 0.89 in pyri-
dine).
H OH
Yeasts, Claviceps purpurea (ergot), Amanita phalloides
About 10 g. were obtained from 4500 kg. of dried yeast.
Some 20 g. were obtained from 17 kg. of dry Amanita
phalloides.
Heinrich Wieland and Gustav Coutelle, Ann. 548 275
(1941). (Isolation)
G. H. Alt and D. H. R. Barton, /. Chem. Soc, 1356 (1954).
(Structure)
345 Fungisterol (A'-Ergosten-3^-ol), C^sH4sO, colorless crystals, m.p.
149°, [a]i,23 -0.2° (in chloroform).
HO
Fungisterol accompanies ergosterol in ergot, occurs in
Amanita phalloides, Penicillium. chrysogenum, Rhizopus
saponicus, Calocera viscosa, Polyporus confiuens Ft., P.
sulfureus (Bull.) Fr., Hydnum imbricatum L., Geaster
fimbriatus Fr.
Heinrich Wieland and Gustav Coutelle, Anii. 548 270
(1941). (Structure)
Akira Saito, J. Fermentation Technol. (Japan) 29 310
(1951).
lyi
Terpenoids and Steroids
346 21 -Hydroxy lanosta-7,9(ll)-24-triene-3-one, CioH^e.Oa, colorless
needles, m.p. 119-121°, [alo +56° (c 0.97 in chloroform).
HOCH
Polyporus pinicola Fr.
The derivative reduced and acetylated in the 3-position
was isolated from the same specimen as were fungisterol
and ergosta-7,22-diene-3-one.
T. G. Halsall and G. C. Sayer, }. Chem. Soc, 2031 (1959).
347 Pinicolic Acid A, C3oH4(.03, colorless needles, m.p. 197-202°,
[a]D +68° (c 0.83 in chloroform).
HOOC
Polyporus pinicola Fr.
Joyce M. Guider, T. G. Halsall and E. R. H. Jones, /. Chem.
Soc, 4471 (1954).
348 Lanosta-7,9(ll)-24-triene-3^,21-diol, C3„H4sOo, colorless needles,
m.p. 194-197°, [x]d +72° (c 1.06 in chloroform).
HOCH,
Pfizer Handbook of Microbial Metabolites
172
Polyporus pinicola Fr.
The corresponding 3-ketone was isolated from the same
specimen as well as a mixture of fungisterol and ergosta-
7,22-diene-3-one.
T. G. Halsall and G. C. Sayer, /. Chem. Soc, 2031 (1959).
349 3/3-Hydroxylanosta-8,24-diene-21-oic Acid (Trametenolic Acid
B), C30H48O3, colorless needles, m.p. 253-258°, [aU +43°
(c 0.94 in pyridine).
HOOC
Trametes odorata (Wulf. ) Fr.
Three other acids were isolated as their methyl esters
from the same specimen: Ester A; m.p. 159-165°, [ci:]d
+49°. Ester B, m.p. 152°, [ajn +66° and Ester C, m.p.
197-199°.
T. G. Halsall, R. Hodges and G. C. Sayer, J. Chem. Soc,
2036 (1959).
T. G. Halsall and E. R. H. Jones, Fortschr. Chem. org.
Naturst. 12 95 (1955). (A review)
350 3a-Oxylanosta-8,24-diene-21-oic Acid, C30H4SO3, isolated as the
methyl ester-acetate.
HOOC
Polyporus pinicola Fr.
J. J. Beereboom, H. Fazakerley and T. G. Halsall, J. Chem.
Soc, 3437 (1957).
1 73 Terpenoids and Steroids
351 Squalene, C^oH-.o, pale yellow oil with blue fluorescence, b.p.
203° (0.15 mm.), Hd^" 1.4965. Often isolated as the hy-
drogen chloride addition product.
Yeasts, Claviceps purpurea (ergot), Amanita phalloides
Squalene may constitute as much as 16% of brewers'
yeast lipide.
A. H. Cook, "The Chemistry and Biology of Yeasts," A. A.
Eddy, Aspects of the chemical composition of yeast. Academic
Press, New York, 1958, pp. 207-208.
K. Taufel, H. Thaler and H. Schreyegg, Fettchem. Umschau
43 26 (1936).
About 3 g. were obtained from 17 kg. of Amanita
phalloides.
Heinrich Wieland and Gustav Coutelle, Ann. 548 275
(1941).
Nearly 25% of the unsaponifiable fraction of the fat of
Torula utilis were found to be squalene.
R. Reichert, Helv. Chim. Acta 28 484 (1945).
352 Lanosterol (Kryptosterol, A®'^*-Lanostadien-3-ol), C30H50O, color-
less crystals, m.p. 138°, [ajn +62° (in chloroform).
Yeasts
Heinrich Wieland, Heinrich Pasedach and Albert Ballauf,
Ann. 529 68 (1937).
Pfizer Handbook of Microbial Metabolites
174
L. Ruzicka, R. Denss and O. Jeger, Helv. Chim. Acta 29 204
(1946).
W. Voser, M. V. Mijovic, H. Heusser, O. Jeger and L. Ru-
zicka, ibid. 35 2414 (1952).
353 Physarosterol, C3i,H-,.0;i, colorless crystals, m.p. 137-139°, [cxW^
—55.3° (c 0.5 in chloroform).
Probably a C3,,, unsaturated, trihydroxy sterol with one
hydroxyl group in the 3y3-position.
Pliysarum polycephaliim
This organism also produces a yellow pigment.
C. F. Emanuel, Nature 182 1234 (1958).
354 Polyporenic Acid C, C;^iH4(j04, colorless crystals, m.p. 273-276°,
[a]D +8° (in pyridine).
HOOC
Polyporus betulirms, P. benzoinus, P. pinicola
A. Bowers, T. G. Halsall and G. C. Sayer, /. Chem. Soc,
3070 (1954).
355 Agaricolic Acid, C;^,H4sO;^ (probably), colorless crystals, m.p.
226°, [or],,-" +34.4° (in pyridine).
Probably a monohydroxy triterpene acid. It occurs
together with ergosterol and eburicoic acid, agaricic acid
and other metabolites.
Polyporus officinalis
J. Valentin and S. Kniilter, Pharm. Zentralhalle 96 478
(1957).
356 Dehydrotumulosic Acid, C31H4SO4.
HOOC
175
Terpenoids and Steroids
Polyporus tumulosus Cooke, P. australiensis Wakefield,
P. betuliuus. Porta cocos
This acid has never been separated completely from its
mixture with tumulosic aicd, but the structure has been
deduced from physical measurements.
L. A. Cort, R. M. Gascoigne, J. S. E. Holker, B. J. Ralph,
Alexander Robertson and J. J. H. Simes, J. Chem. Soc, 3713
(1954).
357 Eburicoic Acid, C;,,H-,„0;., colorless crystals, m.p. 292-293°,
[a]i,'" +50° (c 1.2 in chloroform).
HOOC
Polyporus officinalis Fr., P. anthracophihis, Cooke, P.
eucalyptorum Fr., P. sulfiireiis (Bull.) Fr., P. hispidus
(Bull.) Fr., Porta cocos (Schw.) Wolf, Lentinus dacty-
loides Cleland.
The yield is 50% of the dry mycelial weight in some
cases. The S^g-acetate also occurs naturally in at least
some of these basidiomycetes.
J. S. E. Holker, A. D. G. Powell, Alexander Robertson,
J. J. H. Simes, R. S. Wright and (in part) R. M. Gascoigne, /.
Chem. Soc, 2422 (1953). (Structure)
358 Tumulosic Acid, Ci^H-.^O^, colorless fine needles, m.p. 306°
(dec), [a]„ +8.1° (c 3.30 in pyridine).
HOOC
Polyporus tumulosus Cooke, P. australiensis Wakefield,
P. betulinus Fr., Porta cocos Wolf, Porta cocos (Schw.)
Wolf (syn. Pachyma hoelen Rumph.)
Pfizer Handbook of Microbial Metabolites
176
L. A. Cort, R. M. Gascoigne, J. S. E. Holker, B. J. Ralph,
Alexander Robertson and J. J. H. Simes, /. Chem. Soc, 3713
(1954).
359 Polyporenic Acid A (Ungulinic Acid), C31H50O4, colorless nee-
dles, m.p. 199-200° (dec), [o^W +64° (c 1.28 in pyri-
dine).
COOH
HO ^
HO
Polyporus betulinus Fr.
T. G. HalsaU and R. Hodge, /. Chem. Soc, 2385 (1954).
( Structure )
360 O-Acetyleburicoic Acid, C33H50O4, colorless needles, m.p. 256—
259°, [aln'' +33.4° (in pyridine).
HOOC
CH3— C— O
Polyporus anthracophilus
R. M. Gascoigne, J. S. E. Holker, B. J. Ralph and Alexander
Robertson,-/. Chem. Soc, 2346 (1951).
F. N. Lakey and P. H. A. Strasser, ibid., 873 (1951).
(Structure)
361 Ursolic Acid (probable structure), C3(jH4).03, colorless crystals,
m.p. 291-292°, [(xU~' +72° (in 1:1 chloroform-methanol).
177
Terpenoids and Steroids
Cladonia sylvatica L. Harm., CI. impexa Harm.
This acid also occurs in animals and plants. Since
pentacyclic triterpenes are not characteristic of molds,
they may be produced by the algal partner of the symbiont
lichen.
T. W. Breaden, J. Keane and T. J. Nolan, Sci. Proc. Roy.
Dublin Soc. 23 197 (1944).
A. Ziircher, O. Jerger and L. Ruzicka, Helv. Chim. Acta 37
2145 (1954).
362 Taraxerene, CgoHjo, colorless crystals, m.p. 237°, [ajo +1° (c
0.81 in chloroform).
Cladonia deformis Hoflm.
About 15 mg. of pure hydrocarbon were obtained from
2.9 kg. of dry lichen.
Torger Bruun, Acta Chem. Scand. 8 71 (1954).
363 Friedelin, C30H50O, colorless crystals, m.p. 267-269'
(vac), [a]D -21° (c 2.34 in chloroform).
(dec.)
^Xp^
Cetraria nivalis (L.) Ach., C. islandica (L. ) Ach., C.
cucullata (Bell.) Ach., C. crispa (Ach.) Nyl., C. delisei
(Bory) Th. Fr. (syn. hiascens Fr. ), Cladonia alpestris (L.)
Rabh., Alectoria ochroleuca (Ehrh.) Nyl. and Stereocaulon
paschale (L.) Fr.
Torger Bruun, Acta Chem. Scand. 8 71 (1954).
Pfizer Handbook of Microbial Metabolites
178
364 epi-Friedelinol, CgoH-.oO, colorless crystals, m.p. 280° (vac),
[a]D +23° (c 0.52 in chloroform).
Cetraria nivalis (L.) Ach.
Torger Bruun, Acta Chem. Scand. 8 71 (1954).
365 Zeorin, C:hoH-.202, colorless crystals, m.p. 223-227°, [ajo +54^
(c 0.50 in chloroform).
366
Lecanora sordida, L. thiodes, L. epanora, L. sulfiirea,
Physcia caesia. Ph. endococcina, Anaptychia speciosa, A.
hypoleuca, Parmelia leiicotyliza, Dimelaena oreina,
Haematomma coccineum, H. leiphaemum, H. prophyrium,
Placodium saxicolum, Peltigera malacea, P. horizontalis ,
P. propagiilifera. Nephroma arcticum, N. antarcticum,
N. laevigatum, N. parile, Cladonia deformis, Coccifera
pleurota, C. helUdiflora, Urceolaria cretacea, Lepraria
latebrarum
"Elsevier's Encyclopedia of Organic Chemistry," 14 Suppl.,
Elsevier Publishing Co., London, 1952, p. 1197S. (Occur-
rence)
D. H. R. Barton and T. Bruun, /. Chem. Soc, 1683 (1952).
D. H. R. Barton, P. de Mayo and J. C. Orr, ibid., 2239
(1958).
Lcucotylin, C:^„H-,20:^, colorless prisms, m.p. 333°, [a]i.-* +49.43°,
A triterpenoid compound accompanying zeorin.
Parvielia leiicotyliza Nyl.
Yasuhiko Asahina and Hirosi Akagi, Ber. 71B 980 (1938).
J 79
Terpenoids and Steroids
367 Helvolic Acid (Fumigacin, May = Mycocidin), C;{2H420s, color-
less fine needles, m.p. 211° (dec). [oc]u-'' -124° (in chlo-
roform ) .
Tentative partial structure:
HOOC
^— CHo—
Aspergillus fuinigatus mut. helvola Yuill
Donald J. Cram and Norman L. Allinger, /. Am. Chem. Soc.
78 5275 (1956). (Structure)
E. Chain, H. W. Florey, M. A. Jennings and T. 1. Williams,
Brit. ]. Exp. Pathol. 24 108 (1943). (Isolation)
CIBA Lectures in Microbial Chemistry, E. P. Abraham,
"Biochemistry of Some Peptide and Steroid Antibiotics," The
cephalosporins, John Wiley and Sons, New York, 1957, pp.
30-63. (A review)
Cephalosporins P
These non-peptide compounds accompany cephalospo-
rins N and C in Cephalosporium salmosynnematum fer-
mentations.
TABLE I
368
369
370
371
Compound
Crystal
form
Melting
point
Wn
Molecular
formula
Cephalosporin Pi
colorless nee-
dles
147°
+ 28° (c 2.7 in
chloroform)
C32H48O8
Cephalosporin P2
151°
Cephalosporin P3
white, amor-
phous solid
Cephalosporin P4
Fawn-colored
crystals
220-230°
Cephalosporin Pj resembles helvolic acid (from Asper-
gillus fuinigatus). A complete (steroid) structure has
been determined by T. G. Halsall and associates, but has
not been published yet.
Pfizer Handbook of Microbial Metabolites i8o
H. S. Burton and E. P. Abraham, Biochem. J. 50 168
(1951). (Isolation)
H. S. Burton, E. P. Abraham and H. M. E. Cardwell, ibid.
62 171 (1956).
CIBA Lectures in Microbial Biochemistry, E. P. Abraham,
"Biochemistry of Some Peptide and Steroid Antibiotics," The
cephalosporins, John Wiley and Sons, New York, 1957, pp.
30-63. (A review)
368 Cephalosporin Pj, C32H480,s, colorless crystals, m.p. 147°, [aln^"
+28° (2.7 in chloroform).
Cephalosporium spp.
A number of similar substances, called cephalosporins
P2, P3, P4 and P5 were isolated from the same fermenta-
tion, but were not obtained in high enough yields to per-
mit much structure work.
H. S. Burton and E. P. Abraham, Biochem. J. 50 168
(1951). (Isolation)
H. S. Burton, E. P. Abraham and H. M. E. Cardwell,
Biochem. J. 62 171 (1956).
CIBA Lectures in Microbial Chemistry, E. P. Abraham,
"Biochemistry of Some Peptide and Steroid Antibiotics," The
cephalosporins, John Wiley and Sons, New York, 1957. pp.
30-63. (A review)
10
Tropolone Acids
The detailed biosynthetic origin of the tropolone acids remains
obscure. Various suggestions have been made. One of these^' ^
proposed enlargement of the aromatic ring of 3,5-dihydroxy-
phthalic acid, a known mold metabolite:
HO
COOH
CH2O
OH
COOH
HO
HOCH;
COOH
lO]
COOH
OH
HO COOH
HO
/"^X COOH
O OH
/
COOH
OH
Another^ proposed enlargement of an alicyclic ring in a Cg — C3
type of intermediate from the shikimic acid route:
CO— COOH
HOOC CH2COCOOH HOOC CH
[O] K^ [O]
lO]
10]^^[0]
[O]
IT. R. Seshadri, /. Sci. Ind. Research (India) 14B 248 (1955).
^ R. Robinson, "The Structural Relations of Natural Products,
Oxford Univ. Press, London, 1955.
3 A. J. Birch, Fortschr. Chem. org. Naturstaffe 14 186 (1957^
Pfizer Handbook of Microbial Metabolites
182
COOH
HO /
O
CO~COOH
OH
OH
Labeling studies*- °' '^ show that acetate and formate are the
primary precursors rather than glucose. Tanenbaum, Bassett
and Kaplan found that stipitatic acid isolated from a Penicillium
stipitatum culture grown on 1-C'^-glucose had an activity about
five times as great as phenylalanine or tyrosine (shikimic acid
route) isolated from the same culture. Richards and Ferretti
grew Penicilliuvi aurantio-virens on media containing (a) 1-C^*-
acetate, (b) 2-C'*-acetate and (c) 1-C'^-glucose. Puberulic acid
and puberulonic acid were isolated, separated and degraded.
Their results, in agreement with Bentley's where the same pre-
cursors were used, indicate the incorporation of formate and
acetate as follows:
OH OH
@— ^ + A -
CH3— COOH formate
HO
1=0 HO-,
/-
® COOH
Puberulic
Acid
That is, Cj, C-., C-, and C,s of the tropolones (as numbered in the
puberulonic acid structure shown) are derived from the methyl
carbon atom of acetate, while C^,, C4 and C,j are from the acetate
carboxyl group carbon atom. The C- carbon atom of the trop-
olones was shown by Bentley" to be derived from formate.
The origin of the C9 carbon atoms present in puberulonic and
* John H. Richards and Louis D. Ferretti, Biochem. and Biophys.
Res. Comms. 2 107 (1960).
5 Ronald Bentley, Biochim. et Biophys. Acta 29 666 (1958).
" S. W. Tanenbaum, E. W. Bassett and M. Kaplan, Arch. Bio-
chem. and Biophys. 81 169 (1959).
183 Tropolone Acids
stipitatonic acids remains undetermined. It, too, may arise
from formate. A study has been made" of the enzymatic de-
carboxylation of stipitatonic and puberulonic acids. A biochem-
ical relationship was concluded by way of this enzyme, and the
suggestion made that the intermediate tropolone precursors
must be at least C., compounds, and that direct closure of an
acyclic to a seven-membered ring structure must occur.
The results of Richards and Ferretti seem to leave it an open
question as to whether the tropolone ring is formed by direct
cyclization of a long-chain acyclic compound or by expansion
of a six-membered ring, and the exact nature of the interme-
diate precursors of this interesting series of mold metabolites
remains a mystery.
372 Stipitatic Acid, CsHgOs, pale yellow plates, m.p. 282° (dec).
COOH
Penicillium stipitatum Thom
J. R. Bartels-Keith, A. W. Johnson and W. I. Taylor, J.
Chem. Soc, 2352 (1951). (Synthesis)
Peter L. Pauson, Chem. Revs. 55 9 (1955). (A review of
tropolones )
373 Puberulic Acid, CsH^O,;, nearly colorless plates, m.p. 318°.
O OH
COOH
Penicillium puberulum Bainier, P. aurantio-virens
Biourge, P. cyclopium-viridicatum and P. johannioli Za-
leski
R. E. Corbett, C. H. Hassall, A. W. Johnson and A. R. Todd,
/. Chem. Soc, 1 (1950).
Ronald Bentley and Clara P. Thiessen, Nature 184 552 (1959).
Pfizer Handbook of Microbial Metabolites 1 84
374 Stipitatonic Acid, C9H4O6, yellow crystals, m.p. 237° (dec).
OH
X
\
HO
Penicillium stipitatum Thorn
W. Segal, Chem. and Ind., 1040 (1957). (Isolation)
Kozo Doi and Yoshio Kltahara, Bull. Chem. Soc. Japan 31
788 (1958). (Structure)
W. Segal, Chem. and Ind., 1726 (1958). (Corrected struc-
ture)
375 Puberulonic Acid, C9H4O7, fine yellow needles, m.p. 298° (dec).
O
HO— ((
r\.
■^c 0
II
0
Penicillium johannioli Zaleski, P. cyclopimn-viridica-
tum, P. puberulum Bainier and P. aurantio-virens Biourge
See preceding reference.
Gunhild Aulin-Erdtman, Chem. and Ind., 29 (1951).
Idem., Acta Chem. Scand. 5 301 (1951). (Structure)
376 Compound T, C10H8O4 or Ci,jHi„04, colorless crystals, m.p. 150°.
This compound shows the typical tropolone spectrum,
and it is apparently a new tropolone acid.
Penicillium stipitatum
S. W. Tanenbaum, E. W. Bassett and M. Kaplan, Arch.
Biochem. and Biophys. 81 169 (1959).
n
Phenolic Substances
a. PHENOLS AND PHENOL ETHERS (GENERAL)
Phenolic substances are commonly encountered as microor-
ganism metabolites. Besides the compounds listed in this chap-
ter phenolic moieties are present in other structures such as the
xanthones, altemariol, blastmycin, hygromycin, fulvic acid, cit-
romycetin, atrovenetin, the tetracyclines, mycobactin, anthra-
quinones and naphthoquinones. Benzoquinones are undoubt-
edly oxidation products of phenolic precursors.
Practically all of the phenolic materials in this section are
mold metabolites. Perhaps that is because more isolation work
has been done with fungi than with bacteria. It is evident that
similar compounds are produced by bacteria, since 6-methyl-
salicylic acid, a typical penicillium metabolite, also occurs as a
moiety of mycobactin from Mycobacterium phlei. Also, 2,3-
dihydroxybenzoic acid occurs as a moiety of a metabolite from
Bacillus subtilis, and 2,6-dihydroxybenzoic acid as a part of
pyoluteorin from Pseudomonas aeruginosa. It is interesting
that these bacterial phenolic acids are conjugates of nitrogen-
containing substances.
The phenolic acid production of certain cultures has been
studied in depth. Penicillium brevi-compactum, for example,
has been found to produce the following:
3,5-Dihydroxyphthalic Acid CsHgOg
l-Carboxy-2,5-dioxyphenyl Acetyl Carbinol CioHioOg
2,4-Dioxy-6-pyruvylbenzoic Acid CioHgOg
Pfizer Handbook of Microbial Metabolites i86
Mycophenolic Acid CiyHsoOg
Another investigation^ in fact found a total of 11 different
phenolic substances in a culture of this organism. In addition
to the above were found a compound Ci„Hi„07, two derivatives
of mycophenolic acid, two "intermediates between CigHio07 and
CsH(;0(." and two reduction products of CioHioOj.
The mold Penicillium griseofulvum produces:
6-Methylsalicylic Acid CsHsOo
Orsellinic Acid CsHs04
Griseofulvin CiyHi^OfjCl
Dechlorogriseofulvin Ci^HisOr,
Bromogriseofulvin CiTH^^OgBr
Gentisic Acid €711^,04
Fulvic Acid C14H12OS
Mycelianamide CooHosOriNo
Another study- found three more unidentified phenolic sub-
stances in this culture.
A Penicillium patulum culture has been found^ to produce:
Patulin C-H6O4
Gentisaldehyde C^HgOg
Gentisic Acid C7Hp,04
Gentisyl Alcohol C7HhO;^
6-Methylsalicylic Acid CsHs04
6-Formylsalicylic Acid CsHfi04
3-Hydroxyphthalic Acid CsHgOg
Pyrogallol C.jHjjO^
p-Hydroxybenzoic Acid C7H6O3
Anthranilic Acid C7H7O2N
Also an "aliphatic precursor of patulin" and a depside-like
compound were detected but not entirely characterized.
Many such families of metabolites can be assembled by ref-
erence to the microorganism index. Studies such as those
above facilitate the development of biosynthetic routes. For
example, Bassett and Tanenbaum suggest the following inter-
relationships among the Penicillium patulum phenolic metab-
olites :
1 Paul Godin, Antonie van Leeuxvenhoek J. Microbiol. Serol. 21 215
(1955).
- Paul Simonart and Renaat de Lathouwer, Zentr. Bakteriol.,
Parasitenk., Abt. II 110 339 (1957).
2 E. Bassett and S. Tanenbaum, Experientia 14 38 (1958).
i87
Phenols and Phenol Ethers (General)
Glucose
COOH
Shikimic Acid
COOH
OH
Acetate
CH3
COOH
HO !,„ OH
COOH
OH
6-MethylsalicyIic
Acid
CHO
COOH
OH ^°°" in ^°°"
Gallic Acid J p-Hydroxy- 6-Formylsalicylic 3-Oxyphthalic
benzoic Acid Acid
Acid
i
°" CHO
COOH
i
HO 1^^ OH
Pyrogallol
OH
OH
OH OH
CH2OH I CHO I COOH
OH OH OH
Gentisyl Gentisaldehyde Gentisic Acid
Alcohol
i
OH
OHC
CHO
/I
OH
Pfizer Handbook of Microbial Metabolites i88
i
OH COOH OH COOH
Thus, the acetate and shikimic acid routes to aromatic com-
pounds seem to be operating in a single microorganism.
It was a kind of statistical consideration of the structures of
natural products which led to the revival of the acetate hypothe-
sis of biogenesis as applied to substances other than fatty acids.
Phenolic compounds were particularly instrumental since
the frequent occurrence of weta-hydroxyl groups (resorcinol
and phloroglucinol types) was easy to recognize and challeng-
ing to explain. The case first was stated clearly by Collie many
years ago.* Lately Birch and others have developed a firm ex-
perimental basis for the theory by isotopic labeling and chemi-
cal degradation studies.
Some phenolic compounds which have been shown in this
way to be acetate-derived are :
6-Methylsalicylic Acid^
Griseofulvin"
Mycophenolic Acid"
Emodin^
*John Norman Collie, Proc. Chem. Soc. 23 230 (1907); idem., }.
Chem. Soc. 91 1806 (1907).
•' A. J. Birch, R. A. Massy-Westropp and C. J. Moye, Australian J.
Chem. 8 539 (1955).
^ A. J. Birch, R. A. Massy-Westropp, R. W. Rickards and Herchel
Smith, J. Chem. Soc, 360 (1958).
" A. J. Birch, R. J. English, R. A. Massy-Westropp, M. Slaytor and
Herchel Smith, ibid., 365 (1958); A. J. Birch, R. J. English, R. A.
Massy-Westropp and Herchel Smith, ibid., 369 (1958).
^ Sten Gatenbeck, Acta Chem. Scand. 12 1211 (1958).
1 89
Phenols and Phenol Ethers (General)
Auroglaucin''
Helminthosporin^°
COOH
CH3 I OH
6-Methylsalicylic
Acid
OHC
CH3(CH=CH)
CH3
Griseofulvin
CHa
CH2— CH=C
\
CHs
OH
Auroglaucin
HOOC— CH2— CH2— C=CH— CH
CH3O
Mycophenolic Acid
HO O OH
Helminthosporin
HO O OH
Emodin
Interesting details have been discovered. For example/ the
methyl group attached to the aromatic ring in mycophenolic
acid is furnished by methionine, probably at a relatively early
stage in the synthetic sequence. The methoxyl methyl group
also is furnished by methionine. The aromatic nucleus is ace-
tate-derived, while mevalonic acid was shown to be a specific
» A. J. Birch, J. Schofield and Herchel Smith, Chem. and Ind., 1321
(1958).
^° A. J. Birch, A. J. Ryan and Herchel Smith, /. Chem. Soc, 4773
(1958).
Pfizer Handbook of Microbial Metabolites i go
and irreversible intermediate for the terpenoid side-chain.
There was no incorporation of mevalonic acid into the aromatic
nucleus. Mevalonic acid also was incorporated exclusively into
the isopentene side-chain of auroglaucin.
Both bacteria and fungi are able to hydroxylate aromatic
rings, and the acetate pattern of alternate oxidation often is
confused by further oxidations of this sort.
Other details remain to be determined. The predominance
of metabolites indicating derivation from an even number of
acetate units has led to speculation concerning a four-carbon
intermediate such as acetoacetate. Even larger intermediates
have been proposed, such as orsellinic acids as precursors of
anthraquinones." So far this possibility has not been ruled out
in each case- by rigorous experimental evidence although there
is an intuitive tendency to favor the simplest and most flexible
unit and to apply the accumulated body of knowledge about in-
termediary metabolism. The co-occurrence in a natural source
of the anthraquinone and related phenanthrenequinone men-
tioned in the introduction to the section on quinones is pre-
sumptive evidence against orsellinic acid intermediates, since
the two quinone molecules appear to be formed merely by a
different mode of folding or arrangement on an enzyme surface
of the same intermediate polyketomethylene chain. On the
other hand the isolation of such orsellinic acids from isolated
fungus members of lichens incapable of completing the anthra-
quinone synthesis is interesting.
The structural relationships (some obvious, others more ob-
scure) among the mold products fulvic acid, citromycetin, fu-
sarubin, purpurogenone, etc.^- ^' argue in favor of a flexible
intermediate in the sense of a single polyketomethylene chain
that could be folded and modified in various ways to give re-
lated metabolites. Comparison of the structures of the lactone
moieties of the macrolide antibiotics with those of the tetracy-
clines (both classes of compounds produced by streptomycetes)
also seems to point to intermediates of this type. While this is
a good working hypothesis, such intermediates have not been
isolated and in fact could not long exist in the free state. Per-
haps eventually a better knowledge of enzymes will let us know
" K. Aghoramurthy and T. R. Seshadri, J. Sci. Ind. Research
(India) 13A 114 (1954).
^^ F. M. Dean, R. A. Eade, R. A. Moubasher and A. Robertson,
Nature 179 366 (1957).
"W. B. Whalley, Chem. and Ind., 131 (1958).
igi Phenols and Phenol Ethers (General)
in more detail how such acetate-derived mold metabolites are
formed, and why the chain lengths seldom exceed 14 to 18
carbon atoms.
The recent discovery and characterization of asterric acid,
a mold metabolite in which two phenolic units are joined by an
ether hnkage, have inspired the suggestion that the final phases
of its biogenetic scheme may involve a geodin-like intermediate
and sulochrin as follows:
9^^^3 OH OCH3
O I
-^-^'
HO— <v /^C— ^ \^CH
COOCH3 OH
Sulochrin
OH
COOCH3 COOH
Asterric Acid
The authors believe that the known occurrence of sulochrin
and geodin as mold metabolites supports this argument."
The transformation of sulochrin to dechlorogeodin, inciden-
tally, is an example of intramolecular phenol coupling, a phe-
nomenon discussed at greater length under Part b of this sec-
tion.
377 Pyrogallol, C,jH,;03, colorless crystals which turn brown in air,
m.p. 133°.
Penicillium patnlum
E. W. Bassett and S. W. Tanenbaum, Biochim. et Biophys.
Acta 28 247 (1958).
"R. F. Curtis, C. H. Hassall and D. W. Jones, Chem. and Ind.,
1283 (1959).
Pfizer Handbook of Microbial Metabolites 192
378 p-Methoxytetrachlorophenol (Drosophilin A), C7H4O2CI4, yellow
crystals, m.p. 118°,
Drosophila subatrata (Batsch ex Fr. ) Quel.
The yield was 100 mg. from 31 liters of culture solu-
tion.
Frederick Kavanagh, Annette Hervey and William J. Rob-
bins, Proc. Natl. Acad. Sci. U. S. 38 555 (1952).
379 p-Hydroxybenzoic Acid, CjHeOg, colorless crystals, m.p. 213°.
COOH
Penicillium patulum
E. W. Bassett and S. W. Tanenbaum, Biochim. et Biophys.
Acta 28 247 (1958).
380 Protocatechuic Acid, C7H6O4, white or tan crystalline powder
which darkens in air, m.p. —-200° (dec). Monohydrate
from water.
COOH
Phycomyces blakesleeanus (sugar substrate)
H. B. Schroter, Angew. Chem. 68 158 (1956).
381 Gentisic Acid, C7H6O4, colorless crystals, m.p. 199°.
°" COOH
193 Phenols and Phenol Ethers (General)
Penicillhim griseofulvum Dierckx, P. jenseni, P. diver-
gens
Harold Raistrick and Paul Simonart, Biochem. J. 27 628
(1933).
J. Barta and R. Mecir, Experientia 4 111 (1948).
A. Brack, Helv. Chim. Acta 30 1 (1947). (Isolation)
382 Gallic Acid, CjHgO^, colorless or pale tan crystals (Monohydrate
from water), m.p. 225-250° (dec).
COOH
Phycomyces blakesleeanus (sugar substrate)
Protocatechuic acid and another unidentified phenol
also were shown to be present by paper chromatography.
H. B. Schroter, Angew. Chem. 68 158 (1956).
383 Gentisyl Alcohol, CyHgOg, colorless crystals, m.p. 100°.
OH
CH2OH
Penicillium patulum Bainier, P. divergens Bainier and
Sartory
A. Brack, Helv. Chim. Acta 30 1 (1947). (Isolation)
B. G. Engel and W. Brzeski, ibid. 30 1472 (1947).
J. Barta and R. Mecir, Experientia 4 277 (1948).
384 2,5-Dihydroxyphenylglyoxylic Acid, CgHeOj, yellow needles, m.p.
141°.
COCOOH
Polyporus tumulosus Cooke (artificial medium)
Oxalic acid, homoprotocatechuic acid and 2,4,5-trihy-
droxyphenylglyoxylic acid are produced in the same cul-
ture.
Pfizer Handbook of Microbial Metabolites 194
Otto Neubauer and L. Flatow, Hoppe-Seyler's Zeitschrift
fiirphysiol. Chem. 52 375 (1907).
G. F. J. Moir and B. F. Ralph, Chem. and Ind., 1143 (1954).
385 3-Hydroxyphthalic Acid, CsHeO^, colorless crystals m.p. : anhy-
dride formation near 150°, melting 166°. Sublimes.
COOH
COOH
Penicillium islandicum, P. patulum
A yield of only 1-2 mg. per liter was obtained.
Sten Gatenbeck, Acta Chem. Scand. 11 555 (1957).
E. W. Bassett and S. W. Tanenbaum, Experientia 14 38
(1958).
386 3,5-Dihydroxyphthalic Acid, CgHgOg, colorless prisms, m.p, 188°
(resolidifying at 206°).
HO COOH
OH <=°°"
Penicillium brevi-compactum Dierckx
Albert E. Oxford and Harold Raistrick, Biochem. J. 26 1902
(1932). (Isolation)
John Howard Birkinshaw and Arthur Bracken, J. Chem,.
Soc, 368 (1942). (Synthesis)
387 2,4,5-Trihydroxyphenylglyoxylic Acid, CgHgOe, bright red prisms,
m.p. 193°.
O
OH II
C— COOH
Polyporus tumulosus (artificial medium)
Homoprotocatechuic acid and oxalic acid were present
in the same culture.
195 Phenols and Phenol Ethers (General)
B. J. Ralph and Alexander Robertson, /. Chem. Soc, 3380
(1950).
388 2,6-Dihydroxyacetophenone, CsHhOj, yellow needles, m.p. 154-
158°.
OH
I COCH3
OH
Daldinia concentrica
D. C. Allport and J. D. Bu'Lock, J. Chem. Soc, 654 (1960).
389 6-Methylsalicylic Acid (2,6-Cresotic Acid, 3-Hydroxy-5-toluic
Acid, 6-Hydroxy-2-methylbenzoic Acid), CgHgOy, colorless
needles, m.p. 170°.
COOH
CH3, I ,OH
Penicillium griseofulvum Dierckx, P. flexuosiim, P. pat-
ulum Bainier, P. urticae
Winston Kennay Anslow and Harold Raistrick, Biochem. J.
25 39 (1931).
E. W. Bassett and S. W. Tanenbaum, Experientia 14 38
(1958).
390 p-Hydroxyphenylacetic Acid, CgHgO^, colorless crystals, m.p.
148° (subl.).
HO—/ \— CH2COOH
Hypochnus sasakii Shirai (Corticium sasakii, Pellicu-
laria sasakii)
Ysu Shik Chen, Bull. Agr. Chem. Soc. (Japan) 22 136
(1958).
391 Homoprotocatechuic Acid, C8H8O4, colorless plates, m.p. 128.5°.
CHoCOOH
Pfizer Handbook of Microbial Metabolites 196
Polyporus tumulosus (artificial medium)
B. J. Ralph and Alexander Robertson, J. Chem. Soc, 3380
(1950).
392 Orsellinic Acid, C8H8O4, colorless crystals, m.p. ( Monohydrate )
176°.
?"^ COOH
HO OH
Penicillium griseofulvum, Chaetomium cochlioides
L. Reio, /. Chromatography 1 338 (1958).
Klaus Mosbach, Zeitschr. Naturforsch. 14b 69 (1959).
393 Compound D, CoHgO,^, cream-colored prisms, m.p. 259° (dec).
A meta diphenol with a carboxyl group para to a hy-
droxyl and an aldehyde group ortho to a hydroxyl.
Paecilomyces victoriae V. Szilvinyi
Ustic acid, dehydroustic acid and 4,6-dihydroxy-3-meth-
oxyphthalic acid were isolated from the same culture.
V. C. Vora, J. Sci. Ind. Research (India) 13B 842 (1954).
394 Flavipin, CgHgOg, pale yellow light-sensitive rods, m.p. 233°
(dec).
CHO
CHO
Aspergillus flavipes (Bainier and Sartory) Thom and
Church, A. terreus Thom
P. Rudman, "Metabolic Products of A. fiavipes, A. terreus
and Certain Other Molds," Doctoral Thesis, Univ. of London,
London, 1955.
H. Raistrick and P. Rudman, Biochem. J. 63 395 (1956).
395 4,6-Dihydroxy-3-methoxyphthalic Acid, CgHgO^, colorless prisms,
m.p. 193°.
HO COOH
OCH.^°°"
1 97 Phenols and Phenol Ethers (General)
Paecilomyces victoriae V. Szilvinyi
Ustic acid, dehydroustic acid and another incompletely
characterized phenolic acid were isolated from the same
culture.
V. C. Vora, /. Sci. Ind. Research (India) 13B 842 (1954).
396 2,3-DihydroxybenzoyIglycine, C9H9O5N, colorless needles, m.p.
210°.
HO OH_
\ / O
-C— NH— CH2— COOH
Bacillus subtilis (iron-deficient medium)
Coproporphyrin and succinic acid were also produced.
Takeru Ito and J. B. Neilands, /. Am. Chem. Soc. 80 4645
(1958).
397 8-Hydroxy-3-niethylisocoumarin, CjoHgOg, colorless needles, m.p.
99°.
O
II
HO ,C
O
Marasmius ramealis
Gerd Benz, Arkiv for Kemi 14 511 (1959).
398 2,4-Dioxy-6-pyruvylbenzoic Acid, CioHgOg, fine colorless crystals,
m.p. 125-135°.
HO
\ 00
^ ^C— C— CH3
HO COOH
Penicillium brevi-compactum (syn. P. stoloniferum
Thorn)
Percival W. Clutterbuck, Albert E. Oxford, Harold Ralstrick
and Geo. Smith, Biochem. J. 26 1441 (1932). (Isolation)
Albert E. Oxford and Harold Raistrick, ibid. 27 634 (1933).
Pfizer Handbook of Microbial Metabolites 198
399 Mellein (Ochracin), C10H10O3, colorless prisms, m.p. 58°, [a]D
-124.86° ([aW- -108.i5° in chloroform).
O
II
^CH— CH3
CH2^
Aspergillus melleus Yugawa, A. ochraceus
Eijiro Nishikawa, /. Agr. Chem. Soc. Japan 9 772 (1933).
(Isolation) (Chem. Abstr. 28 2751)
Teijiro Yabuta and Yusuke Sumiki, ibid. 9 1264 (1933).
(Isolation) (Chem. Abstr. 28 2350)
John Blair and G. T. Newbold, J. Chem. Soc, 2871 (1955).
(Structure)
It is interesting to note that a similar compound :
O
OH I
/ >
^CH— CH3
CH3O \h/
has been isolated from carrots which had developed a
bitter taste during cold storage.
Ernest Sondheimer, J. Am. Chem. Soc. 79 5036 (1957).
(Isolation")
400 3,5-Dimethyl-6-oxyphthalide, Ci^HioOg, colorless needles, m.p.
156-158°.
Penicillium gladioli
1 99 Phenols and Phenol Ethers (General)
H. Raistrick and D. J. Ross, Biochem. J. 50 635 (1952).
401 Quadrilineatin, CioHn,04, colorless needles, m.p. 172° (dec.)-
HO CHO
Aspergillus quadrilineatus Thorn and Raper
J. H. Birkinshaw, P. Chaplen and R. Lahoz-Oliver, Biochem.
J. 67 155 (1957).
402 l-Carboxy-2,5-dioxy benzyl Methyl Ketone, Ci„HioO.-,, large dia-
mond-shaped crystals, m.p. 152-156° (dec), remelting
at 220-230°.
\ O
^ \— CH2— C— CH3
HO COOH
Penicillium brevi-compactum (syn. P. stoloniferum
Thom)
Percival W. Clutterbuck, Albert E. Oxford, Harold Raistrick
and Geo. Smith, Biochem. }. 26 1441 (1932).
Albert E. Oxford and Harold Raistrick, ibid. 27 634 (1933).
403 l-Carboxy-2,5-dioxyphenyl Acetyl Carbinol, CioHjoOe, colorless
rhombs, m.p. 202-204° (dec).
"\ OH O
^ V-CH— C— CH3
HO COOH
Penicillium brevi-compactum (syn. P. stoloniferum
Thom)
Percival W. Clutterbuck, Albert E. Oxford, Harold Raistrick
and Geo. Smith, Biochem. J. 26 1441 (1932).
Pfizer Handbook of Microbial Metabolites 200
404 2,6-Dihydroxybutyrophenone, C10H12O3, yellow needles, m.p.
116.5-118°.
OH
1 COCH2CH2CH3
OH
Daldinia concentrica
D. C. Allport and J. D. Bu'Lock, /. Chem. Soc, 654 (1960).
405 Clavatol, C10H10O3, colorless plates, m.p. 183°.
°" COCH.
Aspergillus clavatus
Occurs as a minor product with patulin in this culture.
F. Bergel, A. C. Morrison, A. R. Moss and H. Rinderknecht,
J. Chem. Soc, 415 (1944). (Isolation)
C. H. Hassan and A. R. Todd, ibid., 611 (1947). (Struc-
ture)
406 Sparassol, CiuHjoO^, colorless microcrystals, m.p. 67°.
CH3
I COOCH3
HO OCH3
Sparassis ramosa, Evernia pnaiastri
John Stenhouse, Ann. 68 55 (1848).
Emil Fischer and Kurt Hoesch, ibid. 391 347 (1912).
(Structure)
Richard Falck, Ber. 56B 2555 (1923).
E. Wedekind and K. Fleischer, ibid. 56B 2556 (1923).
(Structure)
Ernst Spath and Karl Jeschki, ibid. 57A 471 (1924).
407 N-Acetyltyramine, CioHi^OoN, colorless crystals, m.p. 135° (s.
128°).
HO—/ V-CH,CH,NHCOCH3
Streptomyces griseiis (Krainski) Waksman et Henrici,
Mycobacteriiiin tuberculosis
201 Phenols and Phenol Ethers (General)
J. Comin and W. Keller-Schierlein, Helv. Chim. Acta 42
1730 (1959).
Yutaka Shirai, Kekkaku (Tuberculosis) 30 628 (1955).
(Chem. Abstr. 50 5839g)
408 Gladiolic Acid, CnHjoOg, colorless needles, m.p. 158-160°.
CHO ="°
Penicillium gladioli McCuU. and Thorn
Yield 300 mg. per liter.
Besides dihydrogladiolic acid and 3,5-dimethyl-6-oxyph-
thalide, a third "contaminant," C11H10O4 (a lactone), was
present in the culture.
John Frederick Grove, Biochem. J. 50 648 (1952). (Struc-
ture)
P. W. Brian, P. J. Curtis and H. G. Hemming, /. Gen.
Microbiol. 2 341 (1948). (Isolation)
409 Cyclopaldic Acid, CnHifjOg, colorless needles, m.p. 224° (subl.).
CHO ^"°
Penicillium cyclopium Westling
J. H. Birkinshaw, H. Raistrick, D. J. Ross and C. E. Stlck-
ings, Biochem. J. 50 610 (1952).
410 Dihydrogladiolic Acid, C11H12O5, colorless crystals, m.p. 135°
(dec).
O
°'="'COOH CH, ?="•!
o
CHO I CH
CH2OH CH2OH I
OH
Penicillium gladioli
Pfizer Handbook of Microbial Metabolites 202
H. Raistrick and D. J. Ross, Biochem. J. 50 635 (1952).
411 Cyclopolic Acid, CnHioOg, colorless plates, m.p. 147° (dec.)-
O
CH3 ?^"^ COOH CH
HO I CHO HO
CH2OH CH2OH I
Penicillium cyclopium
J. H. Birkinshaw, H. Raistrick, D. J. Ross and C. E. Stick-
ings, Biochem. J. 50 610 (1952).
412 Ustic Acid, C11H12O7, colorless crystals, m.p. 169° (dec).
°" COOH
OCH3 CH-C^H,
OH O
Aspergillus ustus, Paecilomyces victoriae, Ustilago zeae
H. Raistrick and C. E. Stickings, Biochem. }. 48 53 (1951).
Yield about 0.5 g. per liter.
V. C. Vora, /. Sci. Ind. Research (India) 13B 842 (1954).
Occurred together with dehydroustic acid, 4,5-dihy-
droxy-3-methoxyphthalic acid and a fourth compound,
C,,Hs05, m.p. 259°; an m-dihydroxyphenol with a carbonyl
group and a carboxyl group.
413 Radicinin,* CjoHioOr,, optically active crystals.
Proposed Structure:
O
O^ /
HO
CH3
I C— CH=CH2
H
O
Stemphylium radicinum
D. D. Clarke and F. F. Nord, Arch. Biochem. and Biophys.
59 269-284 (1955).
See also entry 871.
203 Phenols and Phenol Ethers (General)
414 Alternariol, Ci4Hj„0-,, colorless needles, m.p. 350° (dec.)
and
415 Alternariol Methyl Ether, CisHjoO.-,, colorless needles, m.p. 267°
(dec).
Q / OH
CH3 OH ^
The methyl ether is at one of the positions indicated.
Alternaria tenuis
The yield was about V2 g. per Uter.
H. Raistrick, C. E. Stickings and R. Thomas, Biochem. J.
55 421 (1953).
416 Altertenuol, C14H10O6, buff -colored rods, m.p. 284° (dec. and
subl.).
Forms a triacetate and a trimethyl derivative. Prob-
ably related to alternariol.
Alternaria tenuis
T. Rosett, R. H. Sankhala, C. E. Stickings, M. E. U. Taylor
and R. Thomas, Biochem. }. 67 390 (1957).
417 Sorbicillin, Ci4H|,.03, orange plates, m.p. 113° (remelting at
129°).
CH. ?" ?
"° CH,
Penicillium notatum Westhng
Donald J. Cram and Max Tishler, /. Am. Chem. Soc. 70
4238 (1948). (Isolation from Clinical Sodium Penicillin)
Donald J. Cram, ibid. 70 4240 (1948). (Structure)
Besides sorbicillin several other compounds were iso-
lated from careful investigation of a sample of early clini-
cal sodium penicillin. In view of the source it is hard to
say which of these may be considered true metabohtes.
The other compounds were:
Tiglic Acid, C.^HsOo, m.p. 63°
d-a-Methylbutyric Acid, C5H10O2 b.p. 175°, [ajn'" +15.2°
Furoic Acid, m.p. 129°
Pfizer Handbook of Microbial Metabolites 204
/5-Indole acetic Acid, m.p. 167°
Phenylacetic Acid, m.p. 76°
2-Decenedioic Acid, C10H16O4, m.p. 172°
Pigment I (/?-Penetrin), m.p. 207°.
^-Penetrin is identical with an alkaline hydrolysis prod-
uct of penetrinic acid, a metabolite of P. notatum reported
earlier
Pigment II, CioHuO,;N, orange prisms, m.p. 105°, N.E.
indicates a dicarboxylic acid. Optically inactive. Nega-
tive FeClg test. Decolorizes permanganate. Decolorized
by sodium hydrosulfite and apparently reduced to a hydro-
quinone, m.p. 129°.
Frank H. Stodola, Jacques L. Wachtel, Andrew J. Moyer
and Robert D. Coghill, J. Biol. Chem. 159 67 (1945).
418 Dehydroaltenusin, CigHiaOe, yellow needles, m.p. 189° (dec).
An acidic compound probably related to altenusin.
Alternaria tenuis
T. Rosett, R. H. Sankhala, C. E. Stickings, M. E. U. Taylor
and R. Thomas, Biochem. }. 67 390 (1957).
419 Altenusin, Ci-,Hi406, colorless prisms, m.p. 202° (dec).
An acidic compound which forms a tetramethyl deriva-
tive. Probably related to alternariol.
Alternaria tenuis
T. Rosett, R. H. Sankhala, C. E. Stickings, M. E. U. Taylor
and R. Thomas, Biochem. J. 67 390 (1957).
420 Altenuic Acid I, C15H14O8, colorless needles, m.p. 183°, second
m.p. 224-230° (dec).
A dibasic acid probably related to alternariol.
Alternaria tenuis
T. Rosett, R. H. Sankhala, C. E. Stickings, M. E. U. Taylor
and R. Thomas, Biochem. J. 67 390 (1957).
421 Altenuic Acid II, Ci-,Hi408, colorless plates, m.p. 245° (dec).
A dibasic acid probably related to alternariol.
Alternaria tenuis
T. Rosett, R. H. Sankhala, C. E. Stickings, M. E. U. Taylor
and R. Thomas, Biochem. J. 67 390 (1957).
422 Altenuic Acid III, C].,Hi40s, colorless prisms, m.p. 198-202°,
second m.p. 225° (dec).
A dibasic acid probably related to alternariol.
Alternaria tenuis
T. Rosett, R. H. Sankhala, C. E. Stickings, M. E. U. Taylor
and R. Thomas, Biochem. }. 67 390 (1957).
205 Phenols and Phenol Ethers (General)
423 Penitrinic Acid, C15H17O5N, pale yellow bars, m.p. 217-223°
(dec), [ali)-'^ —549° (in dimethylformamide).
Similar in structure to sorbicillin. The two pigments
occur together.
Penicillhnn notatum Westling
Frank H. Stodola, Jacques L. Wachtel, Andrew J. Moyer and
Robert D. Coghill, J. Biol. Chem. 159 67 (1945).
Kei Arima, Kazuo Kamagata and Hideo Nakamura, /. Agr.
Chem. Soc. Japan 27 389 (1953). (Structure work)
424 d,Z-Erdin, CigHioOyCL, yellow crystals, m.p. 210-212°.
CH3 f OCH3
' OH ^COOH
Aspergillus terreiis Thom
Erdin occurs naturally as the racemate although the
closely related geodin, which is present in the same cul-
ture, is the d-isomer.
Harold Raistrick and George Smith, Biochem. J. 30 1315
(1936). (Isolation)
D. H. R. Barton and A. I. Scott, /. Chem. Soc, 1767 (1958).
( Structure )
425 Curvularin, CieHo.jOg, colorless crystals, m.p. 206°, [ah^^ —36.3°
(c 3.8 in ethanol).
OH
O
il
C(CH2)5 — CH— CH3
/
HO CH2
Curvularia sp.
The yield was 0.40 to 0.48 g. per liter of culture broth.
A second compound CieHigO.r;, m.p. 224.5°, [ajn'^ -83°,
(also phenolic) was isolated from the same culture.
C. Calam (Imperial Chemical Industries), unpublished.
(Isolation)
O. C. Musgrave, /. Chem. Soc, 4301 (1956). (Isolation)
Pfizer Handbook of Microbial Metabolites 206
Idem., ibid., 1104 (1957).
A. J. Birch, O. C. Musgrave, R. W. Rickards and Herchel
Smith, ibid., 3146 (1959). (Structure)
426 d-Geodin, C17H12O7CI2, yellow crystals, m.p. 228-231°, [ah
+ 140° (c 0.80 in chloroform).
OH ^COOCHs
Aspergillus terreus Thorn
Harold Raistrick and George Smith, Biochem. J. 30 1315
(1936). (Isolation)
D. H. R. Barton and A. I. Scott, /. Chem. Soc, 1767 (1958).
( Structure )
427 Geodoxin, Ci^HioOsCL, yellow needles, m.p. 216° (dec).
CH3
.0;
Aspergillus terreus Thom
C. H. Hassall and T. C. McMorris, J. Chem. Soc, 2831
(1959).
428 Sulochrin, Ci^HjeO^, colorless crystals, m.p. 262°.
OCH3
JHO\
Oospora sulfurea-ochracea
Hidejiro Nichikawa, Bull. Agr. Chem. Soc. (Japan) 12 47
(1936).
Idem., J. Agr. Chem. Soc. Japan 13 1 (1937).
207 Phenols and Phenol Ethers (General)
Idem., Bull. Agr. Chem. Soc. (Japan) 16 97 (1940).
429 Geodin-like Antibiotic, yellow crystals, ni.p. 229° (subl. 175° at
3 mm.), [all.'-" +175° (in chloroform).
The chlorine-containing part of the molecule is the same
as that of geodin as shown by hydrolysis fragments. Other
chemical and physical properties are similar to those of
geodin.
Aspergillus fiavipes
Paul Delmotte, Julia Delmotte-Plaquee and Rene Bastin, /.
Pharm. Belg. 11 200 (1956).
430 Griseofulvin (Fulvicin, Grisovin) CiYHi^OfiCl, colorless crystals,
m.p. 220°, [a]„-^ +337° (c 1.0 in acetone).
OCH3O
OCH3
^>c c=o
CH3O i. CH— CH2
CH3
Penicillium griseofulvum Dierckx, P. patidum, P. cd-
bidum Sopp., P. raciborskii Zal., P. vielinii Thom, P. ur-
ticae Bain., P. raistrickii, P. janczeivski Zal. (P. nigricans
Thom and Bainier), Carpenteles brefeldianum Dodge
(Shear)
Albert Edward Oxford, Harold Raistrick and Paul Slmonart,
Biochem. J. 33 240 (1939). (Isolation)
J. C. McGowan, Trans. Brit. Mijcol. Soc. 29 188 (1946).
P. J. Curtis and J. F. Grove, Nature 160 574 (1947).
P. W. Brian, P. J. Curtis and H. G. Heming, Brit. Mycol.
Soc. Trans. 32 30 (1949).
John Frederick Grove, Doreen Ismay, J. MacMillan, T. P. C.
MulhoUand, M. A. Thorold Rogers, Chem. and Ind., 219
(1951). (Structure)
Idem., J. Chem. Soc, 3958 (1952).
John Frederick Grove, J. MacMillan, T. P. C. MulhoUand
and M. A. Thorold Rogers, ibid., 3949, 3977 (1952). (Struc-
ture)
John Frederick Grove, J. MacMillan, T. P. C. MulhoUand
and (Mrs.) J. Zealley, ibid., 3967 (1952).
T. P. C. MulhoUand, ibid., 3987, 3994 (1952).
A. J. Birch, R. A. Massy-Westropp, R. W. Rickards and
Herchel Smith, Proc. Chem. Soc, 98 (1957). (Biosynthesis)
Pfizer Handbook of Microbial Metabolites 208
431 Bromogriseofulvin, Ci7Hi706Br, colorless crystals, m.p. 204°.
O OCH3
OCH3 II I
I C C=CH
\ / \
c c=o
/ \ /
CH3O I O CH — CH2
Br I
CHs
On the proper medium bromogriseofulvin generally can
be produced by the same molds which produce griseoful-
vin.
J. MacMillan, J. Chem. Soc, 2585 (1954). (Isolation)
432 Dechlorogriseofulvin, Ci^HigOg, colorless needles, m.p. 179-
181°, [alo" +390° (c 1 in acetone).
OCH3
?'"7 C=CH
CH3O CH— CH2
CH3
Penicillium griseofulvum Dierckx, P. janczewski Zal.
J. MacMillan, Chem. and Ind., 719 (1951).
Idem., J. Chem. Soc, 1697 (1953).
D. H. R. Barton and T. Bruun, /. Chem. Soc, 603 (1953).
433 Mycophenolic Acid, C17H20O6, colorless needles, m.p. 141°.
CH3
I
HOOCCH2CH2— C=CH— CH
CH3O
_rM>0
Penicillium brevi-compactum Dierckx
C. L. Alsberg and O. F. Black, Bull. U. S. Bur. PI. Ind.,
No. 270 (1913). (Isolation)
Percival Walter Clutterbuck, Albert Edward Oxford, Harold
Raistrick and George Smith, Biochem. }. 26 1441 (1932).
209 Phenols and Phenol Ethers (General)
J. H. Birkinshaw, A. Bracken, E. N. Morgan and H. Rai-
strick, ibid. 43 216 (1948).
J. H. Birkinshaw, H. Raistrick and D. J. Ross, Biochem. J.
50 630 (1952). (Structure)
434 Xanthocillin-X, CisHioOoNo, yellow crystals, m.p. --200° (dec).
HO— /^>— CH=C C=CH— /^>— OH
N N
Penicillium notatum Westling
Xanthocillin constitutes about 70% of a mixture con-
taining a second constituent, xanthocillin-Y.
W. Rothe, Deutsche Med. Wochenschr. 79 1080 (1954).
(Isolation)
I. Hagedorn and H. Tonjes, Pharmazie 11 409 (1956).
(Structure)
Use Hagedorn, Ulrich Eholzer and Arthur Luttringhaus,
Chem. Ber. 93 1584 (1960). (Experimental work)
435 Auroglaucin, C19H22O3, orange-red crystals, m.p. 153°,
CH3
OHC °"
CH,(CH=CHI. .^
On
Aspergillus glaucus, A. mangini, other aspergilli
H. Raistrick, Robert Robinson and A. R. Todd, J. Chem. Soc,
80 (1937).
Adolfo Quilico, Cesare Cardani and Luigi Panizzi, Atti
accad. nazl. Lincei Rend., Classe sci. fis.. Mat. e nat. sci. 14 358
(1953). (Structure)
436 Flavoglaucin, C19H2SO3, pale yellow crystals, m.p. 103°.
CH3
OHC °"
CHslCHzle
Pfizer Handbook of Microbial Metabolites
2IO
Aspergillus glaucus, other aspergilli
H. Raistrick, Robert Robinson and A. R. Todd, /. Chem.
Soc, 80 (1937).
Adolfo Quilico, C. Cardani and G. Stagno d'Alcontres, Gazz.
chim. ital. 83 754 (1953). (Structure)
437 Picrolichenic Acid, Co-H.^hOy, colorless crystals, m.p. 178° (dec).
Proposed structure:
CH3O
CH3CH2CH2CH2CH2
OH
COOH
CH2CH2CH2CH2CH3
Pertusaria amara (Ach.) Nyl., Variola amara (Ach.)
The yield was 5-10 S^ of the dry weight of the lichen.
H. Erdtman and C. A. Wachtmeister, Chem. and Ind., 1042
(1957).
Carl Axel Wachtmeister, Acta Chem. Scand. 12 147 (1958).
(Structure)
438 a-Tocopherol (Vitamin E), Co^H-.^Oo^ viscous oil, b.p. 200-220°
(0.1 mm.), Ud'' 1.5045, U.V. max. 294 m/x.
HO
CHs
CH3
CH;
/^ (CHo)3— CH— (CHo)3— CH— (CHsls— CH— CHs
^O^ CH3 CH3 CH3
CH3
Identified in about a dozen varieties of chlorophyll-con-
taining bacteria by paper chromatographic comparisons.
(Not isolated.)
J. Green, S. A. Price and L. Gare, Nature 184 1339 (1959).
439 Chartreusin (Antibiotic X-465A), C;^2H320l4, greenish yellow
crystals, m.p. 184-186°, [aW^ +132° ±6° (c 0.2 in pyri-
dine).
211 Phenols and Phenol Ethers (General)
Proposed Structure:
D-Digitalose — D-Fucose
CH3
D-Digitalose
Streptomyces chartreusis and probably other Strepto-
myces spp.
Byron E. Leach, Kenneth M. Calhoun, LeRoy E. Johnson,
Charlotte M. Teeters and William G. Jackson, J. Am. Chem.
Soc. 75 4011 (1953). (Isolation)
K. M. Calhoun and L. E. Johnson, Antibiotics and Chemo-
therap7j 6 294 (1956).
Julius Berger, L. H. Sternbach, R. G. Pollock, E. R. LaSala,
S. Kaiser and M. W. Goldberg, /. Am. Chem. Soc. 80 1636
(1958).
L. H. Sternbach, S. Kaiser and M. W. Goldberg, ibid. 80
1639 (1958).
E. Simonitsch, W. Eisenhuth, O. A. Stamm and H. Schmid,
Helv. Chim. Acta 43 58 (1960). (Structure)
440 Chartreusin-like Antibiotic, C32H34O14, m.p. 186°.
A weakly acidic glucoside.
Streptomyces sp.
F. Arcamone, F. Bizioli and T. Scotti, Antibiotics and
Chemotherapy 6 283 (1956).
Pfizer Handbook of Microbial Metabolites 212
b. DEPSIDES AND DEPSIDONES
Lichens are symbiotic partnerships of fungi and algae. While
this slow-growing combination is visible without the aid of
lenses, the extractable metabolites so resemble those of micro-
organisms that they are included in this listing for comparison.
Lichens and the fruiting bodies of the higher fungi were long
used in folk medicine in the damp northern lands where they
are prominent members of the flora. It was only natural, then,
that the tool of organic chemistry was applied at an early date
in these locations to elucidate the structures of their metabolites.
Thus, historically, a large body of knowledge on such structures
existed long before systematic work was begun on the fungi and
streptomycetes, which have been so much more rewarding to
modem medicine.
Depsides, e.g. microphyllic acid and olivetoric acid, frequently
contain aliphatic side-chains attached to their phenolic rings.
The fact that these invariably consisted of an uneven number
of carbon atoms was soon recognized and used as a rule in
structure determinations. It was considered a curious phenom-
enon until it became apparent that such molecules are particu-
larly obvious examples of derivation from acetate.
Certain lichen metabolites, for example some of the anthra-
quinone pigments, have been found also in fungi. Moreover,
some of the fungal partners have been isolated from lichens and
grown alone in pure culture. In a few such cases the same
metabolites have been isolated which are produced by the part-
nership itself . Examples are the anthraquinones phy scion (pa-
rietin) and rhodocladonic acid, the dibenzofurans usnic and
didymic acids, as well as pulvic anhydride (stictaurin) and
the nidulins.^ - *
In contrast there is evidence that depsides and depsidones
cannot be produced by the isolated fungus partner, but are the
unique products of a collaborative effort.* In the work just
cited it was found that the fungal components of various cla-
^ E. Thomas, Beitr. 2. Kryptogamenfiora der Schweiz 9 1 (1939).
-Hempstead Castle and Flora Kubsch, Arch. Biochem. 23 158
(1949).
^ F. M. Dean, A. D. T. Erni and Alexander Robertson, /. Chem.
Soc, 3545 (1956).
* Dieter Hess, Z. Naturforsch. 14b 345 (1959).
213
Depsides and Depsidones
donia, parmelia and placodium species, grown alone in pure
culture, produced no depsides nor depsidones. Orsellinic and
COOH
R=H=Orsellinic Acid
R^CHO=Haematommic Acid
haematommic acids, simpler moieties which could not be shown
to be present as such in the parent lichens, were isolated. This
could indicate that these phenols are precursors, and that the
algae are necessary to effect coupling as well as final, charac-
teristic modifications. It is interesting that orsellinic acid (q.v. )
has been isolated recently from other fungus cultures. Phenolic
acids of this sort are obviously acetate-derived.
Depsidones probably are formed by phenol coupling of the
depsides. Phenol coupling (phenol dehydrogenation) is un-
doubtedly a widespread phenomenon among natural products.
It involves the removal of one electron from the phenol with
formation of a phenol-free radical. Such radicals are relatively
stable due to the resonance possibilities. In complex natural
products such phenol radicals can form new bonds by intra-
molecular attack. Thus the formation of a depsidone (in this
case protocetraric acid) from a depside might be represented
as follows:
COOH
COOH
COOH
Another example of intramolecular carbon-oxygen coupling was
noted earlier in this chapter in the formation of the geodin,
griseofulvin type of skeleton.
Carbon-carbon bonds can be formed similarly (by coupling
Pfizer Handbook of Microbial Metabolites 214
of the ortho and para resonance isomers of the phenol-free
radical). Biphenyl, binaphthyl and fois-anthraquinone skele-
tons might be formed in this way.
A combination of the two types of bond formation (i.e. first
an intermolecular carbon-carbon coupling followed by an intra-
molecular oxygen-carbon coupling) probably occurs in the bio-
synthesis of compounds such as the dibenzofurans, etc.
More thorough considerations of phenol coupling as a bio-
synthetic process have been published. ' ''
In vitro couplings of phenolic compounds have been accom-
plished in the laboratory, by using simple electron acceptors
such as molecular oxygen or ferric chloride, and natural prod-
ucts have been prepared in this way. Yields under such condi-
tions are generally low, and the orienting influence of the en-
zyme surface seems to be required for real efficiency.
Referencing of this section is lean because of the very thor-
ough existing work.' In general the final structure determina-
tion or synthesis is mentioned.
441 Diploicin, C16H10O5CI4, colorless crystals, m.p. 232°.
^' OCH.
CI '-' CH3
Buellia canescens (Dicks.) DeNot.
Thomas J. Nolan, Joseph Algara, Eugene P. McCann, Wm.
A. Manahan and Niall Nolan, Sci. Proc. Roy. Dublin Soc. 24
319 (1948).
442 Variolaric Acid (Ochrolechaic Acid, Parellic Acid), C16H10O7,
colorless crystals, m.p. 296°.
OH
^D. H. R. Barton and T. Cohen, Festschrift Arthur Stoll, 111
(1957).
** Holger Erdtman and Carl Axel Wachmeister, ibid., 144 (1957).
" Yasuhlko Asahina and Shoji Shibata, "Chemistry of Lichen Sub-
stances," Japan Society for the Promotion of Science, Tokyo, 1954.
(In English)
215 Depsides and Depsidones
Lecanora parella Ach.
The yield was about 1 ^^ . Mannitol also was present.
D. Murphy, J. Keane and T. J. Nolan, Sci. Proc. Roy. Dublin
Soc. 23 71 (1943).
443 Lecanoric Acid (Glabratic Acid), C16H14O7, colorless needles,
m.p. 175°.
O
CH
C— O OH
HO OH ! COOH
CH3
Parmelia tinctorum Despr., P. horreri Turm., P. scortea
Ach. and P. latissima Fee.
Emil Fischer and Hermann O. L. Fischer, Ber. 46 1138
(1913). (Synthesis)
444 Diploschistesic Acid, C^Hi^Os, colorless leaflets, m.p. 174°.
CH3
CH. ^°°"
Diploschistes scruposus (L.) and D. bryophilus (Ehrh.)
Lecanoric acid was isolated from the same source.
Yasuhiko Asahina and Masaichi Yasue, Ber. 69B 2327
(1936). (Synthesis)
445 Vicanicin, C17H14O5CI2, colorless needles, m.p. 248-250°.
O
CH,
CI
Teloschistes flavicans
A yield of about 1% of the dry lichen weight was ob-
tained.
Pfizer Handbook of Microbial Metabolites
216
S. Neelakantan, T. R. Seshadri and S. S. Subramanian,
Tetrahedron Letters No. 9, pp. 1-4 (1959).
446 Evemic Acid, C17H16O7, colorless prisms, m.p. 169°.
CH3
CH3O
COOH
Evernia prunastri L., Ramalina pollinaria Wests., Us-
nea jesoensis Asahina
Fukuziro Fuzikawa and Kumao Ishiguro, /. Pharm. Soc.
Japan 56 837 (in German, 149) (1936). (Synthesis)
447 Norstictic Acid, CigHigOg, nearly colorless needles, m.p. 283°
(dec).
COO
CH3
CHO O
OH
CO
CH— O
OH
Lobaria pulmonaria Hoffm., Parmelia acetabulum
Duby., Usnea japonica, Wain., etc.
Yasuhiko Asahina and Masaichi Yanagita, Ber. 67B 799
(1934). "
448 Salazinic Acid (Saxatilic Acid), CigHioOio, colorless needles,
m.p. 260° (dec. from 240°).
ru CH2OH
^"^ COO I OH
"° ino^o/
xo
CH — O
I
OH
217 Depsides and Depsidones
Parmelia cetrata Ach., P. conspersa Ach., P. marmariza
Nyl., P. saxatilis Ach., P. abyssinica Kremp.
Yasuhiko Asahina and Juntaro Asano, Ber. 66B 689, 893,
1215 (1933).
449 Gangaleoidin, C1SH14O7CI2, colorless needles, m.p. 213°.
^"^ OCH3
COOCH3
Lecanora gangaleoides Nyl.
V. E. Davidson, J. Keane and T. J. Nolan, Sci. Proc. Roy.
Dublin Soc. 23 143 (1943). (Structure)
450 Psoromic Acid (Sulcatic Acid, Parelllc Acid), C18H14O8, colorless
needles, m.p. 265°.
COO
CHO '^ COOH
Psoroma crassum Korber, Alectoria zopfii Asahina, etc.
Syozi Shibata, /. Pharm.. Soc. Japan 59 323 (in German,
111) (1939). (Synthesis)
451 Protocetraric Acid (Capraric Acid, Ramalinic Acid), C18H14O9,
colorless fine needles, m.p. 250° (dec. from 220°).
CH3 ^^^ CH2OH
COO I OH
CH3 ^°°"
Parmelia caperata, Ramalina farinacea, etc.
Yasuhiko Asahina and Yaichiru Tanase, Ber. 66B 700
(1933).
Yasuhiko Asahina and Juntaro Asano, ibid. 66B 893, 1215
(1933).
Pfizer Handbook of Microbial Metabolites 218
452 Barbatolic Acid, C18H14O10, colorless crystals, m.p. 206° (dec.)
(s. 190°).
COOCH2 I OH
OH ^"°
Usnea barbata, Alectoria implexa (Hoffm ) Nyl. f. fus-
cidula Am.
Eero E. Suominen, Suomen Kemistileht; 12B 26 (1939).
453 Pannarin, CisHi.PeCl, colorless prisms, m.p. 216°.
Q ^"'
CH,0 i.. \n/ 1„ CHO
On
Pannaria lanuginosa Korb., P. fulvescens Nyl., P. lurida
Nyl.
Itiro Yosioka, /. Pharm. Soc. Japan 61 332 (1941).
454 Obtusatic Acid (Ramalic Acid), C^gHisO^, colorless needles,
m.p. 208° (dec).
CH3O 1.. OH 1^ COOH
CHs
Ramalina pollineria Ach. other Ramalina species
Evemic acid, usnic acid and sometimes sekikaic acid
were isolated from the same sources.
Fukuziro Fuzikawa, J. Pharm. Soc. Japan 56 237 (in Ger-
man, 25) (1936). (Synthesis)
219
Depsides and Depsidones
455 Stictic Acid (Stictaic Acid, Pseudopsoromic Acid, Scopularic
Acid), CiaHi^Ofl, colorless microcrystals, m.p. 268° (dec).
Lobaria pulmonaria Hoffm., L. oregana Miill. Arg.,
Stereocaiilon nabewariense Zahlb., etc.
Yasuhiko Asahina and Masai ti Yanagita, Ber. 67B 1965
(1934).
456 Nornidulin (Ustin), Ci^Hi-O^Cla, hexagonal plates or prisms,
m.p. 185°.
Aspergillus nidulans, NRRL No. 2006
A little succinic acid was isolated from the same cul-
ture.
F. M. Dean, John C. Roberts and Alexander Robertson, /.
Chem. Soc, 1432 (1954).
457 Dechloronornidulin (Ustin II), CigHieOjCL, needles, m.p. 212-
214°.
Partial structure:
Pfizer Handbook of Microbial Metabolites 220
Aspergillus nidulans NRRL No. 2006
F. M. Dean, A. D. T. Erni and Alexander Robertson, /.
Chem. Soc, 3545 (1956).
458 Thamnolic Acid, CigHigOn, pale yellow crystals, m.p. 223°
(dec).
^"' COO. ^"^ COOH
CH3O I OH HO
COOH
Thamnolia vermicularis (Sw.) Schaer., Cladonia poly-
dactyla Flk., CI. digitata, other Cladonia, Parmeliopsis
and Pertusaria spp.
Yasuhiko Asahlna and Michio Hiraiwa, Ber. 69B 330
(1936).
Idem., ibid. 72 1402 (1939).
459 Chloroatranorin, CigHi^OsCl, colorless crystals, m.p. 208°.
CH3
Parmelia furfuracea Ach., P. physodes Ach., Evernia
prunastri, etc., wide occurrence
Georg Roller and Karl Popl, Monatsh. 64 106 (1934).
Idem. f ibid. 64 126 (1934).
460 Atranorin (Atranoric Acid, Usnarin, ParmeHn), CigHigOg, color-
less prisms, m.p. 196°.
^"' coo
Atranorin occurs in about 90 different lichens.
d-Usnic acid also often is present.
221 Depsides and Depsidones
Alexander St. Pfau, Helv. Chim. Acta 9 650 (1926).
461 Baeomycesic Acid, CigHigOs, colorless crystals, m.p. 233°.
CHa
Baeomyces roseus Pers., JB. fungoides Ach., Thamnolia
subverniicularis Asahina
Squamatic acid also was present in some cases.
Georg KoUer and Walter Maass, Monatsh. 66 57 (1935).
462 Squamatic Acid (Sphaerophoric Acid), CigHjgOg, colorless crys-
tals, m.p. 228° (dec).
CHaO
Cladonia bellidifiora var. coccocephala Ach., CI. squa-
mosa Hoffm., CI. uncialis (L. ) Web., Thamnolia sub-
vermiciilaris Asahina
A little ^usnic acid was present also.
Yasuhiko Asahina and Yoshio Sakurai, Ber. 70B 64 (1937).
( Synthesis )
463 Hypothamnolic Acid, CigHigOjo, colorless needles, m.p. 217.5'^
COOH
CHs /COO\ 9*^3
/
CH3O ' ^^OH HO
COOH
Cladonia pseudostellata Asahina
The yield was about 0.1%. Usnic acid was present
also.
Yasuhiko Asahina, Masaru Aoki and Fukuziro Fuzikawa,
Ber. 74B 824 (1941).
Pfizer Handbook of Microbial Metabolites 222
464 Barbatic Acid (Rhizoic Acid, Coccellic Acid), C19H20O7, colorless
prisms, m.p. 187° (dec.)-
CH3O I OH I COOH
Cladonia fioerkeana Sommerf., CI. bacillaris Nyl., CI.
macilenta (Hoff. ) Flk., CI. coccifera (L. ), CI. amauro-
craea (Fl.) Schaer., Rhizocarpon geographicum (L.), Us-
nea longissima Ach.
Usnic acid also was present.
Fukuziro Fuzikawa, /. Pharm. Soc. Japan 56 237 (in Ger-
man, 25) (1936). (Synthesis)
465 Physodalic Acid (Monoacetylprotocetraric Acid), CooHjeOio, col-
orless plates, m.p. 260° (dec. from 230°).
CH3 ^^^ CH.OCOCH3
COO I OH
HO I \r,/ i COOH
CHO O
Parmelia physodes Ach., P. hypotrypella Asahina
Wilhelm Zopf, Ann. 295 287 (1897).
Idem., ibid. 300 350 (1898).
466 Nidulin, CooHi^O.-.CL^, colorless crystals, m.p. 180°.
O
... II
CI T c— o I 0CH3
CsH,
Aspergillus nidulans NRRL, No. 2006
The yield was about 6 g. from 126 g. of dry mycelium;
a little mannitol also was found.
F. M. Dean, John C. Roberts and Alexander Robertson, J.
Chem. Soc, 1432 (1954).
223 Depsides and Depsidones
467 Diffractaic Acid (Dirhizonic Acid), C00H00O7, colorless needles,
m.p. 189°.
CH3O \ OCH3 i COOH
CH3
Usnea diffracta Wain., Usnea longissima Ach., Alecto-
ria ochroleuca Mass.
The yield was 3.6%.
Yasuhiko Asahina and Fukuziro Fuzikawa, Ber. 65B 583
(1932). (Synthesis)
468 Erythrin, CmuHooOj,, colorless needles, m.p. 148°, [ocW^ +10.63°.
?"^ COO OH
HO OH 1 COOCH2— CH— CH— CH2
CHii I I I
OH OH OH
Roccella montagnei Bel. and R. fuciformis DC
This is an erythritol ester of lecanoric acid. The yield
was about 5% of the weight of the lichen. Free erythritol
and rocellic acid were isolated from the same source.
Yosio Sakurai, 7. Pharni. Soc. Japan 61 108 (in German,
45) (1941).
469 Divaricatic Acid, C21H04O7, colorless needles, m.p. 137°.
CH3CH2H,C
CH3O OH I COOH
CH2CH2CH3
Evernia divaricata L., E. mesomorpha f. esorediosa
Miill., Arg.
The yield from E. mesomorpha was recorded as 2.5%
of the lichen weight. Usnic acid was isolated from the
same source.
Pfizer Handbook of Microbial Metabolites 224
Yasuhiko Asahina and Michio Hiraiwa, Ber. 70B 1826
(1937). (Synthesis)
470 Fumarprotocetraric Acid, C22H16O12, colorless needles, m.p. 250—
260° (dec. from 230°).
CH3 , CH2OOC— CH=CH— COOH
COO I OH
Cetraria islandica Ach., Cladonia rangiferina (L. )
Web., CI. sylvatica (L.) Hoffm.
Yasuhiko Asahina and Yaichiro Tanase, Ber. 67B 766
(1934).
471 Sekikaic Acid, C22H26O8, colorless needles, m.p. 147° (dec).
CH3CH2CH2 .COO. OH ^^^,.
\ I COOH
CH3O OH CH3O CH2CH2CH3
Ramalina geniculata Hook et Tayl., R. calicaris Rohl,
and R. intermediella Wain.
The yield was about 1 % . A little d-usnic acid also was
present as well as ramalinolic acid.
Yasuhiko Asahina and Masaichi Yasue, Ber. 68B 132
(1935). (Synthesis)
472 Sphaerophorin, C23H28O7, colorless crystals, m.p. 137°.
CH3
CH3O OH I COOH
CHoCHoCH^CHoCHoCHiCHs
Sphaerophorus fragilis Pers., S. coralloides Pers., S. mel-
anocarpus
225 Depsides and Depsidones
Akira Hasimoto, /. Pharm. Soc. Japan 58 776 (in German,
221) (1938). (Synthesis)
473 Imbricaric Acid, C23H28O7, colorless needles, m.p. 125°.
CH3CH2CH2CH2H2C
CH3O OH I COOH
CH2CH2CH3
Parmelia perlata Ach., Cladonia impexa Harm., CI.
evansi f. Abb., CI. pseudoevansi Asahina
Yasuhiko Asahina and Itiro Yoshioka, Ber. 70B 1823
(1937). (Synthesis)
474 Ramalinolic Acid, CogHogOy, colorless crystals, m.p. 163°.
CH,CH,CH, cOO^ OH ^^^^
CH3O OH HO CH2CH2CH2CH2CH3
Ramalina intermediella Wain., R. calicaris Rohl, R. ge-
niculata Hook et Tayl. and R. usneoides Mont.
Yasuhiko Asahina and Tunaharu Kusaka, Ber. 69B 1896
(1936). (Synthesis)
475 Gyrophoric Acid, C24H20O10, colorless needles, m.p. 220°.
^"^ COO OH ^"^ COOH
HO OH
Gyrophora esculenta Miyoshi, G. proboscidea L., Um-
bilicaria pustulata L. Hoffm. Ochrolechia pallescens, Lo-
baria pulmonaria var. meridionalis (Wain.) Zahlbr.
Yasuhiko Asahina and Itiro Yasioka, Ber. 70B 200 (1937).
(Synthesis)
Pfizer Handbook of Microbial Metabolites 226
476 Hiascic Acid, C24H20OH, colorless crystals, m.p. 190.5° (dec.)-
CH3
COOH
Cetraria hiascens Th. Fr.
Gyrophoric acid also was present.
Yasuhiko Asahina and Tunaharu Kusaka, Bull. Chem. Soc.
Japan 17 152 (in German) (1942).
477 Anziaic Acid, C04H30O7, colorless, fine needles, m.p. 124° (dec).
CHsCH-CHoCHoHoC
COOH
CH2CH2CH.2CH2CH3
Anzia opuntiella Miill. Arg., A. gracilis, A. leucobatoides
f. hypomelaena and Cetraria sanguinea
Yasuhiko Asahina and Michio Hiraiwa, Ber. 70B 1826
(1937). (Synthesis)
478 Homosekikaic Acid (Nemoxynic Acid), C24H30O8, colorless
prisms, m.p. 137.5°.
CH3CH2CH2 .COO,
COOH
CH3O OH CH3O CH2CH2CH2CH2CH3
Cladonia pityrea Flk. f. phyllophora Mudd, Cladonia
nemoxyna (Ach.) Nyl.
The yield was about 0.1%. A little fumarprotocetraric
acid also was present.
Yasuhiko Asahina and Tsunakaru Kusaka, Ber. 70B 1815
(1937). (Synthesis)
227 Depsides and Depsidones
479 Umbilicaric Acid, Co-.HooO,,,, colorless crystals, m.p. 203° (dec.)-
Synthetic sample m.p. 189°.
COOH
Gyrophora polyphylla (L.), G. deiista (L.) and G. vel-
lea (L. )
Yasuhiko Asahina and Itiro Yosioka, Ber. 70B 200 (1937).
(Synthesis)
480 Lobaric Acid ( Stereocaulic Acid, Usnetic Acid), Co.-.HofiOs;, color-
less needles, m.p. 192°.
CH3CH0CH0CH0CO ^^^
I COO OH
CH3O v,/ i ^°o"
CHoCHoCHoCHaCHs
Stereocaulon paschale Ach., S. exutum Nyl., etc. (wide
occurrence )
Yasuhiko Asahina and Masaiti Yasue, Ber. 69B 643 (1936).
481 Glomelliferic Acid, Co-.H^oOs, colorless prisms, m.p. 143°.
CH3CH2CH2COH2C
CH3O OH I XOOH
CH2CH2CHCH2CH3
Parmelia glomellifera Nyl.
W. Zopf, Ann. 297 303 (1897), 313 341 (1900).
Yasuhiko Asahina and Hisasi Nogami, Ber. 70B 1498
(1937).
K. Mlnami, J. Pharm. Soc. Japan 64 315 (1944).
Pfizer Handbook of Microbial Metabolites 228
482 Perlatolic Acid, C25H32O7, colorless needles, m.p. 108°.
CH3CH2Cn2Cn2n2C
COOH
CH2CH2CH2CH2CH3
Parmelia perlata Ach., Cladonia impexa Harm.,
CI. evansi f. Abb., CI. pseudoevansi Asahina
Yasuhiko Asahina and Itiro Yoshioka, Ber. 70B 1823
(1937). (Synthesis)
483 Boninic Acid, C25H32O8, colorless plates, m.p. 134.5°.
COO
CH3CH2CH2 / \ OH ^^^^
CH3O OCH3 CH3O CH2CH2CH2CH2CH3
Ramalina boninensis Asahina
The yield was about 0.5%, and a little d-usnic acid was
present.
Yasuhiko Asahina and Tsunaharu Kusaka, Ber. 70B 1815
(1937). (Synthesis)
484 Tenuiorin, C26H24O10, colorless crystals, m.p. 238° (dec. ) s. 180°.
O
^"^ COOCH3
CH3O OH
Lobaria pulmonaria Hoffm. f. tenuior Hue.
Mannitol also was present.
Yasuhiko Asahina and Masaiti Yanagita, Ber. 66B 1910
(1933).
229 Depsides and Depsidones
485 Physodic Acid (Farinacic Acid), CoeHagOg, colorless prisms, m.p.
205° (dec).
CH3CH2CH,CHoCH2COCH2 ^^^
COO OH
COOH
CH2CH2CH2CH2CH3
Parmelia physodes Ach., P. furfuracea Ach,
A yield of 5% was reported.
Yasuhiko Asahina and Hirasi Nogami, Ber. 67B 805
(1934).
Idem., ibid. 68B 77, 1500 (1935).
486 Olivetoric Acid, CogHgoOg, colorless crystals, m.p. 151°.
CH3CH2CH2CH2CH2COH2C
COO OH
COOH
CH2CH2CH2CH2CH3
Parmelia olivetorum Nyl., Comicularia pseudosatoana
Asahina and C. divergens Ach.
Yasuhiko Asahina and Fukuziro Fuzikawa, Ber. 67B 163
(1934).
487 Alectoronic Acid, C28H32O9, colorless prisms, m.p. 193°.
CH3CH2CH2CH2CH2COCH2
COOH
CH2COCH2CH2CH2CH2CH3
Alectoria japonica Tuck., A. sarmentosa Ach., Cetraria
pseudocomplicata Asahina, Nephromopsis cilialis Hue.
Yasuhiko Asahina, Yoshinari Kanaoka and Fukuziro Fu-
zikawa, Ber. 66B 649 (1933).
Pfizer Handbook of Microbial Metabolites 230
488 a-Collatolic Acid (Lecanorolic Acid, Lecanoral), C29H34O9 color-
less needles, m.p. 124°.
CH3CH0CH.2CH2CH0COCH2 ^^^ ^..
COO OH
CH3O \r,^ I COOH
CH2COCH2CH2CH2CH2CH3
Cetraria collata Miill. Arg., Lecanora atra (Hudson)
Ach., L. grumosa (Pers.) Rohl.
Yasuhiko Asahina, Yoshinari Kanaoka and Fukuziro Fu-
zikawa, Ber. 66B 649 (1933).
489 Microphyllic Acid, C29H36O9, colorless needles, m.p. 116°.
CH3CH2CH2CH2CH2COH2C
CHsO^ ^OH I XOOH
CH2COCH2CH2CH2CH2CH3
Cetraria japonica Zahlbr.
Some chloroatranorin was isolated from the same ex-
tract. The yield of microphyllic acid was about 4^^ of
the lichen weight.
Yasuhiko Asahina and Fukuziro Fuzikawa, Ber. 68B 2022
(1935).
12
Quinones and Related Compounds
Quinones occur widely in nature, and this topic has been re-
viewed.^- -■ ■"' Even allowing for their conspicuousness due to
color, solubility characteristics and (often) quantity, it seems
that they are broadly distributed among plants, and fungi are
no exceptions.
Anthraquinones, in particular, have been isolated frequently
from fungus cultures. Some 80 anthraquinones and related
substances of known structure were listed by W. Karrer'^ as hav-
ing been reported from plant sources in general. About half of
this number have been isolated and characterized from fungi
and lichens. Since no anthraquinones have been reported from
algae, it may be that those present in lichens are formed pri-
marily by the fungus component. There is some evidence, how-
ever, that in lichens both partners are required for the biosyn-
thesis of depsides and depsidones.^
In fungi anthraquinones occur mainly in the mycelium, often
as mixtures of closely related materials. It is likely, for this
reason, that some of the quinones reported in the early litera-
ture were impure.
The frequent identification of anthraquinone pigments in
molds has caused some speculation on their function. Argu-
ments in favor of a biological function have been summarized
^ S. Shibata, Kagaku (Science) 26 391-396 (1956).
~ R. H. Thomson, "Naturally Occurring Quinones," Academic
Press, New York, 1957, 302 pp.
' W. Karrer, "Konstitution und Vorkommen der Organischen
Pflanzenstoffe," Birkhauser Verlag, Basel, 1958.
* Dieter Hess, Zeitschr. Naturforsch. 14b 345 (1959).
Pfizer Handbook of Microbial Metabolites 232
as follows : ^ ( 1 ) Some pigment complexes are produced in
large quantities, up to 30 percent of the total dry weight of the
mycelium. (2) In many cases, the maximal pigment content
is reached while usable carbohydrate is still present. If har-
vesting is delayed, pigment disappears as autolysis sets in.
(3) The same pigment often is present in different genera or
families, suggesting solution of a metabolic problem in the
same way. (4) Reduction products such as anthranols, an-
thrones and quinhydrones sometimes are present together with
the parent quinone, perhaps indicating a hydrogen or electron
transport function. (5) Several mold pigments are antibiotic
toward other fungi and bacteria.
On the other hand, it has been pointed out" that, in fungi,
induced mutations leading to full blocking of the production of
acetate-derived aromatic compounds such as anthraquinones do
not seem to affect the vitality of the organism. The antifunc-
tionalists believe that anthraquinones and perhaps some other
mold metabolites are merely waste or storage products due to
an overflow of acetate metabolism. If some of these products
happen to inhibit competitors, they facilitate species survival.
A similar concept of the significance of such mold metabolites
has been mentioned by Dalgliesh.^ He proposed that enzyme
systems unable to deal with substrate because it is in large ex-
cess, or for some other reason, might convert it to anthraqui-
nones and other substances, which are eliminated, then, in a
kind of "detoxication" disposal mechanism.
An enzyme chemist, F. F. Nord, has suggested- that many of
the metabolites produced in yields exceeding functional re-
quirements, or for which there is no function, accumulate be-
cause some of- the enzyme systems involved in the oxidative
sequences become saturated with respect to their substrates.
They are thus, in his opinion, probably products of anaerobic
^ G. Smith, Congr. intern, botan. Paris, Rapps. et communs., 8
Sec. 83-89 (1954).
^' Gosta Ehrensvard, "Developments in Aromatic Chemistry," Spe-
cial Publication No. 12, English Chemical Society, London, 1958,
p. 29.
7 C. E. Dalgliesh, ibid., p. 14.
^ F. F. Nord and D. D. Clarke, Arch. Biochem. and Biophys. 59
285 (1955).
233
Quinones
metabolism, and arise in a manner analogous to the accumula-
tion of citric acid, which is induced under the same conditions.^
There is no convincing experimental evidence that anthra-
quinones are important in electron transport.
It has been suggested^" that anthraquinones are acetate-de-
rived, and there is some experimental confirmation.^^' ^^' *
This proof was obtained by growing the mold in the presence
of C'*-labeled acetate, isolating the metabolite, which incorpo-
rated the label to some degree, then degrading the molecule by
ingenious chemical methods to determine the sites of labeling.
Although an acetate origin is indicated, the detailed natures
of the intermediates in the biosynthetic mechanism are still
unknown. Intermediates such as orselHnic acid,^^ dihydroxy-
phthalic acid,^* and 6-methylsalicylic acid^^ (all known mold
metabolites) have been proposed, e.g.:
COOH
COOH
3,5-Dihydroxy-
phthalic Acid
COOH
6-Methylsali
cylic Acid
Birch prefers to think in terms of an intermediate formally
resembling a polyketomethylene chain, which can be modified
in various ways on an enzyme surface to yield related metabo-
lites. This concept is supported by the occasional discovery of
related metabolites in the same culture or plant. For example,
the co-occurring anthraquinone and phenanthrenequinone
9 H. A. Krebs, Biochem. J. 31 2095 (1937).
"A. J. Birch and F. W. Donovan, Austral. J. Chem. 6 360 (1953).
" Sten Gatenbeck, Acta Chem. Scand. 12 1211 (1958).
12 A. J. Birch, A. J. Ryan and Herchel Smith, /. Chem. Soc, 4473
(1958).
* Also see addendum for later work.
1^ K. Aghoramurthy and T. R. Seshadrl, J. Sci. Ind. Res. (India)
13A 114 (1959).
"E. L. Tatum, Ann. Rev. Biochem. 13 667 (1944).
15 Harold Raistrick, Acta Chem. Fenn. lOA 237 (1950).
Pfizer Handbook of Microbial Metabolites
234
shown below could be envisaged as derivatives of a common
precursor chain, which is laid down upon the enzyme surface in
different patterns before cyclization.^^
O
It is likely that the dianthraquinones are formed by oxidative
phenoUc radical coupling, e.g.:*
HO O OH
Skyrin
^'' A. J. Birch, private communication.
* See addendum for evidence to the contrary.
235
Quinones
Other metabolites, such as actinorhodhi and the perylene-
quinones may be formed similarly.
Structures such as moUisin and javanicin seem to indicate an
acetate derivation for naphthoquinones.
CH3O
HO
O
CHo— C— CH3
OH O
CH,
Mollisin
Javanicin
The suggestion has been made^' that the terphenylquinones
might be formed by autocondensation of a phenylpyruvic acid
type of molecule in the following sense:
o—
c=o
O— R
R— O
C
o c
CH
,-r\
/
/
o \=
Phenylpyruvcte
OH
HO
o \=/
Polyporic Acid
Similarly p-hydroxyphenylpyruvate would form atromentin.
Polyporic acid might be transformed by oxidation to pulvinic
^'G. Read and L. Vining, Chem. and Ind., 1546 (1959).
Pfizer Handbook of Microbial Metabolites 236
acid, and by further hydroxylations to leucomelone or other
terphenylquinones .
O
\
c o
c c
\/\
c c-
o c
\
o
Pulvinic Acid Leucomelone
If this suggestion can be confirmed experimentally, it will re-
late this type of benzoquinone metabolite to the shikimic acid
route of biogenesis.
The biosynthesis of a benzoquinone, aurantiogliocladin, has
been studied, by using C"-labeled formate and acetate. ^^ The
results demonstrated formation from 4 moles of acetate with de-
carboxylation, C-methylation, post-oxidation in the aromatic
CH3^
' Q
% O
C— CH3 CH3O II CHa
O -^
CH3— ic=o]
Acetate Aurantiogliocladin
ring and 0-methylation of the phenolic hydroxyl groups.
6-Methylsalicylic acid appears to be an intermediate.^^
Aurantiogliocladin, isolated from a gliocladium specimen, re-
sembles the coenzymes Q. These substances occur in the cell
mitochondria of a wide variety of organisms. They are benzo-
quinones substituted similarly to aurantiogliocladin, but with
^^ A. J. Birch, R. I. Fryer and Herchel Smith, Proc. Chem. Soc,
343 (1958).
19 Private communication from Herchel Smith.
237
Quinones
additional polyisoprenoid side-chains. There is a marked re-
CH3O
CH3O
CH3
I
(CH2— CH=C— CH2)nH
Vitamin Kq
semblance to the previously discovered vitamins K. The follow-
ing substances have been isolated, purified, and the structures
determined :
TABLE I
Numbers of
Origin
side-chain
isoprene
units (n)
Number of
carbon
atoms
Melting
point (°C)
Designation
Refer-
ences
Saccharomyces cere-
yisiae
6
39
16°
Coenzyme Qe
20
Torula utilis
7
44
30.5°
Coenzyme Q7
20,21
Azotobacfer vine-
landii
8
49
37°
Coenzyme Qg
20,21
Torula utilis
9
54
45.2°
Coenzyme Q9
20,21
Beef heart
10
59
48°
Coenzyme Qio
21,22
A survey was made, by using methods sometimes short of iso-
lation and purification (paper chromatographic comparisons,
spectra, etc. ) of the occurrence of coenzyme Q and of vitamin K
in a wide variety of biological types. ^^ Many bacteria contain
coenzyme Q. The mycobacteria and streptomycetes seem to
contain vitamin K instead. Escherichia coli and chromatium
species contain both. Obligate anaerobes such as the Clostridia
20 R. L. Lester, F. L. Crane and Y. Hatefi, J. Am. Chem. Soc. 80
4751 (1958).
-1 R. L. Lester and F. L. Crane, Biochim. et Biophys. Acta 32 492
(1959).
2- F. L. Crane, Y. Hatefi, R. L. Lester and Carl Widmer, Biochim.
et Biophys. Acta 25 220 (1957); idem., ibid. 32 73 (1959).
23 R. L. Lester and F. L. Crane, /. Biol. Chem. 234 2169 (1959).
Pfizer Handbook of Microbial Metabolites
238
contain neither, and facultative anaerobes such as Saccharomy-
ces cerevisiae and E. coli contain neither when grown anaero-
bically. A chart of microbial occurrence was published:
TABLE II
Organism
Coenzyme Q
Vitamin K
Saccharomyces cerevisiae (anaerobic)
-
-
Saccbaromyces cerevisiae (aerobic)
Qe
Socchoromyces cavalier!
Qe
Saccharomycei fragilis
Qe
Neurospora crassa
Qio
Mucor corymbifer
Qs)
Sfrepfomyces griseus
+
Mycobacferium smegmafis
+
Mycobacterium tuberculosis
+
Bacillus mesentericus
+
Escherichia coli
Qh
Chromatium spp.
Q7
Rhodospii ilium rubrum
Q9
Pseudomonas fluorescens
Qs
Hydrogenomonas sp.
Qs
Basidiomycetes contain neither coenzyme Q nor vitamin K,
but produce another quinone which seems to have the same
function in this family. It has been extracted and purified to
some extent and called basidioquinone.
A comparison of all the animal, plant and microorganism
sources indicated that, in general, lower organisms contain
lower homologues of coenzyme Q.
Evidence has been obtained for the coenzyme function of the
Q (and K) quihones: ( 1 ) Extraction from mitochondria destroys
enzymatic activity, which is restored by restoration of the coen-
zymes. (2) Inhibitors of electron transport, such as the anti-
biotic, antimycin A, affect the oxidation state of the quinones in
a predictable manner. (3) The rate of oxidation or reduction
in mitochondria is what might be anticipated for participation
in electron transport. The pattern of occurrence in aerobic and
anaerobic microorganisms also is suggestive.
The general structure of the electron transport system in cell
mitochondria in the light of the new discoveries has been re-
viewed.^*
Apparently coenzyme Q is formed by a combination of the
-^ D. E. Green and R. L. Lester, Federation Proc. 18 987-1000
(1959).
239 Quinones
simple acetate and terpenoid biosynthetic routes. Mevalonic
acid was incorporated into the molecule by rats (especially vita-
min A-deficient rats) and by rat liver, while 2,3-dimethoxy-5-
methyl-l,4-benzoquinone and D,L-tocopherol were not.'-'^ This
contrasts with evidence that 2-methyl-l,4-naphthoquinone is
used as a precursor of vitamin K by rats.'-" Evidently, no experi-
mental work has been published on biosynthesis in microor-
ganisms.
a. BENZOQUINONES
490 Tetrahydroxybenzoquinone, C,,H40(j, bluish black plates, no
melting point.
O
HO II OH
HO 11 OH
O
Pseudomonas beiierinckii Hof grown on salted beans.
The substrate is meso-inositol, which probably is a normal
constituent of beans.
T. Hof, Rec. Trav. Botan. Neerland. 32 92 (1935). (Isola-
tion)
A. J. Kluyver, T. Hof and A. G. J. Boezaardt, Enzymologia
7 257 (1939). (Structure)
Paul W. Preisler and Louis Berger, /. Am. Chem. Soc. 64
67 (1942).
491 Gentisylquinone, CjHcOs, yellow needles, m.p. 76°.
O
CHoOH
O
PenicilliuTn patulum Bainier probably produces a little
of this quinone under certain conditions, although it may
be an artifact, since larger quantities of the corresponding
hydroquinone are produced. It has been isolated as a
deep violet colored complex, m.p. 86-89°, with the hydro-
quinone.
-' U. Gloor and O. Wiss, Arch. Biochem. and Biophys. 83 216
(1959).
-«C. Martius and H. O. Esser, Biochem. Z. 331 1 (1958).
Pfizer Handbook of Microbial Metabolites 240
B. G. Engel and W. Brzeski, Helv. Chim. Acta 30 1472
(1947).
492 Terreic Acid, C7H6O4, pale yellow, large, glistening plates, m.p.
127-127.5°, [aln" -28.6° (c 1 in 50% methanol-benzene).
Sublimes.
Aspergillus terreus grown in a glucose and corn-steep
liquor-cottonseed meal medium.
H. M. Florey, E. Chain, N. G. Heatley, M. A. Jennings, A. G.
Sanders, E. P. Abraham and M. E. Florey, "Antibiotics," Ox-
ford University Press, London, 1949 Vol. I p. 388.
Murray A. Kaplan, Irving R. Harper and Bernard Heine-
mann. Antibiotics and Chemotherapy 4 746 (1954). Yield
138 g. from 200 liters.
J. Sheehan, W. Lawson and R. Gaul, J. Am. Chem. Soc.
80 5536-5538 (1958). (Structure)
493 4-Methoxytoluquinone (Coprinin), CgHgOg, yellow spangles,
m.p. 175°.
CH3 ?
OCH3
Coprinus similis B. and Br., Lentinus degener Kalchbr.
grown on a Czapek-Dox medium, containing glucose and
corn-steep solids.
Marjorie Anchel, Annette Hervey, Frederick Kavanagh,
Jerome Polatnick and WUliam J. Robbins, Proc. Nat. Acad.
Sci. U. S. 34 498 (1948). (Isolation)
R. B. Woodward, Franz Sondheimer, David Taub, Karl
Heusler and W. M. McLamore, /. Am. Chem. Soc. 74 4234
(1952). (Synthesis)
241 Benzoquinones
494 2,5-Diniethoxybenzoquinone, C8H8O4, yellow prisms, in.p. 250°
(dec).
CH3O
Polyporus fumosus (Pers.) Fries grown on an artificial
medium including glucose and corn-steep liquor.
Yield: 0.1 g. from 2 liters of culture broth.
J. D. Bu'Lock, J. Chem. Soc, 575 (1955). (Isolation)
E. Knoevenagel and C. Biickel, Ber. 34 3993 (1901). (Syn-
thesis)
495 Fumigatin, C8H8O4, maroon needles, m.p. 116'
CH3 ? OH
0
n OCH3
496 Fumigatin Hydroquinone is produced as well, the ratio of the
two compounds varying with the age of the culture.
OH °<=*
Aspergillus fumigatus Fres. grown on a Raulin-Thom
medium.
Winston Kennay Anslow and Harold Raistrick, Biochem. J.
32 687 (1938). (Isolation)
W. K. Anslow, J. N. Ashley and H. Raistrick, /. Chem. Soc,
439 (1938). (Synthesis)
Pfizer Handbook of Microbial Metabolites 242
497 Spinulosin, CgHgOg, purple-black plates, m.p. 203°.
CH3 ? OH
HO I OCH3
First isolated from three strains of Penicillium spinu-
losiim Thorn grown on a modified Czapek-Dox-glucose
medium. Later isolated from two out of seven strains of
Aspergillus fumigatus examined. Spinulosin as well as
an orange pigment, m.p. 184-185°, with antibiotic prop-
erties resembling those of fumigatin, also has been iso-
lated from an unidentified Penicillium (perhaps Penicil-
lium spinulosumy Penicillium cinerascens Biourge is
another producer.
J. H. Birkinshaw and H. Raistrick, Trans. Roy. Soc. (Lon-
don) B220 245 (1931).
Winston K. Anslow and Harold Raistrick, Biochem. J. 32
687, 2288 (1938). (Isolation)
A. Bracken and H. Raistrick, ibid. 41 569 (1947).
Keichiro Hoshishima, Tohuku J. Exptl. Med. 52 273 (1950).
Winston K. Anslow and Harold Raistrick, Biochem. J. 32
803 (1938). (Synthesis)
498 Aurantiogliocladin, CioHjoOj, orange plates, m.p. 62.5°.
CH3 II OCH3
CH3 I OCH3
The corresponding quinhydrone, a dark red compound
called rubrogliocladin, occurs together with aurantioglio-
cladin.
A Gliocladium specimen, probably G. roseum Bainier
produces these substances as well as :
243
Benzoquinones
499 Gliorosein, C,oHj404, colorless crystals, m.p. 48'
CHa
CH3
OCH3
OCH3
CH3
CH3
OCH3
OCH3
P. W. Brian, P. J. Curtis, S. R. Rowland, E. G. Jeffreys and
H. Raudnitz, Experientia 7 266 (1951). (Isolation)
E. B. Vischer, /. Chem. Soc, 815 (1953). (Structure)
Wilson Baker, J. F. W. McOmie and D. Miles, ibid., 820
(1953). (Synthesis)
500 Phoenicin, C,4H,„0,., yellow-brown tablets, m.p. 231°.
O HO O
Penicillium phoeniceum van Beyma, P. ruhrum O. Stoll.
Theodore Posternak, Hans W. Ruelius and Jacques Tcher-
niak, Helv. Chivi. Acta 26 2031 (1943). (Synthesis)
501 Oosporein (Chaetomidin), Ci^HmOs, bronze plates, m.p. 260-
275°.
Oospora colorans van Beyma, Chaetomium aureum
Chivers, Verticillium psalliotae, Acremonium sp.
F. Kogl and G. C. Van Wessem, Rec. trav. chim. 63 5
(1944). (Isolation)
F. M. Dean, A. M. Osman and Alexander Robertson,
/. Chem. Soc, 11 (1955).
G. Lloyd, Alexander Robertson, G. B. Sankey and W. B.
Whalley, ibid., 2163 (1955).
Pfizer Handbook of Microbial Metabolites 244
502 Isooosporein,* C14H10O8, purple crystals, no m.p., subl. 220-
250°, dec. 250°.
O
HO-// A //
Unclassified citric acid-forming fungus.
Maximal yield 2.5 g. per liter.
Nobuyo Shigematsu, ]. Inst. Polytech., Osaka City Univ.
Ser. C 5 100 (1956).
503 Volucrisporin, C18H12O4, red plates, m.p. >300°.
HO
o W
OH
Volucrispora aurantiaca
Occasionally small quantities of the leuco derivative
(hydroquinone) occur with the pigment.
P. V. Divekar, G. Read and L. C. Vining, Chem. and Ind.,
731 (1959).
504 Polyporic Acid, C18H12O4, bronze leaflets, m.p. 305-307° (dec).
? OH
/
HO "
O
Polyporus nidulans Fries, P. rutilans (Pers.) Fries,
Peniophora fdamentosa (B. and C.) Burt, Sticta coronata
Muell., S. colensoi Bab.
Fritz Kogl, Ann. 465 243 (1928).
J. Murray, J. Chem. Soc, 1345 (1952).
* See addendum.
245 Benzoquinones
The air-dried fruiting body of P. rutilans contains 23%.
It is not produced by the fungal mycelium in artificial
culture.
Robert L. Frank, George R. Clark and James N. Coker,
J. Am. Chem. Soc. 72 1824 (1950).
Polyporic acid is probably identical with the lichen pig-
ment, orygmaeic acid, first described by Zopf.
Wilhelm Zopf, Ann. 317 124 (1901).
505 Atromentin, CjsHioOe, bronze leaflets, no m.p.
HO A , „
OH
Paxillus atromentosus (Batsch.) Fr.
This basidiomycete often grows on old tree trunks and
produces the pigment first in a leuco-form, which air-
oxidizes to the colored form on the outer portions of the
fruiting body and during isolation. The yield was about
2% of the weight of the air-dried fruiting body.
Fritz Kogl, Ann. 465 243 (1928).
506 Leucomelone, CigHiaOj, brown leaflets, m.p. 320° (dec).
HO HO II /\
Polyporus leucomelas Pers. ex Fr.
Yield 3 g. per kilogram of fruiting body.
Masuo Akagi, /. Pharm. Soc. Japan 62 129 (1942). Syn-
thesis)
507 Thelephoric Acid, C20H12O9, lustrous, nearly black prisms, no
m.p.
OH
HO-
Pfizer Handbook of Microbial Metabolites
246
Partial structure:
HO
OH
2 CH2O2
1 OH
Thelephora palmata, other Thelephora spp., Lobaria
retigera Trev., L. pulmonaria (L.) HofFm., Hydnum spp.,
Cantharelliis multiplex Underw., Polystictus versicolor
(L.)Fr.
Fritz Kogl, Hanni Erxleben and Ludwig Janecke, Ann. 482
105 (1930).
K. Aghoramurthy, K. G. Sarma and T. R. Seshadri, Tetra-
hedron Letters No. 8 20 (1959). (Revised structure)
508 Muscarufin, C25Hi609-H20, orange-red needles, m.p. 275.5°.
COOH
HO ?
CH=CH— CH=CH— COOH
COOH
Amanita muscaria (Linn.) Fries
This pigment causes the red color of the caps of this
common poisonous toadstool (fly agaric), yet 500 kg. of
the fungus yielded only 850 mg. of pure material.
Fritz Kogl and Hanni Erxleben Ann. 479 11 (1930).
509 Auriantiacin (Atromentin-3,6-dibenzoate), CgoHooOj-, dark red
needles, m.p. 285-295°.
O
o— c-
Hydnum aurantiacum Batsch.
247 Benzoquinones
Jarl Gripenberg, Acta Chem. Scand. 10 1111 (1956).
510 Protoleucomelone, C32HosO,4, colorless crystals, m.p. 203-205°.
Probable structure:
CH3OCO ^^-^
CH3OCO. I / V-OCOCHs
CH3COO \r^^/ \=/
CHaOCO-f y y ^OCOCH3
OCOCH3
Polyporus leiicomelas Pers. ex Fr.
Yield 3-4 g. per kilogram of mushrooms.
Masuo Akagi, /. Pharm. Soc. Japan 62 129 (1942).
511 Metabolite of Hydnum aurantiarum, C^<iii^^)OlQ, colorless needles.
m.p. 305-307°.
(y^--" <r^o°"
° i=o
Hydnum aurantiacinn Batsch.
Aurantiacin and thelephoric acid are produced by the
same organism.
Jarl Gripenberg, Acta Chem. Scand. 12 1411 (1958).
Coenzymes Q (Mitoquinone, Ubiquinone, Qot.-,. SA).
These compounds occur widely in the cell mitochondria
of microorganisms and higher animals, where they play a
part in the electron transport system. Variations in side-
chain length occur as in the case of vitamin K. Com-
pounds in which n = 6, 7, 8 and 9 have been isolated from
microbial sources. The quinone moiety resembles auran-
tiogliocladin.
Pfizer Handbook of Microbial Metabolites 248
General structure:
O
CH3O
CH3O
512 Coenzyme Qg, C39H58O4, m.p. 16°.
Saccharomyces cerevisiae
513 Coenzyme Q7, C44H66O4, orange crystals, m.p. 30.5°.
Torula utilis
514 Coenzyme Qg, C49H74O4, orange crystals, m.p. 37°.
Azotobacter vinelandii
515 Coenzyme Qg, C54H82O4, orange crystals, m.p. 45.2°.
Torula utilis
R. L. Lester, F. L. Crane and Y. Hatefi, /. Am. Chem. Soc.
80 4751(1958). (Isolation)
F. W. Heaton, J. S. Lowe and R. A. Morton, J. Chem. Soc,
4094 (1956).
b. NAPHTHOQUINONES
516 Flaviolin, CioH^Og, garnet red rhombs containing solvent of
crystallization, m.p.: dec. near 250°.
Aspergillus citricus (Wehmer) Mosseray
J. E. Davles, F. E. King and John C. Roberts, Chem,. and
Ind., 1110 (1954). (Structure)
517 6-Methyl-l,4-naphthoquinone, CnHgOa, golden yellow needles,
m.p. 90-91°.
O
CH3 II
Marasmius gramineum Lib.
249 Naphthoquinones
Gerd Bendz, Acta Chem. Scand. 2 192 (1948).
Idem., ibid. 5 489 (1951).
518 Phthiocol, CiiHsOg, yellow prisms, m.p. 173-174°.
? CHs
11 OH
Mycobacterium tuberculosis var. hominis, Corynebac-
terium diphtheriae
R. J. Anderson and M. S. Newman, J. Biol. Chem. 103 197
(1933).
Rudolph J. Anderson, R. L. Peck and M. M. Crelghton, ibid.
136 211 (1940).
Michizo Asano and Hideo Takahashi, /. Pharm. Soc. Japan
65 17 (1945).
M. Terni, Boll. soc. ital. biol. sper. 25 60 (1949).
There is evidence that phthiocol is an artifact, and that
the precursor is a compound related to vitamin K,, but of
higher molecular v^^eight.
J. Francis, J. Madinaveitia, H. M. Macturk and G. A. Snow,
Nature 163 365 (1949).
519 Mollisin, C14H10O4CI2, orange-yellow needles, m.p. 202° (dec).
HO O
I II CI
^"^ CH. & ^'
I
c=o
CH3
Mollisia caesia, Sacc. sensu Sydow, M. gallens Karst.
G. J. M. van der Kerk and J. C. Overum, Rec. trav. chim.
76 425 (1957).
520 Javanicin, C15H14O6, red laths, m.p. 208°.
OH O
CH3O I II CH2COCH3
Pfizer Handbook of Microbial Metabolites 250
Fusarium javanicum Koorders
Yield about 20 mg. per liter (purified pigment). Oc-
curs together with fusarubin.
H. R. V. Arnstein and A. H. Cook, J. Chem. Soc, 1021
(1947). (Isolation)
521 Fusarubin (Oxyjavanicin), Ci.-,Hi407, red prisms, m.p. 218°
(preheated block).
CH3O
Fusarium solani (Mart.) App. and Wr.
Yield about 50 mg. per liter (mixed with javanicin).
H. R. V. Arnstein and A. H. Cook, /. Chem. Soc, 1021
(1947).
Hans W. Ruelius and Adeline Gauhe, Ann. 569 38 (1950).
After ether extraction of the acidified broth, a water-
soluble derivative of fusarubin remains behind. This has
been identified as a sulfate ester occurring at one of the
hydroquinone hydroxyl groups and was called fusarubino-
gen. Fusarubinogen actually is present in the broth in a
reduced form, which is probably a derivative of ^-hydro-
naphthazarin.
Hans W. Ruelius and Adeline Gauhe, Ann. 570 121 (1951).
522 Bostrycoidin, C1SH14O7 (proposed), red or brown lath clusters,
m.p. 243°.
A substituted naphthoquinone similar to javanicin.
Fusarium bostrycoides Wr. and Rkg.
Mary Alice Hamilton, Marjorie S. Knorr and Florian A.
Cajori, Antibiotics and Chemotherapy 3 853 (1953).
F. A. Cajori, Theodore T. Otani and Mary Alice Hamilton,
J. Biol. Chem. 208 107 (1954). (Isolation)
523 4,9-Dihydroxyperylene-3,10-quinone, C00H10O4, dark red needles,
dec. near 350°.
o=< >=( >=o
Daldinia concentrica (Bolt) Ces. and de Not.
251 Naphthoquinones
J. M. Anderson and J. Murray, Chem. and Ind., 376 (1956).
(Isolation)
It has since been reported that this perylenequinone is
524 probably an artifact of 4,5,4'5'-tetrahydroxy-l,r-dinaphthyl.
This polyphenol was obtained from the same organism.
It was found to oxidize in part to a dark, melanin-like
polymer, and in part to the perylenequinone. The struc-
ture was proved by synthesis.
J. D. Bu'Lock and D. C. AUport, Proc. Chem. Soc, 264
(1957).
D. C. Allport and J. D. Bu'Lock, /. Chem. Soc, 654 (1960).
525 Mycochrysone, C20H14O7, orange-red crystals, m.p. : slow dec.
above 180°.
No N, — OCH3, C— CH3 nor halogen. Three active hy-
drogens.
Partial structure:
-OH (phenolic or enolic)
-H12O3
An inoperculate discomycetous fungus.
G. Read, P. Shu, L. C. Vining and R. H. Haskins, Can. J.
Chem. 37 731 (1959).
526 Actinorhodin, C32H26-30O14, bright red needles, dec. 270°.
R,] 2COOH
R2 i,2CH3
R3 I C8Hi2_16
' HO O O OH
Streptomyces coelicolor (Miiller) Waksman and Hen-
rici
Pfizer Handbook of Microbial Metabolites
252
The yield was about 15% of the mycelial weight.
Hans Brockmann and Ernst Hieronymus, Chem. Ber. 88
1379 (1955).
This compound has been shown to be an artifact, and
by careful isolation under acidic conditions the precursor,
protoactinorhodin, with the nucleus below, can be isolated.
OH OH
OH OH
OH OH
-> Actino-
rhodin
527 Protoactinorhodin was isolated as pale red prisms, dec. near
330°, probably C30H30O14.
Hans Brockmann and Volkmar Loeschcke, Chem. Ber. 88
778 (1955).
528 Xylindein, C34H26O11, deep brown high-melting, pleochroic leaf-
lets.
The structure is obscure, but an extended quinone sys-
tem of the type
was postulated.
Chlorosplenium aeruginosum (Oeder ex Fries) De Not
Fritz Kogl and G. von Taeuffenbach, Ann. 445 170 (1925).
Fritz Kogl and Hanni Erxleben, ibid. 484 65 (1930).
529 Rhodomycetin, gradual darkening at 300°.
Dark fed powder, red in acid solution and blue in alka-
line. U.V. 235, 540, 580 m^x.
Reddish violet in H0SO4, positive FeCla, H0O2 and
Na2So04-2HoO reduction.
Resembles actinorhodin.
Streptomyccs griseus
Gerald Shockman and Selman A. Waksman, Antibiotics
and Chemotherapy 1 68 (1951).
530 Naphthoquinone from Mycobacterium phlei, yellow oil, U.V. 243,
249, 261, 270, 328 m^ in isooctane.
Appears to have about 30 carbon atoms and is probably
a vitamin K,. Mol. wt. about 620.
^53
Naphthoquinones
Mycobacterium, phlei
Ten mg. were obtained from 450 g. of wet cells.
A. F. Brodie, B. R. Davis and L. G. Fieser, /. Am. Chem.
Soc. 80 6454 (1958).
Vitamins K^:
Vitamin Ko was first isolated from putrefied fish meal In
1939 by Doisy and collaborators. Tishler and Sampson
later found that it was produced by pure cultures of Bacil-
lus brevis. Isler and collaborators corrected the structure
originally proposed to A. below. They also isolated a
lower isoprenolog, B., from putrefied fish meal. Both
structures were proved by synthesis. The later group also
determined the structure of (and synthesized) a higher
isoprenolog C. isolated earlier in England.
531 A., CiQH(i^0.2, hght yellow plates, m.p. 54°.
CHs
^CH2— CH=C—
I
CH3
— CH2— CH2— CH=C —
I
CH3
-CHs
Bacillus brevis
R. W. McKee, S. B. Binkley, Sidney A. Thayer, D. W. Mac-
corquodale and Edward A. Doisy, J. Biol. Chem. 131 327
(1939).
M. Tishler and W. Sampson, Proc. Soc. Exp. Biol. 68 136
(1948).
532 B., C41H56O2, hght yellow plates, m.p. 50°.
O
CH2— CH=C-
CH3
-CH2— CH,— CH=C—
I
CH3
— CH3
O. Isler, R. Riiegg, L. Chopard-dit-Jean, A. Winterstein and
O. Wiss, Helv. Chim. Acta 41 786 (1958).
Pfizer Handbook of Microbial Metabolites 254
533 C. CseHgoOo, yellow crystals, m.p. 58-59°.
O
CHo— CH=C— — CH2— CH2— CH=C— 1— CH3
CH3 CH3 8
Mycobacterium tuberculosis (Brevannes)
This substance constituted about 0.59c of the dry cell
weight.
J. Francis, J. Madinaveitia, H. M. Macturk and G. A. Snow,
Nature 163 365 (1949). (Isolation)
H. Noll, R. Riiegg, U. Gloor, G. Ryser and O. Isler, Helv.
Chim. Acta 43 433 (1960). (Structure and synthesis)
C. ANTHRAQUINONES
534 Anthraquinone pigment from Gibberella fujikuroi, probably
C14H10O7, red crystals, m.p. 325° (sealed tube).
Partial and tentative structure:
CHoOH
+ 20H
O OH
The structure may resemble that of cynodontin.
Gibberella fujikuroi (Saw.) Wollenweber
Yukihiko Nakamura, Tokuji Shimomura and Joji Ono,
J. Agr. Chem. Soc. Japan 31 669 (1957). (Isolation)
535 Clavorubin, C14H12O9, red crystals.
Has one C — CH3 group. U.V. absorption resembles a
1,5,8-trihydroxyanthraquinone. The leuco-acetate (like
that of chrysergonic acid) has a diphenyl-like absorption.
Claviceps purpurea
B. Franck and T. Reschke, Angew. Chem. 71 407 (1959).
536 Emodic Acid, C].-,Hs07, orange needles, m.p. 363-365°.
O
COOH
^'JO
Anthraquinones
Penicillium cyclopium Westling
Winston K. Anslow, John Breen and Harold Raistrick,
Biochem. J. 34 159 (1940).
537 Boletol, Ci-.HsO-, red needles, m.p. 275-280° (dec).
O COOH ._ HO O
HO O HO O COOH
Boletus luridus Schaeff. ex Fries, B. badius Ft., B.
chrysenteron Bull., B. satanas Lenz, B. subtomentosus
Linn.
The higher yielding species gave about 1 g. of pure
material from 20 kg. of fruiting body.
Fritz Kogl and W. B. Deijs, Ann. 515 10, 23 (1935). (Syn-
thesis )
538 Pachybasin, C15H10O3, yellow needles, m.p. 78°.
O
Pachybasium candidum (Sacc.) Peyronel
Pachybasin, like most of the other anthraquinone pig-
ments, occurs as one constituent of a mixture of pigments.
Chrysophanol was identified as one of the other con-
stituents of this mixture.
Shoji Shibata and Michio Takido, Pharm. Bull. (Tokyo) 3
156 (1955).
539 Chrysophanol ( Chry sophanic Acid), C15H10O4, dark yellow leaf-
lets, m.p. 196°.
O
Penicillium islandicum Sopp, Pachybasium candidum
(Sacc.) Peyronel, Chaetomium affine Corda
The 9-anthrone corresponding to chrysophanol has been
isolated from higher plants.
Pfizer Handbook of Microbial Metabolites 256
B. H. Howard and H. Raistrick, Biochem. J. 46 49 (1950).
Shoji Shibata, Kagaku (Science) 26 391 (1956).
540 Islandicin, C15H10O5, dark red plates, m.p. 218°.
O OH
Penicillium islandicum Sopp.
This mold produces a complex mixture of pigments
constituting up to 20% of the mycelial weight.
B. H. Howard and H. Raistrick, Biochem. J. 44 227 (1949).
Islandicin seems to be identical with funiculosin, a
trihydroxyanthraquinone pigment of the same melting
point and empirical formula isolated from Penicillium
funiculosum Thom, a species closely related to P. is-
landicum.
Hisanao Igarasi, J. Agr. Chem. Soc. Japan 15 225 (1939).
541 Helminthosporin, CigHioOg, dark maroon needles, m.p. 227°.
"? ? CH.
HO O OH
Helm,inthosporium gramineum Rabenhorst, H. cyno-
dontis Marignoni, H. catenarium, H. triticivulgaris
Nisikado
About 30% of the dry myceUum of H. gramineum con-
sisted of anthraquinone pigments, mainly helmintho-
sporin and catenarin.
Harold Raistrick, Robert Robinson and Alexander R. Todd,
J. Chem. Soc, 488 (1933).
542 Emodin (Frangula-Emodin), C15H10O5, orange needles, m.p.
255°.
257 Anthraquinones
Cortinariits sanguineus (Wulf. ) Fries, Chaetomium
affine Corda.
A yield of about S'c of the dry mycelial weight has been
mentioned.
Fritz Kogl and J. J. Postowcky, Ann. 444 1 (1925).
R. A. Jacobson and Roger Adams, J. Am. Chem. Soc. 46
1312 (1934). (Synthesis)
543 Versicolorin, Ci^HjoOe, yellow-orange needles, m.p. 282°.
HO O OH ^^^^ HO O OH ^^ ^^
I II I CH2OH I II I CH2OH
II OH HO II
O O
Aspergillus versicolor (Vuillemin) Tiraboschi
The same organism produces an uncharacterized xan-
thone pigment.
Yuishi Hatsuda and Shlmpei Kuyama, J. Agr. Chem. Soc.
Japan 29 11 (1955).
544 Cynodontin, Cj^HioOe, bronze plates, m.p. 260°.
HO O OH
HO O OH
Helminthosporium cynodontis Marignoni, H. euclaenae
Zimmermann, H. avenae Ito and Kurib, H. victoriae
Winston Kennay Anslow and Harold Raistrick, Biochem. J.
34 1546 (1940). (Synthesis)
545 oj-Hydroxyemodin ( Citreorosein ) , CjgHioOe, orange needles,
m.p. 288°.
n
CH2OH
Penicillium cyclopium Westling, P. citreo-roseum
Dierckx.
Winston K. Anslow, John Breen and Harold Raistrick,
Biochem. J. 34 159 (1940).
Pfizer Handbook of Microbial Metabolites 258
Theodore Posternak, Compt. rend. soc. phys. his. nat. Ge-
neve 56 28 (1939).
546 Catenarin, Ci^HiyOe, red plates, m.p. 246°.
HO ° °"
Helminthosporium catenarium Drechsler, H. grami-
neum Rabenhorst, H. velutinum Link, H. triticivulgaris
Nisikado, Penicillium islandicum Sopp, Aspergillus am-
stelodami (Mangin) Thorn and Church
More than 15% of the mycelial weight of H. catenarium
was catenarin.
Winston Kennay Anslow and Harold Raistrick, Biochem. J.
35 1006 (1941). (Synthesis)
547 Asperthecin, Ci^HioO^j, chestnut brown needles, no m.p.
O HO O
CH.OH HO 1 I! CH2OH
Aspergillus quadrilineatus Thom and Raper and other
species of the Aspergillus nidulans group
S. Neelakantan, Anna Pocker and H. Raistrick, Biochem. J.
66 234 C1957).
A closely related pigment has been observed, which may
have been a tautomeric or reduced form of asperthecin.
It could not be isolated because of its ready conversion to
asperthecin.
B. H. Howard and H. Raistrick, Biochem. J. 59 475 (1955).
548 Fallacinal, Ci«Hi„0,., orange-yellow needles, m.p. 251°.
CH3O ? CHO
259 Anthraquinones
Xanthoria fallax (Hepp.) Arn.
Takao Murakami, Pharm. Bull. (Tokyo) 4 298 (1956).
549 Tritisporin ( to-Hydroxycatenarin ) , Cjr.HioO;, brown needles,
m.p. 260-262°.
°" CH,OH
Helminthosporium triticivulgaris Nisikado
S. Neelakantan, Anna Pecker and H. Raistrick, Biochem. J.
64 464 (1956).
550 Flavoskyrin, Ci.-,Hi^O.-,, yellow crystals, m.p. 208° (dec), [cf]u
-295° (in dioxane).
PenicilHvm islandiciim Sopp.
Shoji Shibata, Takao Murakami and Michio Takito, Pharm.
Bull. (Tokyo) 4 303 (1956). (Structure)
551 Compound A ( 1,4,7, 8-Tetrahydroxy-2-methylanthraquinone),
Ci,Hi,0,.
An optically inactive compound (no melting point
given). Treatment with cone. H2SO4 yields an anthraqui-
none, Ci.-Hi„0.,, red crystals, m.p. 255°, with the follow-
ing structure:
O
Penicillium islandicum
Sten Gatenbeck, Acta Chem. Scand. 12 1985 (1958).
Idem., ibid. 13 705 (1959).
Pfizer Handbook of Microbial Metabolites 260
552 Endocrocin, CieHjoOj, copper-red leaflets, m.p. 318° (dec.)-
O
HO II CH3
I II I COOH
HO O OH
Nephromopsis endocrocea Asahina
Yasuhiko Asahina and Fukuziro Fuzikawa, Ber. 68B 1558
(1935).
Aspergillus amstelodami (Man gin) Thorn and Church.
Shoji Shibata and Shinsaku Natori, Pharm. Bull. (Tokyo) 1
160 (1953).
553 Clavoxanthin, CieHioOy, yellow needles, m.p. 340° (dec).
Apparently similar to endocrocin.
Claviceps purpurea
B. Franck and T. Reschke, Angew. Chem. 71 407 (1959).
554 Parietinic Acid, Ci^HioOy, yellow needles, m.p. --'300° (sub-
limes).
CH3O II COOH
Xanthoria parietina (L.) Th. Fr.
Walter Escherich, Biochem. Z. 330 73 (1958).
555 Physcion (Partetin), CigHisOg, orange-yellow leaflets, m.p. 207°.
O
CH3O
Aspergillus glaiicus spp., A. chevalieri, A. ruber
(Mangin) Raper and Thom, Penicillium herquei Bainier
and Sartory, Xanthoria parietina (L.) Beltram, X. fallax,
Teloschistes fiavicans (Sw.) Norm., T. exilis Wainio,
Placodium spp., Caloplaca elegans (Link)
26 1 Anthraquinones
F. Rochleder and W. Heldt, Ann. 48 1 (1843).
Harold Raistrick, Enzymologia 4 76 (1937).
H. Raistrick, Robert Robinson and A. R. Todd, /. Chem.
Soc, 80 (1937).
Julius Nicholson Ashley, Harold Raistrick and Taliesin
Richards, Biochem. }. 33 1291 (1939).
T. R. Seshadri and S. Sankara Subramanian, Proc. Indian
Acad. Sci. 30A 67 (1949).
Walter B. Mors, Bol. Inst. Quim. Agric. No. 23 7 (1951).
S. Neelakantan and T. R. Seshadri, /. Sci. Ind. Research
(India) IIB 126 (1952).
Shoji Shibata and Shinsaku Natori, Pharm. Bull. (Tokyo) 1
160 (1953).
Mitizo Asano and Yosio Arata, /. Pharm. Soc. Japan 60 521
(1940).
J. A. Galarraga, K. G. Mill and H. Raistrick, Biochem. J. 61
456 (1955).
Jiro Kitamura, Uzuhiko Kurimoto and Matatsugu Zoko-
yama, /. Pharm. Soc. Japan 76 972 (1956).
556 Macrosporin, CjfiHisO^, orange-yellow rhombic crystals, m.p,
300° (dec).
CH3O
Macrosporium porri Elliott
R. Suemitsu, Y. Matsui and M. Hiura, Bull. Agr. Chem. Soc.
(Japan) 21 1-4, 337 (1957). (Isolation)
R. Suemitsu, M. Nakajima and M. Hiura, ibid. 23 547
(1959).
557 Teloschistin (Fallacinol), CigHisOe, orange plates, m.p. 245-
247°.
CH3O II CH2OH
Teloschistes flavicans (Sw. ) Norm., Xanthoria fallax
(Hepp.) Am.
Pfizer Handbook of Microbial Metabolites 262
T. R. Seshadri and S. Sankara Subramanian, Proc. Indian
Acad. Sci. 30A 67 (1949).
558 Roseopurpurin (Carviolin), CieHjoOg, yellow needles, m.p.
286°.
CH2OH
HO O OCH3
Penicillium roseopurpureum Dierckx
559 A second pigment, carviolacin, CooHjeO;, light brown
needles, m.p. 243° (dec), was isolated from this mold.
It is apparently closely related in structure.
Theodore Posternak, Helv. Chim. Acta 23 1046 (1940).
H. G. Hind, Biochem. J. 34 67, 577 (1940).
560 Erythroglaucin (Catenarin 6-Methyl Ether), CigHisOg, deep red
plates or needles, m.p. 205°.
CH3O
Aspergillus glaucus (ten spp.)
The former rubroglaucin was shown to be a mixture of
physcion and erythroglaucin.
Julius Nicholson Ashley, Harold Raistrick and Taliesin
Richards, Biochem. J. 33 1291 (1939).
561 Neophromin, CieHisO,,, ocher colored needles, m.p. 198° (dec).
A quinone-like pigment.
Neophromium lusitanicinn
O. Hesse, J. prakt. Chem. 57 409 (1898).
562 Dermocybin, C^^-H^.^O-, red needles, m.p. 228°.
This is an incompletely characterized anthraquinone
pigment. It has five nuclear hydroxyl groups, one of
them methylated. It is produced along with emodin by
^^3 Anthraquinones
Cortinarius sanguineus (Wulf.) Fries and constitutes
0.2-0.4% of the mycelial weight.
Cortinarius cinnabarinus Fries produces a pigment
which is the same or similar.
Fritz Kogl and J. J. Postowsky, Ann. 444 1 (1925).
563, 564 Physcion Anthranols, Ci,jHi404, m.p.'s 260° and 181°.
CHsO^ II ,CH3 CH3O CH3
and
OH HO O OH
Aspergillus glaucus (five types)
Julius Nicholson Ashley, Harold Raistrick and Tallesin
Richards, Biochem. J. 33 1291 (1939).
565 Rhodocladonic Acid, Ci^Hj.Oc,, red needles, m.p. >360°.
O
'^
\
COOCHj
Thirteen Cladonia species
Shoji Shibata, Michio Takido and Osamu Tanaka, /. Am
Chem. Soc. 72 2789 (1950).
566 Nalgiolaxin, CisHi-OgCl, yellow plates or needles, m.p. 248°
[a].579o" +40.3° (in chloroform).
H3O
Penicillium nalgiovensis Laxa
H. Raistrick and J. Ziffer, Biochem. J. 49 563 (1951).
Pfizer Handbook of Microbial Metabolites 264
567 Nalgiovensin, CigHisOg, orange needles or plates, m.p. 199-
200°, [a]579o'° +39.7° (in chloroform).
OH
CH3O II CH2— CH— CH3
Penicillium nalgiovensis Laxa
H. Raistrick and J. ZifFer, Biochem. J. 49 563 (1951).
(Isolation)
A. J. Birch and R. A. Massy-Westropp, /. Chem. Soc, 2215
(1957). (Structure)
568 Thermophillin, CisHigOg, golden plates, m.p. subl. 245° (dec.
260° sealed tube).
Quinonoid properties.
Lenzites thermophila
H. S. Burton, Nature 166 570 (1950).
569 Phomazarin,* CigHiYOgN, orange needles, m.p., 197° (dec).
CH3CH2CH2CH2 O CH3CH2CH2CH" O
CHaO^ I II /COOH CH3O
I II OH I II I COOH
HO O HO O OH
Phoma terrestris Hansen
F. Kqgl and J. Sparenburg, Rec. trav. chim. 59 1180
(1940).'
F. Kogl and F. S. Quackenbush, ibid. 63 251 (1944).
F. Kogl, G. C. van Wessem and O. I. Elsbach, ibid. 64 23
(1945). (Synthesis)
570 Atrovenetin, CigHigOe, brownish yellow prisms, m.p. 295°
(dec), [a]546i'' +154° (c 0.486 in dioxan).
Penicillium atrovenetum G. Smith
* See addendum.
265 Anthraquinones
K. G. Neill and H. Raistrick, Chem. and Ind., 551
(1956). (Isolation)
Idem., Biochem. J. 65 166 (1957). (Isolation)
D. H. R. Barton, P. de Mayo, G. A. Morrison and H. Rai-
strick, Tetrahedron 6 48 (1959). (Structure)
571 Norherqiieinone, C19H1SO7, dark red needles, m.p. 279° (dec),
[a],r' +1080° ±60° (c 0.048 in pyridine).
Structure: Unmethylated herqueinone
See herqueinone for organism, structure and references.
572 Herquein, CigHooOg (proposed), yellow-brown crystals, m.p.
129° (decO.
Water-soluble. Fluoresces in alkali.
Penicillium herqiiei
H. Stowar Burton, Brit. J. Exptl. Path. 30 151 (1949).
573 Herqueinone, CooHoqOj, red needles, m.p. 226° (dec.) (sub-
limes), [aW- +440° ±40° (c 0.063 in ethanol).
Partial structure:
Penicillium herquei Bainier and Sartory
A crude pigment yield of 17% of the weight of the dry
mycelium was obtained. The major constituents were
norherqueinone and its methyl ether, herqueinone. Mi-
nor constituents were physcion and meso-erythritol.
The plant pigment, haemocorin, also contains the peri-
naphthenone nucleus.
Frank H. Stodola, Kenneth B. Raper and Dorothy 1. Fen-
neU, Nature 167 773 (1951). (Isolation)
J. A. Galarraga, K. G. NeUl and H. Raistrick, Biochem. J. 61
456 (1955).
D. H. R. Barton, P. de Mayo, G. A. Morrison, W. H. Schaeppi
and H. Raistrick, Chem. and Ind., 552 (1956). (Structure)
Robert E. Harman, James Cason, Frank H. Stodola and
A. Lester Adkins, /. Org. Chem. 20 1260 (1955).
574 Solorinic Acid, C01H20O7, red-brown plates, m.p. 203.5°.
CH3O 11 OH
\
CO(CH2)4CH3
OH
Pfizer Handbook of Microbial Metabolites 266
Solorina crocea (L. ) Ach.
G. Roller and H. Russ, Monatsh. 70 54 (1937).
575 Resistomycin, CouHi^Og, yellow needles, m.p. 315° (dec.) (sub-
limes from 215°).
CH3—
OH O
Streptomyces resistomycificus
Hans Brockmann and Giinter Schmidt-Kastner, Chevi. Ber.
87 1460 (1954). (Isolation)
H. Brockmann, E. Meyer and K. Schrempp, Dissertations,
University of Gottingen, 1954, 1958. (Partial structure by
courtesy of Prof. Brockmann)
576 Granatacin, C20H20O10, pomegranate-red crystals, m.p. 204-
206° (dec).
A tricyclic tetrahydroxyquinonedicarboxylic acid with
antibiotic properties.
Streptomyces olivaceus (Waksman) Waksman and
Henrici
R. Corbaz, L. Ettlinger, E. Gaumann, J. Kalvoda, W. Keller-
Schierlein, F. Kradolfer, B. K. Manukian, L. Neipp, V. Prelog,
P. Reusser and H. Zahner, Helv. Chim. Acta 40 1262 (1957).
577 Luteomycin (Antibiotic 289), C2cH;5;.OioN (proposed), (Hydro-
chloride) orange-yellow crystals, m.p. 199° (dec).
Color changes to purple in alkali. Positive quinone-
Na^COg, FeClg. Negative ninhydrin, biuret, MoUsch,
Fehling, Sakaguchi. Can be precipitated as reineckate,
helianthate or pier ate.
Streptomyces flaveolus, S. tanashiensis related to S. an-
tibiotic us
Toju Hata, Tomojiro Higuchi, Yoshimoto Sano and Katuko
Sawashi, Kitasato Arch. Exptl. Med. 22 229 (1949).
Hamao Umezawa, Tomio Takeuchi, Kazuo Nitta, Kenji
267
Anthraquinones
Maeda, Tadashi Yamamoto and Seizaburo Yamaoka, /. Anti-
biotics (Japan) 6A 45 (1953).
Teisuke Osato, Koki Yagishita, Ryozo Utahara, Masahiro
Ueda, Kenji Maeda and Hamao Umezawa, ibid. 6A 52 (1953).
Berislav Govorcin, Tehnicki Pregled 8 43 (1956).
578 Luteoleersin, C.uH.isOy, yellow crystals, m.p. 135°, [(z]r,46i" 214°
(c 0.456 in ethanol).
Believed to be a substituted quinone, containing two
active hydrogens. It was accompanied by a reduction
product :
579 Alboleersin, CoeH^nO^, colorless crystals, m.p. 215°, [a].r546i^^
274° (c 6.430 in ethanol).
Contains three active hydrogens.
Helmiiithosporiuin leersii Atkinson
Julius N. Ashley and Harold Raistrick, Biochem. J. 32 449
(1938).
580 Skyrin (Endothianin), C;^„HisOt,i, dark orange rods, m.p.
>380°.
Penicillium islandicum Sopp, P. wortmanni Klocker, P.
tardum Thom, P. rugulosum Thorn, Endothia parasitica
(Murr. ) Anderson and Anderson, E. fiuens Shear and
Stevens
All of these fungi produce a mixture of skyrin with
rugulosin.
F. Kogl and F. S. Quackenbush, Rec. trav. chim. 63 251
(1944).
Pfizer Handbook of Microbial Metabolites
268
Shoji Shibata, Osamu Tanaka, Goro Chihara and Horoshi
Mitsuhashi, Pharm. Bull. (Tokyo) 1 302 (1953).
Shoji Shibata, Takao Murakami, Osamu Tanaka, Goro Chi-
hara, Isao Kitagawa, Masashi Sumimoto and Chikara Kaneko,
ibid. 3 160 (1955). (Structure)
Shoji Shibata, Takao Murakami, Osamu Tanaka, Goro Chi-
hara and Masashi Sumimoto, ibid. 3 274 (1955).
J. Breen, J. C. Dacre, H. Raistrick and G. Smith, Biochem. J.
60 618 (1955).
Shoji Shibata, Michio Takido and Terumi Nakajima,
Pharm. Bull. (Tokyo) 3 286 (1955).
Yuzuru Yamamoto, Takeo Yamamoto, Skoichi Kanatomo
and Kiyoshi Tanimichi, /. Pharm. Soc. Japan 76 192 (1956).
Yazuru Yamamoto, Akira Hamaguchi, Isao Yamamoto and
Sumie Imai, ibid. 76 1428 (1956).
581 Pigment B: CsoHigOn.
CH2OH
HO O OH
582 Pigment C: CgoHigOia.
HO O OH
CHoOH
CH2OH
HO O OH
These are oxidized skyrins.
269
Anthraquinones
Penicilliiim islandicuvi N.R.R.L. 1175
Shoji Shibata, Michio Takido and Terumi Nakajima,
Pharm. Bull. (Tokyo) 3 286 (1955).
583 Iridoskyrin, CgoHigOig, irridescent red rods or plates, m.p. 358°.
HO O OH
HO O OH
Penicillium islandicum Sopp.
B. H. Howard and H. Raistrick, Biochem. J. 57 212 (1954).
584 Aurofusarin, CyijHooOio, m.p. >360°.
This Incompletely characterized pigment produced by
Fusarium culinorum W. G. Smith may be a dianthraqui-
none.
Julius N. Ashley, Betty C. Hobbs and Harold Raistrick,
Biochem. J. 31 385 (1937).
585 Penicilliopsin, C30H22O8, orange crystals, m.p. 330° (dec.)-
HO O OH
Penicilliopsis clavariaeformis Solms-Laubach
H. Brockmann and H. Eggers, Angew. Chem. 67 706 (1955).
Pfizer Handbook of Microbial Metabolites
270
586 Rugulosin (Radicalisin), C30H00O10, yellow prisms, m.p. 293'
(dec), [a]546i'' +605° (dioxane).
Penicillium rugulosum Thorn, P. tardum Thorn, P.
wortmanni Klocker, Endothia parasitica (Murr. ) Ander-
son and Anderson, E. fiiiens Shear and Stevens.
About 20% of the dry weight of P. rugulosum myce-
lium is rugulosin.
J. Breen, J. C. Dacre, H. Raistrick and G. S. Smith,
Biochem. J. 60 618 (1955).
Shoji Shibata, Osamu Tanaka, Goro Chihara and Horoshl
Mitsuhashi, Pharm. Bull. (Tokyo) 1 302 (1953).
Shoji Shibata, Takao Murakami, Osamu Tanaka, Goro Chi-
hara, Isao Kitagawa, Masashi Sumimoto and Chikara Kaneko,
ibid. 3 160 (1955). (Structure)
Shoji Shibata, Takao Murakami, Osamu Tanaka, Goro Chi-
hara and Masashi Sumimoto, ibid. 3 274 (1955).
Yazuru Yamamoto, Akira Hamaguchi, Isao Yamamoto and
Sumie Imai, J. Pharm. Soc. Japan 76 1428 (1956).
Shoji-Shibata and Isao Kitagawa, Pharm. Bull. (Tokyo) 4
309 (1956). (Structure)
587 Rubroskyrin, C30H22O12, dark red plates, m.p. 289° (dec).
O O OH
271 Anthraquinones
Penicilliinn islaudiciim Sopp.
This pigment is produced in a mixture including is-
landicin, iridoskyrin, erythroskyrin, catenarin, luteoskyrin
and skyrin. The weight of the pigment mixture is about
10% of the weight of the dry mycelium.
Shoji Shibata and Isao Kitagawa, Pharm. Bull. (Tokyo) 4
309 (1956).
588 Luteoskyrin, C;^oH^,._.0,^,, yellow needles, m.p. 273° (dec), [aln^^
-880° (in acetone).
HO
OH
HO
HO
O OH
O OH
CHs
CH3
^1
HO
OH
Penicillium islandicum Sopp.
Shoji Shibata and Isao Kitagawa, Pharm. Bull. (Tokyo) 4
309 (1956). (Structure)
589 Cercosporin, C^oH.sO^o, red crystals, m.p. 241°, [a]:,,,,!.'" +470°
(c 0.5 in chloroform).
This pigment contains two methoxyl groups, two
quinoid carbonyls, two phenolic hydroxyls and two alco-
holic hydroxyls. The yield was 79 mg. per gram of dry
mycelium.
Shimpei Kuyama and Teiichi Tamura, /. Am. Chem. Soc.
79 5725, 5726 (1957).
3,591 Chaetochrysin and Chaetoflavin, C^iHoj-Oi,, yellow crystals, no
592 melting point, and Chaetoalbin, CaoHo^.-joOj], white crys-
tals, no melting point.
These uncharacterized compounds were isolated from
mycelial extracts along with chrysophanol. They seem to
be modified dianthraquinones. They yield some chrysoph-
anol on alkaline oxidation, contain one methoxyl group
and have high optical rotations.
Chaetomiiim affine Corda
Vincent Arkley, F. M. Dean, Peter Jones, Alexander Robert-
son and John Tetaz, Croat. Chem. Acta 29 141 (1957).
Pfizer Handbook of Microbial Metabolites 272
593 Rifomycin B, C39H51O14N, m.p. 160-164° (dec).
A dibasic acid (pKs 2.8, 6.7). Probably a quinone
(U.V. peaks at 400-460, also at 223, 234).
Streptomyces mediterranean
P. Sensi, A. Greco and R. Ballotta, 7th Annual Symposium
on Antibiotics, Washington, 1959.
594 Vinacetin, yellow platelets, m.p. 157°.
Apparently quinoid. Positive FeClg, violet color in
alkali, positive Molisch, Liebermann, Fehling. Negative
ninhydrin, Millon, Sakaguchi.
Streptomyces sp.
Kyuzo Omachi, J. Antibiotics (Japan) 6A 73 (1953).
595 Rhodophyscin, red leaflets, m.p. 260° (dec).
A quinone-like substance.
Physica endococcina
Wilhelm Zopf, Ann. 340 276 (1905).
13
Tetracycline, Analogues and Related Sub-
stances
The tetracycline antibiotics display features indicative of an
acetate origin. The oxygenation pattern is generally consistent
as are the points of occurrence of methyl groups and halogen
atoms. There is also at least a superficial resemblance to
proved acetate derivatives such as the anthraquinones. So far
the experimental evidence published concerning the biosyn-
thetic origin of the tetracyclines has been limited, and some in-
teresting obscurities remain.
The general concept of an acetate-derived precursor in the
sense of a polyketomethylene chain is, in the case of oxytetra-
cycline as follows:
./
C, lO]
C C
/
[O]
\
Ci
10]C
/
c
/ \
o o o o
loi
A 6-demethyltetracychne has been isolated from a fermentation
broth, and tetracycline itself is a 5-deoxyoxytetracychne as well
as a 7-dechlorochlortetracycUne; so sometimes some of the steps
in the biosynthetic scheme are omitted.
Pfizer Handbook of Microbial Metabolites 274
The production by Streptomyces rimosus of oxytetracy-
cline-X\ a modification of Terramycin in which there is an
acetyl group instead of a carboxamide group at position 2, sup-
ports the acetate theory since terramycin-X is more directly in
the line of descent from a polyketomethylene chain (ten head
to tail condensed acetate units) than is Terramycin itself.
The dehydro derivatives which have been isolated- also may
be considered as precursors of the other tetracyclines since the
additional double bond may be the (as yet unreduced) result of
an aldol type of condensative ring closure with elimination of a
water molecule.
More experimental work has been reported on the biosyn-
thetic origin of oxytetracycline than on that of related sub-
stances. Addition of C^Hj-methionine and 2-C^*-acetic acid to
oxytetracycline-producing fermentations yields radioactive oxy-
tetracycline (Terramycin). Quantitative degradation and
counting studies show that methionine furnishes the C,5-methyl
and the N-methyl groups. The radioactivity of the degradation
fragments from the molecule which had incorporated 2-C'^-
acetic acid indicated that most of the molecule is in quantitative
agreement with the theoretical requirements for acetate deriva-
tion.^' *
Results are entirely consistent with formation of the ring
skeleton at least from C- to C^o by head to tail linkage of acetate
units. Glutamic acid has been considered as a possible precur-
sor of part of the A-ring (carboxamide side-chain, carbon atoms
2, 3, 4, 4a and the 4-amino nitrogen) and 2-C^ '-labeled glutamic
acid yielded a labeled oxytetracycline.-^ Later evidence'' indi-
cates that acetate also is capable of furnishing these carbon
atoms although the level of activity in the A-ring seems to be
somewhat lower than the theoretical, particularly in Terramycin
isolated from older fermentations. The degradation fragments
^ F. A. Hochstein, M. Schach von Wittenau, Fred W. Tanner, Jr.
and K. Murai, /. Am. Chem. Soc. 82 (1960). (In press)
- J. R. D. McCormick, Philip A. Miller, John A. Growich, Newell O.
Sjolander and Albert P. Doerschuk, ibid. 80 5572 (1958).
3 A. J. Birch, J. F. Snell and P. L. Thompson, ibid. 82 2402 (1960).
4 A. J. Birch and P. L. Thompson, ibid. 82 (1960). (In press)
^ J. F. Snell, R. L. Wagner, Jr. and F. A. Hochstein, Internal.
Conf. on Peaceful Uses of Atomic Energy, 431 (1955); J. F. Snell,
Symposium on Uses of Isotopes, Uniontown, Pa., 1957.
'A. J. Birch and P. L. Thompson, ]. Am. Chem. Soc. 82 (1960).
(In press)
275 Tetracycline, Analogues and Related Substances
from this portion of the molecule are not satisfactory for the
clarification of the origin of the A-ring. It remains to be seen
whether or not a less direct mechanism of acetate incorporation
prevails in this area.
The isolation and identification of oxytetracycline-X (2-acetyl-
2-decarboxamidooxytetracycline), a lower potency antibiotic,
from cultures of Streptoviyces rimosus, the Terramycin pro-
ducer, seem to support in a general way the idea of the acetate
derivation of ring A. It is tempting to speculate that oxytetra-
CHj CH3
CH3 OHOH^N
cycline-X may be a precursor of oxy tetracycline, but this has not
been proved.
With the acetate theory as a guide, it is possible to extrapolate
some predictions from the tetracyclines isolated and character-
ized to date. It would seem probable that other mutations of
the producing organisms might be obtained in which one minor
biosynthetic step is blocked. Thus, retention of an oxygen atom
at position 8 might be expected. Similarly, other tetracyclines
lacking the Cfi-methyl and/or hydroxyl groups, the Ci2a-hydroxyl
group and perhaps the N-methyl groups may be found. It is
also possible that glycosides may be isolated as in the pyrromy-
cinones.
The pyrromycinones are produced by streptomyces species,
and they bear some resemblance to the tetracyclines. The four
linear rings appearing in various states of oxidation and the
similarity in the number of carbon atoms make it seem that
their biogenetic origin may be similar to that of the tetracy-
clines. Apparently no experimental work has been published
on this point. There is probably a close relationship among the
pyrromycinones, rhodomycinones and quinocyclines. All of
these pigments are found occasionally as glycosides, but no
tetracycline glycosides have been reported yet.
The rhodomycins are a complex of red pigments produced
by Streptomyces purpurascens. The original complex was sepa-
Pfizer Handbook of Microbial Metabolites 276
rated into four components; rhodomycin A, isorhodomycin A,
rhodomycin B and isorhodomycin B. The first three were iso-
lated in the crystalline state. These substances contained nitro-
gen, and, on mild acid hydrolysis, yielded an amino sugar, rho-
dosamine, CgHi703N, plus the aglycones (rhodomycinones,
isorhodomycinones ) .
The same organism has yielded a number of other pigments
which do not contain nitrogen. These also have been desig-
nated rhodomycinones. Three of these, ^, e and iso-e have been
obtained crystalline. It has been reported (no experimental
details) that a y-rhodomycinone and six other rhodomycinones
have been isolated "in substance" and that three others have
been demonstrated by paper chromatography. The rhodomy-
cinones seem to resemble the pyrromycinones, quinocyclines,
cinerubins and rutilantinone.
596 Rhodomycin A (Hydrochloride), C20H29O7NHCI, fine, dark red
needles, m.p. 193° (dec.) (preheated block).
Hans Brockmann and Use Borchers, Chem. Ber. 86 261
(1953).
597 Isorhodomycin A (Hydrochloride), CooHsgOgNHCl (proposed),
m.p. 220°, [a]606-76o'' +268 ±30° (c 0.1 in methanol).
Hans Brockmann and Peter Patt, Chem. Ber. 88 1455
(1955).
598 Rhodomycin B (Hydrochloride), C19H27O7NHCI, red prisms,
m.p. 180°, [a]606-76o'' +174 ±10° (c 0.05 in methanol).
An isorhodomycin B also was present.
Hans Brockmann and Peter Patt, Chem. Ber. 88 1455
(1955).
599 ^-Rhodomycinone, C2oHi40g (proposed), dark red needles, m.p.
225°.
Hans Brockmann and Burchard Franck, Chem. Ber. 88
1792 (1955). (Isolation)
Hans Brockmann and P. Boldt, Naturwissenschaften 44 616
(1957). (Revised empirical formula)
600 €-Rhodomycinone, C2iH220g, thick red prisms, m.p. 185° (dec.
at 208°)
and
601 £ -Isorhodomycinone, C20H20O9, dark red leaflets, m.p. 245°
(dec).
277
Tetracycline, Analogues and Related Substances
Hans Brockmann and Burchard Franck, Chem Ber 88 1792
(1955). (Isolation)
Other references:
Hans Brockmann and Klaus Bauer, Naturivissenschaften 37
Hans Brockmann, Klaus Bauer and Use Borchers Chem
Ber. 84 700 (1951).
Hans Brockmann and Enno Spohler, Naturivissenschaften
42 154 (1955). (Characterization of rhodosamine)
Hans Brockmann, German Patent 913,813 (1954).
602 7-Chloro-6-demethyltetracycline, C,iH,iOsNoCl (isolated as the
sesquihydrate), yellow crystals, m.p. 174-178° (dec )
[<x]^-' -258° (0.5% in 0.1 N sulfuric acid). ' '
CONH2
Streptomyces aureofaciens Duggar (mutant)
J. R. D. McCormick, NeweU O. Sjolander, Ursula Hirsh
Ekner R. Jensen and Albert P. Doerschuk, /. Am. Chem Soc
79 4561 (1957).
603 6-Demethyltetracycline, CaiHssOgNoCl (isolated as the hydro-
chloride hemihydrate), yellow crystals, m.p. 203-209°
(dec), [aJD -259° (c 0.5 in 0.1 N sulfuric acid).
CONH2
Streptomyces aureofaciens Duggar (mutant)
J. R. D. McCormick, Newell O. Sjolander, Ursula Hirsh,
Elmer R. Jensen and Albert P. Doerschuk, /. Am. Chem. Soc
79 4561 (1957).
Pfizer Handbook of Microbial Metabolites 278
604 7^-Pyrromycinone, C22H16O7, red needles, m.p. 236° (sublimes).
OH O OH
CH3
XH3^
OH O COOCH3
Streptomyces spp.
Hans Brockmann and Werner Lenk, Chem. Ber. 92 1880
(1959). (Structure)
Hans Brockmann and Hans Brockmann, Jr., Naturwissen-
sctiaften 47 135 (1960). (Revised structure)
605 ^-Pyrromycinone, CooHooO^, orange-red needles, m.p. 216° (sub-
limes), [air,.'" +74 ±6° (in chloroform).
OH O
CH
OH O COOCH3
Streptomyces spp.
Brockmann and collaborators have isolated about a
dozen pigments of this type from various unclassified
streptomycetes.
Hans Brockmann and Burchard Franck, Chem. Ber. 88 1792
(1955).
H. Brockmann, Luis Costa Pla and W. Lenk, Angew. Chem.
69 477 (1957).
H. Brockmann and P. Boldt, Naturwissenschaften 44 616
(1957).
Hans Brockmann and Werner Lenk, Chem. Ber. 92 1880
(1959). (Structure)
Idem., Naturwissenschaften 47 135 (1960). (Revised
structure)
606 c-Pyrromycinone (Rutilantinone), C2L.H2()Of,, orange-red needles,
m.p. 213°, [aW +143 ±7° (c 1.0 in chloroform).
XHo
OH O COOCH3
Streptomyces spp.
279
Tetracycline, Analogues and Related Substances
607
6-Pyrromycinone occurs as such and also as the chro-
mophore of the antibiotics pyrromycin and the cinerubins.
It is identical with rutilantinone.
Hans Brockmann and Werner Lenk, Chem. Ber. 92 1880
(1959). (Structure)
Idem., Naturwissenschaften 47 135 (1960). (Revised
structure)
H. Brockmann, H. Brockmann, Jr., J. J. Gordon, W. Keller-
Schierlein, W. Lenk, W. D. Ollis, V. Prelog and I. O. Suther-
land, Tetrahedron Letters No. 8, p. 25 (1960).
W. D. Ollis, I. O. Sutherland and J. J. Gordon, Tetrahedron
Letters No. 16, p. 17 (1959).
7-Chloro-5a(Ila)-dehydrotetracycline, C<,.H.iOsN^Cl, [ajo^' 15.5°
(c 0.65 in 0.03 N hydrochloric acid).
CONH2
OH O O O
Streptomyces aiireofaciens Duggar inutant
The analogous compounds in which the chlorine atom
is replaced by H and Br are also claimed.
J. R. D. McCormick, Philip A. Miller, John A. Growich,
Newell O. Sjolander and Albert P. Doerschuk, /. A?n. Chem.
Soc. 80 5572 (1958).
608 Chlortetracycline (Aureomycin, Biomycin), C22H23O8N2CI, fine
yellow crystals, m.p. 168°, [aln'' -274.9° (in methanol).
CH3 CH3
CONH2
OH O OH O
Streptomyces aureofaciens
R. W. Broschard, A. C. Dornbush, S. Gordon, B. L. Hutch-
ings, A. R. Kohler, G. Krupka, S. Kuchner, D. V. Lefemine and
C. Pidacks, Science 109 199 (1949). (Isolation)
Benjamin M. Duggar, U. S. Patent 2,482,055 (1949).
C. R. Stephens, L. H. Conover, F. A. Hochstein, P. P. Regna,
F. J. Pilgrim, K. J. Brunings and R. B. Woodward, /. Am.
Chem. Soc. 74 4976 (1952).
Pfizer Handbook of Microbial Metabolites 280
C. W. Waller, B. L. Hutchings, R. W. Broschard, A. A. Gold-
man, W. J. Stein, C. F. Wolf and J. H. Williams, ibid. 74 4981
(1952).
609 Bromotetracycline, CooHogOgN.Br, m.p. 170-172°, [ale'" -196°
(in 0.1 N hydrochloric acid).
000
H H
CONH2
Streptomyces aureofaciens
P. Sensi, G. A. DeFerrari, G. G. Gallo and G. Holland, II
Farmaco Ed. sci. (Pavia) 10 337 (1955).
610 Oxytetracycline ( Terramycin ) , C00H04O9N2, light-yellow crys-
tals, m.p. (anhydride) '--'185° (dec), [ajo'^ (dihydrate)
-196.6° (c 1.0 in 0.1 N hydrochloric acid).
CH3 CH3
CH3 OH OH N
OH
CONH2
OH O OH ^
Streptomyces rimosus
A. C. Finlay, G. L. Hobby, S. Y. P'An, P. P. Regna, J. B.
Routien,-D. B. Seeley, G. M. ShuU, B. A. Sobin, I. A. Solomons,
J. W. Vinson and J. H. Kane, Science 111 85 (1950). (Iso-
lation)
Ben A. Sobin, Alexander C. Finlay and Jasper H. Kane,
U. S. Patent 2,516,080 (1950).
Peter P. Regna, I. A. Solomons, Kotaro Murai, Albert E.
Timreck, Karl J. Brunings and W. A. Lazier, J. Am. Chem.
Soc. 73 4211 (1951).
C. R. Stephens, L. H. Conover, F. A. Hochstein, P. P. Regna,
F. J. Pilgrim, K. J. Brunings and R. B. Woodward, ibid. 74
4976 (1952).
F. A. Hochstein, C. R. Stephens, L. H. Conover, P. P. Regna,
R. Pasternack, P. N. Gordon, F. J. Pilgrim, K. J. Brunings and
R. B. Woodward, ibid. 75 5455 (1953). (Structure)
611 Antibiotic X-340, CosHooOe, yellow needles, m.p. 330° (dec).
An antibiotic isolated from the mycelium of an uniden-
28l
Tetracycline, Analogues and Related Substances
tified streptomycete. The molecular weight was about
390. Contained 3 — OH groups (one acidic) and one
C — CH;5 group. Monomethyl derivative with diazometh-
ane. Mono- and tri-acetates were formed, depending on
method. The infrared absorption pattern was similar to
that of Terramycin. The following partial structure was
proposed :
— CH3
—OH
— CH=CH
I — 2H
— CH=CH
2 double bonds
_1 unplaced O-atom
V. C. Vora, K. Shete and M. M. Dhar, J. Sci. Ind. Research
(India) 16C 182 (1957). (Isolation)
612 2- Ace tyl-2-decarboxamidooxy tetracycline ( Terramycin-X ) (Hy-
drochloride), CogHsgOgN-HCl, ycllow crystals, m.p. 201-
203°, [ale'" -46.6° (c 0.9 in 0.1 N hydrochloric acid).
Streptomyces rimosus
F. A. Hochstein, M. Schach von Wittenau, F. W. Tanner, Jr.
and K. Murai, /. Am. Chem. Soc. 82 (1960). (In press)
613 Tetracycline (Achromycin, Tetracyn, Polycycline, Panmycin),
C22H24OSN0, yellow crystals, m.p. 170-175° (dec), [aW^
-239° (c i.O in methanol).
CONH2
Streptomyces sp.
Pfizer Handbook of Microbial Metabolites
282
Tetracycline was first prepared by catalytic dechlorina-
tion of chlortetracycline but was later isolated as a pri-
mary fermentation product.
P. Paul Miuieri, Melvin C. Firman, A. G. Mistretta, Anthony
Abbey, Clark E. Bricker, Neil E. Rigler and Herman Sokol,
"Antibiotics Annual 1953-1954," Medical Encyclopedia, Inc.,
New York, p. 81. (Isolation)
614 Quinocyclines (PA-121)
A complex of tetracyclic amphoteric antibiotic yellow
pigments, which in some respects resemble nitrogen-con-
taining hydroxy anthraquinones.
Six active components have been separated and analy-
ses and color reactions were determined.
Two components have an aglycone with the probable
empirical formula Co-H^oOc.N^.
Streptomyces sp.
W. D. Celmer, K. Murai, K. V. Rao, F. W. Tanner, Jr. and
W. S. Marsh, "Antibiotics Annual 1957-1958," Medical En-
cyclopedia, Inc., New York, p. 484. (Isolation)
Charles R. Stephens, unpublished. (Empirical formula)
615 7;-Pyrromycin, C30H35O11N (Hydrochloride), red crystals, m.p.
162° (dec), [a]c,r" +132 ±27° (c 0.4 in methanol).
CH3I
>Rhodosamine
OH O
CH2
COOCH3
A streptomycete
The relationship to e-pyrromycinone and to the cineru-
bins should be noted.
Hans Brockmann and Werner Lenk, Chem. Ber. 92 1904
(1959). (Structure)
Hans Brockmann and Hans Brockmann, Jr., Naturwis-
senschaften 47 135 (1960).
283 Tetracycline, Analogues and Related Substances
616 Aklavin, C:^oH;i-0,,N (Hydrochloride) orange crystals, m.p.
197°.
Amphoteric. Contains an amino sugar, C.^Hj^OiN, iso-
meric with mycaminose or amosamine linked glycosidi-
cally to the secondary hydroxyl group.
Streptomyces sp.
F. Strehtz, H. Flon, U. Weiss and I. N. Asheshor, ]. Bacte-
riol. 72 90 (1956).
617 Cinerubins
Cinerubins A and B are isomeric red bases, with the
empirical formula C44H.-,.,OisN±CHo. The chromophoric
aglycone has been shown to be identical with e-pyrromy-
cinone. Both cinerubins also contain three sugars, two
of these being the same in both compounds, but the third
one being characteristic. The structures of these sugars
have not been reported yet.
Streptomyces antihioticus (Waksman and Woodruff)
Waksman et Henrici, S. galiloeus Etthnger et al., S. niveo-
ruber Ettlinger et al.
Leopold Ettlinger, Ernest Gaumann, Ralf Hiitter, Walter
Keller-Schierlein, Frlederich Kradolfer, Lucien Neipp, Vlado
Prelog, Pierre Reusser and Hans Zahner, Chem. Ber. 92 1867
(1959).
14
Aromatic Compounds Not Classified
Elsewhere
This chapter includes a heterogeneous group of aromatic
compounds which arise from different biosynthetic routes. Cin-
namic acid and its derivatives undoubtedly are formed by way
of the shikimic acid pathway.^' ^ The occurrence of anisalde-
hyde and anisic acid derivatives in the same fermentation with
methyl p-methoxycinnamate suggests that the former may be
degradation products of the latter.
Chloramphenicol, too, has a Ce-Ca skeleton which seems to
relate it to the shikimic acid pathway. It has been shown that
p-nitrophenylserinol does not act as a precursor, and, when it is
added to fermentations, it is acetylated but not dichloroacety-
lated. C"-Labeled p-nitrophenylserinol is not incorporated into
the chloramphenicol molecule nor is C"-labeled dichloroacetic
acid. Thus, what appears to be a logical step in the biosynthe-
sis— the dichloroacetylation of p-nitrophenylserinol — does not
occur.^
The tricarboxylic acid produced by Chaetomium indicum is
evidently formed by the condensation of a-ketoglutaric acid with
phenylpyruvic acid.
The lichen acids of this chapter show a provocative symme-
try, and the incorporation of amino acids into two of them is in-
teresting. The diphenylbutadiene structure has been found
also in xanthocillin. Apparently there has been no experimen-
tal study of their biogenesis.
^ Friedrich Weygand and Heinz Wendt, Z. Natiirforsch. 14b 421
(1959).
2T. A. Geissman and T. Swain, Chem. and Ind., 984 (1957).
3 David Gottlieb, P. W. Robbins and H. E. Carter, J. Bacterial. 72
153 (1956).
285 Aromatic Compounds Not Classified Elsewhere
618 Benzoic Acid, C7H,;0o, colorless tablets, m.p. 122.5°.
COOH
Yeast
Richard Kuhn and Klaus Schwarz, Ber. 74 1617 (1941).
619 Anisaldehyde, CsHgOo, oily liquid, b.p. 248°, n^'^ 1.5764.
CHO
OCH3
Trametes suavolens (Linn.) Fr., Lentinus lepideus,
Daedalea juniperina
J. H. Birkinshaw, A. Bracken and W. P. K. Findlay,
Biochem. }. 38 131 (1944).
J. H. Birkinshaw and P. Chaplen, ibid. 60 255 (1955).
620 trans-Cinnamic Acid, CgHgOs, colorless crystals, m.p. 133°.
/ ^CH=CH— COOH
Ceratostomella firnbriata (on sweet potato culture)
Takashi Kubota and Keizo Naya, Chem. and Ind., 1427
(1954).
621 trans-Cinnamic Acid Amide, C9H9ON, colorless crystals, m.p.
147-149°.
/ '^CH=CH— CONH2
Streptomyces sp.
Yasuharu Sekizawa, /. Biochem. Japan 45 9 (1958). (Iso-
lation )
622 Methyl Anisate, C9H10O3, colorless crystals, m.p. 48°, b.p. 256°.
COOCH3
OCH3
Pfizer Handbook of Microbial Metabolites 286
Travietes suavolens (Linn.) Fr., Lentinus lepideus
J. H. Birkinshaw, A. Bracken and W. P. K. Findlay, Biochem.
J. 38 131 (1944).
623 Methyl trans-Cinnamate, CioHk.Oo, clear, pale yellow oil, b.p.
94-110° (2-3 mm.) or white crystals, m.p. 35-37°, nn'^
1.5766
rv<
CH=CH— COOCH3
Lentinus lepideus Fr. (artificial medium)
John Howard Birkinshaw and Waher Phihp Kennedy Find-
lay, Biochem. J. 34 82 (1940).
624 Methyl p-Coumarate, CioHjoOg, colorless crystals, m.p. 137-
139°.
HO—/ \— CH=CH— COOCH3
Lentinus lepideus
H. Shimazono and F. F. Nord, Arch. Biochem. and Biophys.
78 263 (1958).
625 Methyl p-Methoxycinnamate, CnHioOy, colorless crystals, m.p.
88°.
CH3O— / y-CH=CH— COOCH3
Lentinus lepideus Fr. (artificial medium)
John Howard Birkinshaw and Waker PhiHp Kennedy Find-
lay, Biochem. J. 34 82 (1940).
626 Chloramphenicol (Chloromycetin, Levomycetin),CiiHi20.-,NoCl2,
colorless crystals, m.p. 149.7°, [oc]d-'' —25.5° (in ethyl ace-
tate).
OH
O2N— <^^>— CH— CH— CHoOH
NHCOCHCI.
Streptomyces venezuelae
John Ehrlich, Quentin R. Bartz, Robert M. Smith, Dwight A.
Joslyn and Paul R. Burkholder, Science 106 417 (1947). (Iso-
lation)
John Controulis, Mildred C. Rebstock and Harry M. Crooks,
Jr., J. Am. Chem. Soc. 71 2463 (1949). (Synthesis)
287 Aromatic Compounds Not Classified Elsewhere
Loren M. Long and H. D. Troutman, ibid. 71 2469 (1949).
627 1,8-Dimethoxynaphthalene, C,^.H,oO.>, colorless crystals, m.p.
158-161°.
CH3O OCH;,
Daldinia concentrica
8-Methoxyl-l-naphthol also was identified (by paper
chromatography ) .
D. C. Allport and J. D. Bu'Lock, /. Chem. Soc, 654 (1960).
628 4-Carboxy-2-oxo-3-phenylhept-3-enedioic Acid, C14H12O7, colorless
prisms, m.p. 170° (dec).
O COOH
HOOC— C— C=C— CH.— CH.— COOH
Chaetomium indicum Corda
The yield was 250-500 mg. per liter. In addition to
the acid above, two uncharacterized compounds were iso-
lated in smaller quantities: Metabolite A, C2,jH:^70(;N, pale
yellow needles, m.p. 159°, [a],r" +11.4° (c 1.022 in chlo-
roform). Yield 1.5-2.0 g. from 100 1. of broth. Soluble
in aqueous NaHCOg. Wine red FeCl, test. Formed an
insoluble green-blue copper derivative.
Metabolite B, colorless prisms, m.p. 146°, [a],,-" +120°
(c 1.01 in chloroform).
Analysis: C 68.1, H 8.2, N 2.7, C-methyl 12^^. Same
color tests as A above.
D. H. Johnson, Alexander Robertson and W. B. Whalley, /.
Chem. Soc, 2429 (1953).
629 Pulvic Anhydride, CiyHi„04, yellow needles, m.p. 222-224°.
o c=o
o=c-
Sticta aurata Ach.
Pfizer Handbook of Microbial Metabolites 288
O. Hesse, J. prakt. Chem. 170 334 (1900).
630 Calycin, CisHjoOg, orange-red crystals, m.p. 244°.
o c=o
^-cJ-c=c-Q)
\ c — -o
OH,|
o
Lepraria candelaris Schaer., Sticta aurata Ach. and
Sticta crocata Ach.
Mitizo Asano and Yukio Kameda, Ber. 68 1568 (1935).
631 Vulpinic Acid, C19H14O5, yellow crystals, m.p. 148°.
COOCH3
0-kc-c=c-Q)
I OH I
o c=o
Evernia vul-pina L., Cyphelium chrysocephalum Ach.,
Calicium chlorinum Korper, Cetraria juniperina Fr. var.
tubulosa Schaer and Cetraria pinastri (Scop.)
P. Karrer, K. A. Gehrckens and W. Heuss, Helv. Chim. Acta
9 446 (1926). (Structure)
632 Pinastric Acid ( Chry socetraric Acid), CooHigOe, orange needles,
m.p. 200-203°.
OH COOCH3
_ CH3O— /^^c=c— c=c— ^^>
o=c o
Lepraria fiava (Schreber. ) f. quercina, Cetraria pinastri
(Scop.), Cetraria tubulosa (Schreb.), Cetraria juniperina
L. (Ach.)
Mitizo Asano and Yukio Kameda, Ber. 68 1565 (1935).
(Structure)
633 Leprapic Acid (Leprapinic Acid, Methyl 2-Methoxypulvlnate ) ,
CsoHieOg, golden plates, m.p. 159°.
COOCH3 OH
\^ o — c=o
OCH3
289 Aromatic Compounds Not Classified Elsewhere
Lepraria citrina
O. P. Mittal and T. R. Seshadri, J. Chem. Soc, 3053 (1955).
(Isolation)
Idem., ibid., 1734 (1956). (Synthesis)
634 Mycolutein, C00H24O6N (proposed), bright yellow tablets, m.p.
157°, [afn"' +54° (c 1 in chloroform).
Contains an aromatic nucleus. Alkali-unstable. Neg-
ative FeCla. Decolorizes bromine with HBr evolution.
Streptomijces sp.
Henry Schmitz and Robert Woodside, Antibiotics and
Chemotherapy 5 652 (1955).
635 Epanorin, CosHojOoN, yellow needles, m.p. 135°, [ajo^^ -1.86
±0.2° (c 6.48 in chloroform).
CH2— CH(CH3)2
I
NH— CH— COOCH3
I
C=0 OH
<Q>-C=C-C=C-Q)
o c=o
Lecanora epanora Ach.
Zeorin was found in the same extract.
Robert L. Frank, S. Mark Cohen and James N. Coker, /. Am.
Chem. Soc. 72 4454 (1950). (Structure and synthesis)
636 Rhizocarpic Acid, CogHssOeN, yellow needles, m.p. 177°, [ajn^"
+ 110.4° ±2.1° (c 1.22 in chloroform).
COOCH3
NH— CH— CH2— (^^>
C=0 OH
<Q_kc-c=c-Q>
o c=o
Rhizocarpon geographicum L.,R. viridiatrum Flk., Cali-
cium hyperellum Ach.
Robert L. Frank, S. Mark Cohen and James N. Coker, /. Am.
Chem. Soc. 72 4454 (1950). (Synthesis)
15
Amines
Much remains to be learned concerning the earlier stages of
nitrogen metabolism in microorganisms. Practically, the abil-
ity of certain soil bacteria (in combination with legumes) to fix
gaseous nitrogen has been exploited for many years. Research
in this area has been reviewed.^ Ammonia, methane, hydrogen
and water probably were present in the atmosphere of the primi-
tive earth, and it has been shown- that amino acids can be
formed by electric discharges through such mixtures.
While we are primarily concerned in this compilation with
metabolites isolated from microorganisms growing in the wild
state or cultivated on an essentially glucose medium, the more
complex amines are generally only remotely derived from sugar,
often by way of the amino acids. A large hterature exists on
the ability of bacteria to decarboxylate amino acids to amines,
these experiments generally involving addition of the amino
acid to the medium. It has been shown,^ however, that many
bacteria which produce amines on a casein hydrolysate medium
do not do so on a synthetic medium with ammonium salts the
only nitrogen source. Studies with Escherichia coli* indicate
that aspartic acid and alanine and perhaps glutamic acid serve
as important nitrogen entry vehicles. These acids can supply
the total nitrogen requirement if no ammonium ion is available,
^ William D. McElroy and Bentley Glass, "Inorganic Nitrogen
Metabolism," Johns Hopkins Press, Baltimore, 1956.
2 Stanley L. Miller, Science 117 528 (1953); idem., J. Am. Chem.
Soc. 77 2351 (1955).
3 H. Proom and A. J. Woiwod, J. Gen. Microbiol. 5 930 (1951).
* "Studies of Biosynthesis in E. coli," Carnegie Institute of Wash-
ington Publication 607, Washington, 1955.
291 Amines
and, even when it is, much of the cellular nitrogen is derived
from them by transamination.
Within the frame of our present endeavor there seems to have
been little systematic, comparative study of the amine metab-
olites of microorganisms. This has been true particularly of
the fungi, which generally have been considered to have a
poorer nitrogen metabolism than the bacteria. Apparently this
situation is being remedied, at least for higher fungi. Recently
the amine content of 105 species, representing 18 families of
higher fungi, was investigated.^ It was found that ammonia
was distributed universally, and that the ammonia content in-
creased with the age of the fruiting body. Methylamine oc-
curred in 22 species, diinethylamine in 10, trimethylamine in 8,
isoamylamine in 19 and /^-phenylethylamine in 4. Earlier work
was reviewed also, a distinction being made between the amines
present in fresh fruiting bodies and those present after au-
tolysis.
Also an exceptionally thorough analysis was made recently
of the basic constituents of the fruiting body of a single basidio-
mycete, Polyporus sulfureusJ' These included amines, basic
amino acids, nucleotides and betaines. Many of the simple
amines produced by Claviceps purpurea have been identified
during the extensive studies of ergot, and these are listed in the
introduction to the section on ergot alkaloids in the chapter on
Heterocycles.
Muscarine, a compound which might have been classified un-
der several different chapter headings, is apparently a deriva-
tive of a l-amino-3,6-desoxyhexose and is probably more di-
rectly connected with sugar metabolism than many of the
amines listed here.
Amino sugars and other complex amines are listed elsewhere
under more appropriate classifications.
It has been shown that putrescine furnishes the 4-carbon
atom moiety of spermine and spermidine in Neurospora crassaj
and that methionine supplies the 3-carbon chain of spermidine
in the same organism."^ It is known that ATP and Mg"* are re-
^Elard Stein von Kamienski, Planta 50 331 (1958).
6 P. H. List, Planta Med. 6 424 (1958).
^ H. Tabor, S. M. Rosenthal and C. W. Tabor, Federation Proc. 15
367 (1956).
8 Ronald C. Greene, /. Am. Chem. Soc. 79 3929 (1957).
Pfizer Handbook of Microbial Metabolites
292
quired. A mechanism such as the one shown here (abbreviated)
11'^+ HiNlCHilaNHlCHshNHi
Spermidine
CH3— S— CH2
OH OH
CH— COOH
I
NH2
S-Methyl-S-adenosyl-
methionine
toH
OH OH
may be operative.
637 Ammonia, NH3, colorless gas.
NH3
Widely distributed in the fruiting bodies of the higher
fungi and lichens. The content increases with age.
Elard Stein von Kamienski, Planta 50 331 (1958).
638 Methylamine, CH5N, colorless gas.
CH3NH2
Russula (11 spp.), Lactarius deliciosus, L. vellereus,
L. helvus. Boletus edulis, B. appendiculatus, Scleroderma
vulgare-; Anthurus muellerianus, Mutinus caninus, Tra-
chypus versipellis, Dermocybe (Cortinarius) cinnamo-
mea, Lepiota clypeolaria, Pholiota mutabilis, Sticta fulig-
inosa, S. sylvatica, Polyporus sulfureus
Elard Stein von Kamienski, Planta 50 331 (1958).
P. H. List, Planta Med. 6 424 (1958).
639 Ethylamine, C2H7N, volatile liquid, b.p. 16.6°.
CH3CH2NH2
Claviceps purpurea, Polyporus sidfureus
Maximilian Steiner and Elard Stein von Kamienski, Natur-
wissenschaften 42 345 (1955).
P. H. List, Planta Med. 6 424 (1958).
293 Amines
640 Dimethylamine, CoH^N, colorless gas, b.p. 7°.
CHs— NH— CH3
Phallus impudicus, Clathriis ruber, Russula aurata
Gustav Klein and Max Steiner, Jahrb. wiss. Bot. 68 602
(1928).
R. sardonia, R. turci, R. lepida, R. cyanoxantha, R.
grisea, R. olivacea, R. vesca, R. alutacea, Sticta sylvatica,
Polyporus sulfureus
Elard Stein von Kamienski, Planta 50 333 (1958).
P. H. List, Planta Med. 6 424 (1958).
641 Ethanolamine, C2H7ON, colorless oil, b.p. 171°, Hd^" 1.4539.
HOCH0CH0NH2
Neurospora crassa (and probably in) Boletus edulis,
B. versipellis, Xerocomus badius, Lepiota clypeoloris,
Pholiota mutabilis, Tricholoma nudum, Russula macu-
lata, R. turci, Lactarius vellercus, Amanita muscaria,
Polyporus sulfureus
George L. Ellman and Herschel K. Mitchell, /. Am. Chem.
Soc. 76 4028 (1954).
Elard Stein von Kamienski, Planta 50 331 (1958).
P. H. List, Planta Med. 6 424 (1958).
642 Aminoacetone, C3H7ON, colorless crystals, m.p. 130.5°.
CH3COCH2NH2
Staphylococcus aureus
W. H. Elliot, Nature 183 1051 (1959).
643 Trimethylamine, C3H9N, colorless gas (fishy odor), b.p. 3°.
CH3 CH3
CH3
Boletus edulis, Ustilago maydis. Phallus impudicus,
Claviceps purpurea, Tilletia laevis, T. tritici, Clathrus
ruber, Russula spp. Sticta spp.
J. Zellner, Monatsh. 31 617 (1910).
William Fielding Hanna, Hubert Bradford Vickery and
George W. Pucher, /. Biol. Chem. 97 351 (1932). (Isolation)
Maximilian Steiner and Elard Stein von Kamienski, Natur-
wissenschaften 42 345 (1955).
Pfizer Handbook of Microbial Metabolites 294
644 n-Propylamine, C3H9N, liquid, b.p. 50°.
CH3CH2CH2NH2
Claviceps piirpiirea, Polyporiis sulfiirens
Maximilian Steiner and Elard Stein von Kamienski, Natur-
wissenschaften 42 345 (1955).
P. H. List, PZanta Med. 6 424 (1958).
645 Isopropylamine, C;{H,)N, liquid, b.p. 33°.
CH3— CH— CHs
NH2
Claviceps purpurea
Maximilian Steiner and Elard Stein von Kamienski, Natur-
wissenschaften 42 345 (1955).
646 Methylaminoethanol, C.iHgON, slightly viscous liquid, b.p. 159°.
HOCH2CH2NHCH.S
Neurospora crassa mutant
N. H. Horowdtz, J. Biol. Chem. 162 413 (1946).
647 n-Hexylamine, C6H,-,N, liquid, b.p. 129°.
CH3(CH2)5NH2
Claviceps purpurea
Maximilian Steiner and Elard Stein von Kamienski, Natur-
wissenschaften 42 345 (1955).
648 Isobutylamine, C4H11N, liquid, b.p. 68°.
CH3
\
CH— CHo— NHo
/
CH3
Claviceps purpurea
Maximilian Steiner and Elard Stein von Kamienski, Natur-
wissenschaften 42 345 (1955).
649 l-Amino-2-methyl-2-propanol, C,Hi,ON, liquid, b.p. 151°.
CH3
H2N— CH2— C— CH3
OH
Neurospora crassa
^95 Amines
George L. Ellman and Herschel K. Mitchell, 7. Am. Chem.
Soc. 76 4028 (1954).
650 Putrescine, C4H10N0, crystals, m.p. 27°.
H2NCH.CH,CHoCH,NHo
Boletus edulis, B. luteus, B. elegans, Amanita muscaria
C. Reuter, Z. physiol. Chem. 78 167, 223 (1912).
Albert Kiing, ibid. 91 241 (1914).
Werner Keil and Hans Bartmann, Biochem. Z. 280 58
(1935).
651 Histamine, C.-^H^Nj^, deliquescent needles, m.p. 83° (Hydrochlo-
ride) m.p. 244-246° (Picrate) m.p. 160°.
r^^— CH2CH0NH2
Nv. .NH
Claviceps purpurea, Coprinus comatis Gray
Paul Heinz List, Arch. Pharm. 291 502 (1958).
652 Isoamylamine, C-,Hi;jN, liquid, b.p. 95-97°.
CH3
\
CH— CH2— CH2— NH2
/
CH3
Boletus edulis, B. sanguineus, B. queletii, B. luridus,
B. regius, B. appendiculatus. Phallus impudicus, Claviceps
purpurea, Amanita phalloides, Marasmium peronatus,
Russula foetens, R. turei, R. maulata, Trachypus scaber,
Xeroeomus sanguineus, X. suhtomentosiis , Mutinus cani-
nus, Lycoperdon piriforme, L. gemmatum, Phlegmacium
mellioleus, Nematoloma fasciculare, Polyporus sulfureus
Maximilian Steiner and Elard Stein von Kamienski, Natur-
wissenschaften 40 483 (1953).
Elard Stein von Kamienski, Planta 50 334 (1958).
P. H. List, Planta Med. 6 424 (1958).
653 Dimethylhistamine, C-H,;^N;j ( Dihydrochloride ) m.p. 245-250°
(dec).
CH3
/
1^^— CH2CH2N
N^ NH CH3
Pfizer Handbook of Microbial Metabolites 296
Coprinus comatis Gray
Paul Heinz List, Arch. Pharm. 291 502 (1958).
654 Acetylcholine, C7H17O3N, colorless, hygroscopic powder.
(CHslsN— CH2CH2OCOCH3
® 0
Streptobacteriuvi plantarum
Acetylcholine is produced also by the ergot fungus,
Claviceps purpurea, and probably by many other micro-
organisms.
Yield: about 160 y per milUUter from the first organ-
ism above.
Adolf Wacker, Adolf Roth, Heinz Sucker and Otto Dann,
Ann. 601 202 (1957).
655 Spermidine, C7H19N3, unstable oil, b.p. 128° (14 mm.).
H2N(CH2)3NH(CH2)4NH2
Yeast, Neurospora crassa
Occurs as the phosphate.
H. Tabor, S. M. Rosenthal and C. W. Tabor, Federation
Proc. 15 367 (1956).
Ronald C. Greene, J. Am. Chem. Soc. 79 3929 (1957),
656 ^-Phenylethylamine, CgHuN, liquid, b.p. 196-198°.
/ V-CHsCHzNHz
Boletus edulis, B. luteus, Claviceps purpurea, Polyporus
sulfureurS, Marasmius peronatus, Phlegmaciuni melliolus,
Nematoloma fasciculare, Pholiota mutabilis
C. Reuter, Z. physiol. Chem. 78 167 (1912).
Werner Keil and Hans Bartmann, Biochem. Z. 280 58
(1935).
Elard Stein von Kamienski, Planta 50 335 (1958).
P. H. List, Planta Med. 6 424 (1958).
657 Tyramine, CsHj^ON, colorless crystals, m.p. 164°. (Picrate),
m.p. 206°.
HO—/ V-CH2CH,,NH2
Coprinus comatis Gray, Claviceps purpurea
Paul Heinz List, Arch. Pharm. 291 502 (1958).
297 Amines
658 Muscarine, CgHigOoN, white crystals, Hydrochloride [a]u^°
+ 1.57° (in water).
Amanita muscaria
F. Kogl, C. A. Salemink, H. Schouten and F. Jellinck, Rec.
trav. chim. 76 109 (1957). (Structure)
E. Hardegger and F. Lohse, Helv. Chim. Acta 40 2383
(1957). (Synthesis and configuration)
P. J. Fraser, Brit. J. Pharmacol. 12 47 (1957). (Pharma-
cology)
659 Muscaridine, CgHooOoNCl, isolated as the chloroaurate,
CgHooAuCl^O.N, " m.p. 129-131° (dec), [aW +20.5°
±0.5° (c 8.3 in water).
CI® CH3
© I
CH3— N— CH2— CH2— CHo— CH— CH— CH3
I I I
CH3 OH OH
Amanita muscaria L.
F. Kogl, C. A. Salemink and P. L. SchuUer, Rec. trav.
chim. 79 485 (1960). (Isolation)
C. A. Salemink and P. L. SchuUer, ibid. 79 278 (1960).
(Synthesis)
660 Spermine, C10H26N4, deliquescent, C02-absorbing crystals.
Phosphate: m.p. 230-234° (dec).
H2N(CH.2)3NH(CH2)4NH(CH2)3NH2
Yeast, Neurospora crassa
Occurs phosphorylated.
H. Tabor, S. M. Rosenthal and C. W. Tabor, Federation
Proc. 15 367 (1956).
Ronald C. Greene, J. Am. Chem. Soc. 79 3929 (1957).
661 Bufotenin, CioHigONo, colorless crystals, m.p. 146°.
HO
-CH2CH2N(CH3)2
Oj
H
Pfizer Handbook of Microbial Metabolites 298
Amanita mappa and certain related species
Bufotenin occurs also in the skin secretions of toads.
Theodor Wieland and Werner Motzel, Ann. 581 10 (1953).
662 Necrosamine, C..,)H44N2 (Hydrochloride) crystals, m.p. ~275°
(dec).
CH3— (CHoJu— CH— CH— CH2— CH2— CH3
NH2 NH2
Escherichia coli
This amine was a component of the phospholipide frac-
tion.
Miyoshi Ikawa, J. B. Koepfli, S. G. Mudd and Carl Niemann,
J. Am. Chem. Soc. 75 3439 (1953).
16
Amino Acids and Related Compounds
A general review of the intermediary metabolism of amino
acids would be disproportionate to the scope of this book. It is
only possible to sketch in here some relationships and biosyn-
thetic sequences which may serve as reminders or as guides for
the novice.
As in acetate metabolism microorganisms have been used to
explore the network of metabolic relationships among the amino
acids. Many of these have proved quite general, yet it is only
necessary to consider the unusual amino acids which have been
isolated from microbial sources to realize the differences from
human metabolism.
In this section principally free amino acids are considered.
Polypeptides are listed and discussed in the succeeding section.
Amino acid isolation and assay formerly were tedious and gen-
erally confined to analysis of hydrolysates of total proteins. Pa-
per chromatography and reliable microbiological assays have
made possible the separation and assay of the low concentra-
tions of amino acids evolved into fermentation broths.
The older work on fungi has been reviewed.^ A semiquanti-
tative survey of the free amino acids of a taxonomic range of
fungi gave the results shown in Table P on page 300. In
general there were found no outstanding differences in the
quantities or types of amino acids produced by the different
fungi, nor in the types produced by fungi as compared with
those of higher plants. The absence of tryptophan in all species
examined is noteworthy. Four unidentified compounds were
found in various fungi. These were suggested tentatively as
1 Jackson W. Foster, "Chemical Activities of Fungi," Academic
Press, New York, 1949.
2R. Close, Nature 185 609 (1960).
P P: c -^
— a
UJ ^
< j:
^1
+ + + +
+ + +
+ +CN^
£ a
+++ 1 1 +++ 1
1 + + +
1 + + +
1 H — h -^' <> o
CO 3
a
+ + +
+ +
i^
+ + +
+
+ +CSO.
D 1
++++++++ 1
+ + +
1 ++ 1
+ + + '*<)->»•
if 0
+++ +++
+ +
+ +
+ +
+
IP
+++ +++
+
+ +
+ + +^r.
s 1
'11
+++ 1 ++++ 1
1 ++ 1
1 + + + + + + ;; K^ 1
+ + + +
+
+
■omo-
rea
lulosa
+++ +++
+ +
+ +
+ + +CN-
+++ 1 ++++ 1
+++++++ 1
+ + +W «i^
5 "i
+ + +
+
+
+ +
Thorn -
nidium
elegans
+ + + + +
+ +CNO
+++++++ 1 +
+ + +
1 ++ 1
+ + + 1
+ + + '*' CO «0
+ +
• ^ +
O u
+++ ++++
+ +
+ +
+ + CNK
1-g
++++++++ 1
+ + + 1
+ + + 1
1 + + ->t <d <o
a. E .^
+ + +
+
+ +
■ S 1
o i; ?
+++++++++
+ + +
+ +
+ +^.
>.. j: o
+++++++++++++
1 + + + + + + ;; ^ o. 1
■^ a 8
+ + + +
+
+ +
E E "^
3 3 O
+++ + ++
+ + +
+ +
+ + + ^<n
:£ E Q
+++ 1 ++++ 1
1 + + +
1 ++ 1
+ + + CO uS o
a. 3 ^
+
+
+
"O
II
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o
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-a
u
fe "o
^1 1^
" u 4> «> J° 4>
u .= c c 0 a, c
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£ c «
° a .S «>
E
:2 41 ■■=
U C 4) c
0 5) .£ X 3- 0
t = ■£ 'E .E (u c c «>
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2 o) ti •:;
5J = 4) £
u < O ^ it ^
i;
30I
Amino Acids and Related Compounds
a-aminoadipic acid, 3,4-dihydroxyphenylalanine, ethanolamine
and taurine.
The amino acids of some algae have been reported,^ and also
those of Fusariinn lycopersici:' A quantitative study was made
of the amino acid composition of Usiilago maydis fermentation
broth.' Of the 3.5 mg. per milliliter of NH4" nitrogen added,
2.9 mg. per milliliter remained extracellular. This extracellular
nitrogen contained 1.17 mg. per milliliter of organic nitrogen
and 1.74 mg. of residual NH4* nitrogen.
TABLE II
Amino Add Composifion of Usfilago maydis Fermenfafion Broth
Amino acid*
Unhydrolyzed broth
Hydrolyzed broth
/xgm /ml.
jugm.N/ml.
^igm./ml.f
Atgm.N/ml.f
Lysine
387
997
155
200
894
200
290
387
276
276
263
267
139
40
65
64.2
320.5
42.0
21.0
85.1
38.1
25.7
41.3
29.5
30.1
32.0
22.6
10.7
5.6
6.0
413
1136
182
506
945
295
406
279
368
212
307
237
289
389
383
79 2
Arginine
Histidine
Aspartic acid . . .
Glutamic acid. . .
Glycine
Alanine!
Valine
365.3
49.3
53.2
90.0
55.0
63.8
33 4
Leucine
Isoleucine
39.3
22.7
40.9
Threoninel
27.9
35.2
Phenylalanine. . .
Tyrosine
Tryptophan
Methionine
33.0
29.6
4.79 mgm.
0.774 mgm.
6.35 mgm.
1.02 mgm.
* The amino acids in the hydrolyzed broth and the bosic amino acids in the unhydrolyzed broth were
separated chromatographically and assayed colorimetrlcally. The other amino acids in the unhydrolyzed
broth were assayed microbially.
t Values expressed as ^gm. per milliliter in terms of original broth.
t Valid microbial assays were not obtained.
3L. Fowden, ibid. 167 1030 (1951); Borje Wickberg, Acta Chem.
Scand. II 506 (1957).
4V. Fliick and K. H. Richie, Phytopath. Z. 24 455 (1955).
5 Eugene L. Dulaney, E. Bilinski and W. B. McConnell, Can. J.
Biochem. and Physiol. 34 1195 (1956).
Pfizer Handbook of Microbial Metabolites
302
In this case the broth was hydrolyzed and compared with the
original to eUminate interference by small peptides in the mi-
crobial assays. Tryptophan and methionine were destroyed by
the hydrolysis and chromatography procedure and are absent
from the second part of the table. It was found that 53% of
the extracellular organic nitrogen was represented by free amino
acids. Some strains of Ustilago maydis produce 200—300 jxg.
of lysine per milliliter."
A study of the extracellular nitrogen of several molds' gave
the results in the accompanying table.
TABLE ill
Amounf of Nitrogen Assitnilafed Which Appeared in fhe Medium After Seven Days Growth
Fungus
Nitrogen
source
Extracellular nitrogen
(as % initially added
nitrogen)
NH4 +
NO.r
NH4+
Nor
NH4+
NOr
NH4+
7.5
3.5
20.0
7.5
27.0
36.0
23.5
The extracellular nitrogen was related to the nitrogen supplied
in two cases:
TABLE IV
Formation of Extracellular Nitrogen in Relation to Initially Added Nitrogen Which
Disappeared
Nitrogen
Source
Amount of nitrogen supplied (mg. /flask)
Fungus
6.6 13.2 6.6 + 6.6
Extracellular N as % N assimilated
Scopulariopsis brevicaulis
Penicillium griseofulvum
NH4-
NOr
NO3-
25.35 ± 5.58 25.80 ± 2.86
20.03 ± 4.47 1 6.62 ± 2.08 1 6.50 ± 1 .98
1 3.00 ± 3.35 1 2.50 ± 0.70 1 2.34 ± 2.73
M. Richards and R. H. Haskins, Can. J. Microbiol. 3 543 (1957).
A. G. Morton and D. Broadbent, 7. Gen. Microbiol. 12 248 (1955).
303
Amino Acids and Related Compounds
In this earlier study most of the extracellular nitrogen appeared
to be peptide in nature, yielding some 14 amino acids on hy-
drolysis. In the one case tested one of the fungi was unable to
use the extracellular nitrogen formed, but assimilated the con-
stituent amino acids when these were liberated by acid hydroly-
sis.
A quantitative report has been made on the free amino acids
present in an alcohol extract of Miicor miLcedo.^ They were as
follows :
TABLE V
Amino Acids Present in 75% Alcohol Extracfs of Mucor mucedo (as % Tofai Nitrogen)
Amino acid
Hydrolysate of
insoluble residue
Alanine
/3-Alanine
Arginine
Asparagine
Aspartic acid
-)-Aminobutyric acid
Citrulline
Cystine
Giutamine
Glutamic acid
Glycine
Histidine
iso-Leucine
Leucine
Lysine
Methionine
Proline
Phenylalanine
Serine
Threonine
Tyrosine
Valine
6.7
12.2
16.4
2.2
35.2
3.8
1.6
0.7
5.2
3.8
1.1
4.2
1.0
3.3
2.2
2.1
4.4
These values were compared with those of other plants over a
taxonomic range.
A report of the free amino acids produced by Penicillium
roquefortii indicated the following to be most prominent:^
^K. Mansford and R. Raper, Nature 174 314 (1954).
^ J. Kolousek and S. Michalik, Sbornik Ceskoslov. Akad. Zemedel
Ved. 27A 281 (1954). (Chem. Abstr. 50 4295c)
Pfizer Handbook of Microbial Metabolites
304
Aspartic Acid
Glutamic Acid
Serine
Threonine
a-Alanine
Valine
Methionine
Leucine
Isoleucine
The free and combined amino acids of the uredospores of
ten wheat rust strains have been determined quantitatively.^"
The intracellular amino acids of microorganisms have been
studied. Gale demonstrated the presence of such a pool in
Streptococcus faecalis}^ Gale and Taylor extended the investi-
gation to a variety of bacteria and yeasts with particular atten-
tion to lysine and glutamic acid.^- Fuerst studied several
fungi." The free intracellular amino acids of certain strains
of Neurospora crassa have been explored." The relative quan-
tities of amino acids present varied widely among the various
mutants. In all some 35 ninhydrin-positive substances were en-
countered among the 28 different strains studied. The free
amino acids of Staphylococcus aureus have been determined,
and the ability of bacteria to concentrate amino acids strikingly
demonstrated by comparison of the concentrations of internal
and external acids. ^^
TABLE VI
Free Amino Acids in Exponenfially Growing Staphylococcus aureus Cells Growing in Synfhefic
Medium
Amino Acid
Quantity (jumoie/g.)
in internal pool
Ratio of internal to
external concentration
39.6
38
16.8
8.3
2.6
6.7
25.4
22.6
23.2
13.3
4.5
8.3
1" M. E. McKillican, Can. J. Chem. 38 244 (1960).
"E. F. Gale, /. Gen. Microbiol, 1 53 (1947).
12 E. F. Gale and E. S. Taylor, ibid. I 77 (1947); E. S. Taylor, ibid.
1 86 (1947).
" R. Fuerst and J. Awapara, Texas Repts. Biol, and Med. 10 424
(1952).
^^ Robert Fuerst and Robert P. Wagner, Arch. Biochem. and Bio-
phys. 70 311 (1957).
15 R. Hancock, Biochim. et Biophys. Acta 28 402 (1958).
305
Amino Acids and Related Compounds
TABLE VI — Continued
Free Amino Acids in Exponentially Growing Sfaphylococcus aureus Cells Crowing in S/nfhef/c
Medium
Amino Acid
Alanine
Cystine and cysteine
Serine ,
Glycine
Tyrosine
Lysine <
Arginine ■
Histidine ,
Phenylalanine
Threonine ,
Tryptophan ,
Quantity (^umole/g.)
Ratio of internal to
in internal pool
external concentration
8.1
5.4
5.5
3.4
5.4
2.8
2.3
2.4
3.1
2.2
4.6
2.2
3.0
1.7
2.2
1.3
1.8
1.0
1.6
0.3
All the amino acids found in the internal protein of the cell
were present in the internal pool of free amino acids.
A new amino acid, S-methyl-L-cysteine, has been isolated
from Neurospora crassa.'^*' An isomer of ^-methyllanthionine
has been isolated from yeast." Urocanic acid has been detected
in Micrococcus lysodeikticus}^
CHa— S— CH2— CH— COOH
NHo
S-Methylcysteine
HOOC— CH— CH2— S— CH— CH— COOH
NHo CH3 NH2
/3-Methyllanthionine
HOOC— CH—CH— COOH
NH2 NH2
a,/3-Diaminosuccinic Acid
New, partially characterized a-amino acids have been isolated
from boletus and lactarius species. ^'''' ^"^ -^ a,/3-Diaminosuccinic
acid has been isolated from production filtrates of the antibiotic
^•^ James B. Ragland and James L. Liverman, Arch. Biochem. and
Biophys. 65 574 (1956).
"PhyUis F. Downey and Simon Black, /. Biol. Chem. 228 171
(1957).
'^^ Jana Gregoire and Jean Gregoire, Compt. rend. 245 2553 (1957).
^^ A. I. Virtanen and O. Ayrapaa, Suomen Kern. SIB 190 (1958).
20 Atsushi Komamine and Artturi I. Virtanen, Acta Chem. Scand.
13 2141 (1959).
21 J. Casimir and Artturi I. Virtanen, ibid. 13 2139 (1959).
Pfizer Handbook of Microbial Metabolites 306
oxytetracycline (Streptomyces rimosiis).-^ The structures of
certain other unusual amino acids are listed in this section.
Production of glutamic acid by streptomycetes on synthetic
medium containing glycine has been investigated.-' Yields of
extracellular glutamic acid were 0.25-1.75 g. per liter. It was
the only amino acid or nitrogenous material present after four
and seven days, but after ten days some alanine, phenylalanine,
aspartic acid and glycine appeared. Strains examined were:
Streptomyces anmilatus, S. aureofaciens, S. fradiae, S. olivaceus
and S. rimosus.
The high proportions and amounts of L-glutamic acid syn-
thesized by microorganisms have led to the development of an
economical process for its commercial production. Certain mi-
crococcus and bacillus species produce more than a 20% yield
(molar basis) from the glucose supplied.-^ A similar yield of
valine has been reported.-"'
L-Lysine is also produced commercially by a direct process
(micrococcus, bacillus)-'* and by a two-stage process (Escher-
ichia coli, Aerobacter aerogenes),-' 2,6-diaminopimelic acid be-
ing the intermediate in the latter case.
Tryptophan production by E. coli and by Salmonella typhi has
been reported as small unless indole is added.-'' The indole
apparently competitively inhibited tryptophanase. Many mi-
croorganisms are able to synthesize tryptophan from indole and
serine.
A survey of 20 genera, 72 species and 334 strains of aerobic
bacteria for amino acid accumulation revealed no marked tax-
onomic difference except that facultative aerobes such as escher-
ichia, aerobacter and bacillus species were superior to obligatory
aerobes such, as pseudomonas. Production and accumulation
were more dependent on strain and conditions.-"
The biosynthesis and metabolic interrelationships of amino
acids can be considered here only in briefest summary because
of the breadth and complexity of the subject. More thorough re-
22 F. A. Hochstein, /. Org. Chem. 24 679 (1959).
23 D. Perlman and E. O'Brien, /. Bad. 75 611 (1958).
-^ Toshinobu Asai, Ko Aida and Kunio Oishi, Bull. Agr. Chem. Soc.
(Japan) 21 134 (1957).
25 Zenjiro Sugisaki, Nippon Nogei-kagakii Kaishi -54 153 (1960).
2" Shukuo Kinoshita, Kiyoshi Nakayama and Sohei Kitada, J. Gen.
Appl. Microbiol. 4 128 (1958).
27 Lester E. Caslda, Jr., U. S. Patent 2,711,396 (1956).
2sp. Fildes, J. Gen. Microbiol. 15 636 (1956).
2" Hiroshi lizuka and Kazuo Komagata, Nippon Nogei-kagashu
Kaishi 34 27 (1960).
307
Amino Acids and Related Compounds
views are available*"' ^^' ■*- and references to some of the vast
literature on this subject can be found there.
The occurrence studies cited demonstrate the importance of
glutamic acid. It is a constituent of folic acid and related sub-
stances, and of glutathione, and various antibiotics. It occurs
in the cell wall of bacteria and, as a polypeptide, is the sole
capsular substance of certain bacilli. Its wide distribution re-
flects its cross-roads position in nitrogen metabolism.
Synthesis of glutamic acid by most aerobic microorganisms
involves ainination of a-ketoglutaric acid (a reversible reac-
tion), thus tying it in with the citric acid cycle. It is a pre-
cursor of ornithine, proline and in some cases lysine.
O
I amination
HOOC— CHo— CH,— C— COOH ;:^ ^ HOOC— CHo— CH2— CH— COOH
a-Ketoglutaric Acid I
NH2
Glutamic Acid
In E. coli, at least, the route to ornithine involves N-acetylated
intermediates. The intermediates shown accumulate in appro-
HOOC— CHo— CH2— CH— COOH
NH2
Glutamic Acid
reduction
OHC— CH2— CH2— CH— COOH _-^
CH2— CH2
NH2
Glutamic Acid Semialdehyde
. . I
amination
CH CH— COOH
N
A^-Pyrroline-5-
carboxylic Acid
H2N— CH2— CH2— CHo— CH-
-COOH
reduction
CH2— CH2
NHo
Ornithine
CH2 CH— COOH
\ /
N
H
Proline
30 Bernard D. Davis, Advances in Enzymol. 16 247-312 (1955).
^'^ Alton Melster, "Biochemistry of the Amino Acids," Academic
Press, New York, 1957, pp. 256-394.
■^-Joseph S. Fruton and Sofia Simmonds, "General Biochemistry,"
John Wiley and Sons, Inc., New York, 1958, pp. 771-896.
Pfizer Handbook of Microbial Metabolites 308
priate auxotrophs and can be isolated. This scheme has been
found in a variety of molds, yeasts and bacteria.
Ornithine reacts with carbamyl phosphate to form citrulline,
an intermediate in the biosynthesis of arginine:
H2N— CH2— CH2— CH2— CH— COOH
I
NH2
Ornithine
O
I H2N— C— O— PO3H2
o
II
H2N— C— NH— CH2— CH2— CH2— CH— COOH
I
NH2
Citrulline
HOOC— CH— CH2— COOH
NH2
e
00c— CH—CH2— COOH
I
©NH
H2N— C— NH— CH2— CH2— CH2— CH— COOH
I
NH2
Argininosuccinate
^ > HOOC— CH=CH— COOH
NH ^
II
H2N— C— NH— CH2— CH2— CH2— CH— COOH
I
NH2
Arginine
Arginine can complete the "urea cycle" by losing urea to form
ornithine. Enzymes for all these steps have been found in var-
ious microorganisms.
Glutamic acid acts as an ammonia carrier by formation of its
half amide, glutamine, and in this way contributes nitrogen to
the biosynthesis of purines and amino sugars.
Aspartic acid also occupies a central position in nitrogen
metabolism. In microorganisms it can be synthesized either by
amination of oxaloacetic acid or by the addition of ammonia
309 Amino Acids and Related Compounds
to fumaric acid, the former process probably being more preva-
lent.
O NH2
HOOC-
-c-
-CHj— COOH
amina
Hon
HOOC-
-CH-
-CHo-
-COOH
Oxc
HOOC-
iloacetic Acid
-CH=CH— COOH
NH3
Aspartic Acid
NH..
HOOC— CH— CH>-
COOH
F
jmaric Acid
A
spartic Acid
Either equation ties aspartic acid in with the citric acid cycle.
Like glutamic acid, aspartic acid acts as an ammonia carrier
through its half amide, asparagine. One role of aspartic acid
was seen above in the biosynthesis of arginine. Aspartic acid
has been proved a precursor of pyrimidines in certain microor-
ganisms. It is also a precursor of threonine and of both a- and
/3-alanines. Separate enzymes control the selective decarboxyla-
tions to form the alanines.
-CO2
HOOC— CH2— CH— COOH -
1
>
CH3— CH— COOH
1
NH2 X,^^
NH2
Aspartic Acid
X-COz
a-Alanine
HOOC— CH2— CH2— NH2
j3-Alanine
a-Alanine (either isomer) can be synthesized, too, from py-
ruvic acid by a wide variety of biological systems. Some mi-
croorganisms effect this amination directly from ammonia, but
the transamination from glutamate is probably more prevalent.
Alanine, therefore, is also closely connected with carbohydrate
and fat metabolism, and it is used as an energy source by many
microbes. Through pyruvate it also may be considered a pre-
cursor of glycine, serine, cysteine and of valine, leucine and
O NH2
CH3— C— COOH + HOOC— CH—CH2—CH2— COOH ^ CH3— CH— COOH +
NHo
Pyruvic Acid Glutamic Acid a-Alanine
O
I
HOOC— C—CH2—CH2— COOH
a-Ketoglutaric Acid
Pfizer Handbook of Microbial Metabolites 310
isoleucine. D-Alanine occurs in bacterial cell walls and spores
and frequently in antibiotics. Some bacteria even require an
exogenous source of D-alanine, particularly on a medium devoid
of pyridoxine, since pyridoxal phosphate is a coenzyme for the
racemase. ^-Alanine is a component of coenzyme A. A re-
lated substance, ^-nitropropionic acid has been isolated from an
aspergillus species.
Glycine and serine are reversibly interconvertible in most or-
ganisms, tetrahydrofolic acid transferring the hydroxymethyl
group. Glycine also is formed by amination of glyoxylate in
some microorganisms.
pyridoxal phosphate
THFA CH2OH
CH2— COOH ( : =± HOCH2— CH— COOH
I I
NH2 NH2
Glycine Serine
glutamate
or
ammonia
OHC— COOH — ==^ NHo— CH2— COOH
Glyoxylic Acid Glycine
In E. coll serine is probably to be regarded as the precursor of
glycine. The origin of serine is still obscure. There is a possi-
bility that it may arise from phosphoglyceric acid from the gly-
colysis scheme:
COOH COOH COOH COOH
CH— OH ;=iC=0 ;=±CH— NH2 ^ CH— NH2
CH2OPO3H. CH2OPO3H2 CH2OPO3H2 CH2OH
3-Phospho- 3-Phospho- Phospho- Serine
glyceric hydroxy- serine
Acid pyruvic Acid
Glycine is a precursor of the porphyrins, purines, glutathione
and sarcosine.
Serine contributes the carbon skeleton of cysteine in most or-
ganisms. Most microorganisms can use sulfate but not methio-
nine as a sulfur source, while mammals require methionine for
this purpose but cannot use sulfate. The conversion route of
methionine to cysteine has been worked out for higher animals,
but is not entirely understood in microorganisms.
Thiosulfate is used by some molds, and cysteine-S-sulfonate
has been found to be an intermediate. Hydrogen sulfide has
been reported as a precursor in yeast. Threonine has been iso-
lated as an intermediate to cysteine in a neurospora auxotroph.
311
Amino Acids and Related Compounds
Cysteine is a component of glutathione and of penicillin.
Methionine is important in transmethylation reactions. The
entire topic of one-carbon metabolism cannot be reviewed here.
The transfer of methyl groups from methionine to oxygen and
nitrogen atoms, and probably to carbon atoms in biosynthetic
sequences requires ATP, and the active complex has been iden-
tified as S-adenosylmethionine.
NH2
^'^^M
0 © "^\ Jl J
OOC— CH— CH2— CH2— S— CH2 ^N-^-N^
NH2 CH3
OH OH S-Adenosylmethionine
Several labile methyl group compounds (choline, betaine, ser-
ine) probably can contribute the methyl group of methionine
by way of the proper coenzymes (Bj^, THFA). Some neurospora
mutants have been found which seem to synthesize methionine
from cysteine and, ultimately, from aspartic acid. The follow-
ing scheme has been suggested:
ATP TPN
HOOC— CH,— CH— COOH > H2O3P— OOC— CH.— CH— COOH >
I
NH2
Aspartic Acid
OHC— CH,— CH— COOH
NH.j
Aspartic ^-Semialdehyde
TPN
NHo
/i-Aspartyl Phosphate
HOCH2— CHo— CH— COOH,
NH..
Homoserine
/
HS— CH>— CH,— CH— COOH CH,— CH,— CH— COOH
NH, S NH2
Homocysteine CH,— CH— COOH
NH,
Cystathionine
CH3— S— CH2— CH2— CH— COOH
CH3— CH— CH— COOH
OH NH2
Threonine
CH2SH
CH— NH2
COOH
Cysteine
NH2
Methionine
Pfizer Handbook of Microbial Metabolites 312
Homoserine also is a precursor of threonine in neurospora
mutants, with ATP and pyridoxal phosphate required. Threo-
nine is synthesized by most microorganisms although it is an
essential in mammalian diets.
The fact that lysine-requiring neurospora mutants use a-ami-
noadipic acid makes probable a biosynthetic scheme in which
the terminal carboxyl group is reduced and aminated as in the
biosynthesis of ornithine from glutamic acid. Some molds even
are able to use a-ketoadipic acid, which strengthens the argu-
ment. Labeling studies indicate formation of the a-ketoadipic
acid by condensation of acetate with either a-ketoglutarate or
with the "active succinate" from the citric acid cycle, the acetate
carboxyl furnishing the carboxyl group of lysine. Proposed
lysine biosynthesis in molds:
HOOC— CHo— CH2— CO— CoA(COOH) HOOC— CH2— CH2— CH2— C— COOH
Active Succinate — > a-Ketoadipic Acid
CH3-CO-C0A aminationj
Acetate
HOOC— CH2—CH2—CH2—CH— COOH
I
NH2
OCH— CH2— CH2— CH2— CH— COOH < a-Aminoadipic Acid
NH2
H2N— CH2— CH2— CH2— CH2— CH— COOH
NH2
a-Aminoadipic Acid
«-Semialdehyde
amination
Lysine
a-Aminoadipic acid is produced by Penicillium chrysogenum as
a component of a tripeptide isolated from the mycelium. It also
occurs as a moiety of the antibiotic synnematin-B (cephalo-
sporin N) produced by the mold Cephalosporium salmosynne-
matum, and it has been isolated from Aspergillus oryzae.
a,€-Diaminopimelic acid is a precursor of lysine in E. coli and
in many other bacteria. L,L-Diaminopimelic acid is formed in
E. coli by condensation of pyruvic acid with aspartic acid.
Later a specific racemase converts it to the meso-form. A com-
plete mechanism for lysine biosynthesis in bacteria has been
proposed :
313
Amino Acids and Related Compounds
COOH
CH— NH,
HOOC
— CH
Succ
2— CH,— COOH
nic Acid
^COOH
CH— NH
-CO— CH2-
-CH2-
-COOH
CHo
COOH
ATP
>
CH,
c=o
Aspartic CH3
Acid 1
C=
0
CH2
c=o
COOH
Pyruvic Acid
_COOH
1
-
COOH
COOH
CH— NH
— CO-
-CH:-
-CH,-
COOH
CH— NH-
-CO— CH2-
-CH2-
-COOH
CHo
CH2
CH2
-
>CH2
CH2
CH2
c=o
CH— NH2
1
COOH
COOH
CH2— NH2
\
COOH
COOH
—CO
2
/-u <
+
^n2 <
1
CH— NH2
CH,
CH2
1
1
1
CH,
CH,
CH2
1
1
1
CH,
COOH
CH— NH,
1
Succinic
1
CH,
Acid
COOH
1
Lysine
CH— NH,
COOH
Diaminopimeiic
Acid
Intermediate III has been isolated and identified, and there is
some evidence for the existence of II. Rather similar interme-
Pfizer Handbook of Microbial Metabolites 314
diates have been suggested as precursors of 2,6-dipicolinic acid,
which is formed in some bacterial spores. Free diaminopimelic
O
II
c
CHo CHo
HOOC— I I — > /^N-
CH C HOOC COOH
\ ■i^\ Dipicolinic Acid
NH2 O COOH
acid has been isolated from vegetative cells of such spore-form-
ers. It has never been found in yeasts and molds.
a,£-Diaminopimelic acid replaces lysine in the repeating pen-
tapeptide unit of the bacterial cell wall in Corynehacterium
diphtheriae , E. coli and certain other bacteria (especially gram
negatives). Some E. coli strains accumulate considerable quan-
tities of diaminopimelic acid, and this faculty has been ex-
ploited in a two-step commercial production process.
Many microorganisms metabolize lysine to pipecolic acid, a
component of several antibiotics.
CH2
CH2 CH2
-"' o.
CHo CH— COOH ^N'
\ / H COOH
_ NH2 NH2 Pipecolic Acid
Lysine
The amino acids discussed to date are closely integrated with
carbohydrate and fat metabolism. Those remaining to be con-
sidered are more remotely derived.
Valine, isoleucine and leucine are essential to the mammalian
diet and are required also by many microorganisms. This
seems to indicate enzymatic difficulties in the biosynthesis of
these branched-chain amino acids.
Much evidence has accumulated concerning the biosynthesis
of valine and isoleucine, and the following pathway is indi-
cated (for valine):
315
Amino Acids and Related Compounds
O OH
CH3— C— COOH > CH3— C— C— COOH
(3) ® ® CH3CHO® ® I®®
Pyruvic Acid ® ® CH3
"active acef- ®
aldehyde" a-Acetolactic Acid
thiamine
O' pyrophosphate
II
CH3— C— COOH
rearrangement
O OH OH
II H2O I I TPNH
CH3— CH— C— COOH <- CH3— C— CH— COOH <
CH3
a-Ketoisovaleric
Acid
transamination
reduction
CH3
a,/3-Dihydroxy-
isovaleric Acid
OHO
CH3— C— C— COOH
® ® I @ ®
CH3
®
a-Keto-/3-hydroxy-
isovaleric Acid
CH3
CH— CH— COOH
CH3
NH2
Valine
The intermediates, a-acetolactic acid and a,^-dihydroxyiso-
valeric acid, have been isolated from a variety of microorgan-
isms and are well characterized. a-Keto-^-hydroxyisovaleric
acid has not been reported yet, although when it is mixed with
enzyme preparations from molds and yeasts together with
TPNH, it is reduced to a,^-dihydroxyisovaleric acid. a-Ketoiso-
valeric acid is aminated by numerous microorganisms.
The scheme for isoleucine is believed to be analogous, but
with a-ketobutyric acid replacing pyruvic acid as the initial sub-
stance. This four-carbon acid is, in turn, derived from homo-
serine or threonine, and ultimately from aspartic acid. Some
of the steps of the valine and isoleucine syntheses are known to
share common enzymes.
Leucine biosynthesis is apparently the same as that of valine
up to the final amination step. Leucine, however, requires 3
moles of pyruvate for its 6-carbon atom chain rather than the
Pfizer Handbook of Microbial Metabolites
316
2 required by valine. The remaining steps of the proposed
leucine biosynthesis in microorganisms are;
CH3 O
\ II -CO,
CH— C=0 + CH3— C— COOH -*
/ I Pyruvic Acid [O]
CH3 COOH
a-Ketoisovaleric
Acid
"CHa
CH3
CH3 CH3
\
CH — CH2— CH— COOH amination
/ I <
CHs
OH
I
CH— C— CH2— COOH
' I
COOH
CH— CH2— C— COOH*-
CH3
NH2
Leucine
a-Ketoisocaproic Acid
This partial scheme is based on labeled media experiments in
yeasts, molds and bacteria.
The biogenetic scheme of the aromatic amino acids phenyl-
alanine and tyrosine was briefly outlined in the introduction to
the section on simpler ahcyclic compounds. The final stages
of this route are shown here, beginning with shikimic acid:
COOH Pyruvic Acid
^> V
HO
CH2— CO— COOH
H — COOH
Prephenic Acid
Shikimic Acid
5-Phosphate
HO
_ p-Hydroxyphenyllactic Acid
-CH2— CH— COOH
CH2— CO— COOH
Phenylpyruvic Acid
kNH3
f2H
HO— f V-CH2— CO— COOH ( \-CH2— CH— COOH
\=/ \=/ I
p-Hydroxyphenylpyruvic Acid NH2
l^NHs Phenylalanine
HO
i
CH2— CH— COOH
NH2
Tyrosine
3^7
Amino Acids and Related Compounds
The benzene ring of tryptophan also arises from the shikimic
acid route. The intermediates are unknown between shi-
kimic acid and the first aromatic member of the sequence,
anthranilic acid:
NHo
— COOH
:OOH
Anthranilic Acid
Shikimic Acid
The remainder of the sequence in its present state of devel-
opment is as follows:
COOH 5-Phosphoribosyl-
1 -pyrophosphate
COOH
NH2
Anthranilic Acid
CH— CH— CH— CH— CH2— O— PO3H2
NH OH OH
N-(2-Carboxy phenyl)-! -aminoribose-5-phosphate
Co
^CH— CH— CH2
I I I
OH OH O— PO2H2
Triose- ^^
phosphate
lndolyl-3-glycerol
Phosphate
L-Se
Amadori rearrangement
COOH
NH— CH2— CO— CH— CH— CH2— OPOaHs
OH OH
1 -Deoxy-1 -(o-carboxyanilino)-ribulose
,CH.— CH— COOH
I
NH2
Indole Tryptophan
There appears to be some question as to whether the Amadori
rearrangement product is a bona fide member of this sequence.
It has been isolated from Aerobacter aerogenes and character-
ized as derivatives, and it substitutes for anthranilic acid in bac-
terial mutants requiring the latter.
The anthranilic acid carboxyl group is known to be lost as
carbon dioxide during the formation of the pyrrole ring, and
the first two carbon atoms of ribose are known to form the 2
and 3 positions of the indole ring. Glucose also can furnish
these two carbon atoms. In this connection it should be men-
Pfizer Handbook of Microbial Metabolites
318
tioned that N-fructosylanthranilic acid has been isolated from
a yeast. Probably indole never exists in the free state to any
appreciable extent during the tryptophan synthesis, but is en-
zyme-bound.
Ribose contributes also to the biosynthesis of histidine. Here
purines are catalytic, furnishing a carbon atom and a nitrogen
atom from the pyrimidine ring to form positions 2 and 3 of the
histidine ring. The purine is then regenerated by reaction with
a Ci substance. Adenine is the most efficient purine for this
purpose. The following scheme has been worked out, largely
on the basis of auxotroph work: (P = phosphate, R = ribose).
HO
CH,
I
CH2— CH— CH— CH
NH2
I Ribose-5- vik ^
^j:?:\^N. phosphate | ^^
I iT )> ^ CH2— CH— CH— CH I
NH2
ATP
P— O OH OH OH
R— P
Adenosine
Monophosphate
Ci substance,
reamination
R— P
Glutamine
HC-
CH>— CH— CH— C-
P— O OH OH
4-(D-ery tfiro- 1 ',2'-dihydroxy-
3'-phosphopropyl) imidazole
(Imidazoleglycerol Phosphate)
R— P
5-Amino-l-D-
(5'-phospho-
ribosyl)-4-
imidazolecarboxamide
Some chemicals which inhibit purine synthesis also cause ac-
cumulation of such intermediates. To continue with the bio-
synthesis of histidine:
319 Amino Acids and Related Compounds
HC C CH— CH-CH,— O— P H,0 HC=C— CH.— C— CHj— O— P
N NH OH OH -^-^ N NH O
c c
H H
Imidazole glycerol Imidazoleacetol
Phosphate Phosphate
glutamate
— » a-ketoglutarate
H3PO, +
HC=^C— CHo— CH— CH,— OH H,0 HC=— C— CH,— CH— CH2— O— P
N NH NH2 ^ '^— N NH NH2
\/ \/
C C
H H
L-Histidinol L-Histidinol
2DPN
2DPNH
HoO Phosphate
©
2H
HC=C— CH,— CH— COOH
N NH NH>
\/
C
H
Histidine
It is interesting that the final stages of this synthesis differ
from those in the tryptophan sequence when some of the inter-
mediates are so closely related. Perhaps in some species a
lesser difference will be found.
Histidine is converted to ergothioneine in microorganisms by
methylation to form hercynine, followed by direct introduction
of the thiol group.
663 Glycine, C.H,,O.N, colorless crystals, m.p. -'280-290° (dec.)
(rapid heating).
H,N— CH,— COOH
Widely distributed.
664 Sarcosine, C3H7O0N, colorless crystals, m.p. 212° (dec).
CH,NHCH,COOH
Cladonia sylvatica
Also a component of the actinomycin antibiotics.
P. Linko, M. Alfthan, J. K. Miettinen and Artturi I. Virtanen,
Acta Chem. Scarid. 7 1310 ri953).
Pfizer Handbook of Microbial Metabolites 320
665 L-Alanine, C3H7O2N, colorless crystals, m.p. 297° (dec), [cnW^
+8.5° (9.3% solution of the hydrochloride in water).
CH3— CH— COOH
NH2
Widely distributed.
666 /^-Alanine, C3H7O2N, colorless crystals, m.p. 207° (dec.) (pre-
heated bath).
H2N— CH2— CH2— COOH
Widely distributed.
667 L-Serine, C3H7O3N, colorless crystals, m.p. 228° (dec.) (sub-
limes 150° at 10-* mm. Hg), [aW +14.45° (0.5 g. per
5.6 g. of 1 N hydrochloric acid).
HO— CH2CH— COOH
I
NH2
Widely distributed.
668 L-Aspartic Acid, C4H7O4N, colorless crystals, m.p. 270° (sealed
capillary, preheated bath) (dec), [a]D-* +24.6° (c 2 in 6 N
hydrochloric acid).
HOOC— CH2— CH— COOH
NH2
Widely distributed.
669 L-Asparagine, C4H8O3N2, colorless crystals ( Monohydrate ) , m.p.
234°, (dec) (preheated bath), [ajn'" -5.5° (c 1.3 in wa-
ter).
O
H2N— C— CH2— CH— COOH
NH2
Widely distributed.
321 Amino Acids and Related Compounds
670 d-Diaminosuccinic Acid, C4HSO4N0, colorless crystals, m.p.
(dec), 240-290°, [aW +28° (c 2.0 in 5% sodium hy-
droxide solution).
HOOC— CH— CH— COOH
I I
NH2 NH2
Streptomyces rimosus
This amino acid sometimes crystallizes from oxytetra-
cycline broth concentrates. The yield is about 250-500
mg. per liter.
F. A. Hochstein, /. Org. Chem. 24 679 (1959).
671 O-Carbamyl-D-serine, C4H8O4N2, colorless needles, m.p. 226-
234° (dec), [ah -19.6° (c 2 in N hydrochloric acid).
O
il
H2N— C— O— CHo— CH— COOH
I
NH2
Streptomyces polychromogenes
D-Serine or derivatives is also present in polymyxin,
echinomycin, cycloserine and amicetin.
G. Hagemann, L. Penasse and J. Teillon, Biochim. et Bio-
phys. Acta 17 240 (1955).
672 Allantoic Acid, C4HSO4N4, colorless needles, m.p. 165° (dec).
H2NCONH
\
CH— COOH
/
H2NCONH
Coprinus miraceus, Collybia dryophila
R. Fosse and A. Brunei, Compt. rend. 197 288 (1933).
673 y-Aminobutyric Acid, C4H9O2N, colorless crystals, m.p. 202°
(dec) rapid heating.
H2N— CH2— CH2— CH2— COOH
Widely distributed.
Pfizer Handbook of Microbial Metabolites 322
674 L-(+)-a-Aminobutyric Acid, C4H9O0N, colorless crystals, m.p.
270-280° (dec), [a]ir" +8.0° (c 1.0 in water).
CH3— CHo— CH— COOH
I
NH2
Escherichia coli, Corynebacterium diphtheriae
A. Poison, Nature 161 351 (1948).
Elizabeth Work, Biochim. et Biophys. Acta 3 400 (1949).
675 L-Threonine, C4H9O3N, colorless crystals, m.p. 255-257° (dec),
[a]D-'" -28.3° (c 1.1 in water).
CH3— CH— CH— COOH
I I
OH NHo
Widely distributed.
676 S-Methyl-L-cysteine, C4H,,03NS, colorless crystals, m.p. --164°
(dec), [alo'' +125° (c 2.5 in water).
CH3— S— CH>— CH— COOH
NHo
Neurospora crassa
James B. Ragland and James L. Livermore, Arch. Biochem.
and Biophys. 65 574 (1956). (Isolation from neurospora)
Clayton J. Morris and John P. Thompson, /. Am. Chem.
Soc. 78 1605 (1956). (Physical properties)
677 4-Imidazolyacetic Acid, C-.H^OoN^, colorless needles (Hydrate),
m.p. 222° (dec).
N C— CH2— COOH
II II
HC CH
H
Polyporus sulfureus
P. H. List, Planta Med. 6 424 (1958).
678 Azaserine (Diazoacetyl-L-serine), C-,H704N;^, light yellow-green
crystals, dec 146-162°, [a],,"' '' -0.5° (c 8.46 in water at
pH 5.18).
N.— CH— CO— O— CH,— CH— COOH
NH,
An unclassified streptomycete
323 Amino Acids and Related Compounds
James A. Moore, John R. Dice, Ernest D. Nicolaides, Roger
D. Westland and Eugene L. Wittle, /. Am. Chern. Soc. 7(i 2884
(1954). (Synthesis)
C. Chester Stock, H. Christine Reilly, Sonja M. Buckley,
Donald A. Clarke and C. P. Rhoads, Nature 173 71 (1954).
John Ehrlich, Lucia E. Anderson, George L. Coffey, Arthur
B. Hillegas, Mildred P. Knudsen, Harold J. Koepsell, Dorothy
L. Kohberger and Julian E. Oyaas, ibid. 173 72 (1954).
Quentin R. Bartz, Carole C. Elder, Roger P. Frohardt, Salva-
tore A. Fusari, Theodore H. Haskell, Doris W. Johannessen and
Albert Ryder, ibid. 173 72 (1954). (Isolation)
679 L-Proline, C.^HciOoN, colorless crystals, m.p. 220-222° (dec.)
(rapid heating), [x],,-"' —80° (c 1.0 in water).
CH. — CH2
CH2 CH— COOH
H
Widely distributed.
680 L-GIutamic Acid, C-,H.,04N, colorless crystals, m.p. 247° (dec),
[a]n--* +31.4° (c 1 in 6 N hydrochloric acid).
HOOC— CH2— CHo— CH— COOH
NH2
Micrococcus varians
A 17% molar yield (from glucose) was reported.
Toshinobu Asai, Ko Aida, Kunio Oishi, Bull. Agr. Chem. Soc.
(Japan) 21 134 (1957).
681 L-Glutamine, C.-jHjoO^N^, colorless crystals, m.p. 185° (dec),
[a]ir' +5.9° (c 4.0 in water).
O
H ,N— C— CH2— CH2— CH— COOH
i
NH2
Widely distributed.
682 L-Valine, C-,Hi,O.N, colorless crystals, m.p. 315° (dec.) (closed
capillary). Sublimes, [a]ir'' +14°(c0.9in water).
CH3
\
CH— CH— COOH
/ I
CH3 NH2
Pfizer Handbook of Microbial Metabolites 324
Widely distributed.
683 Betaine, C5H11O2N, white prisms or leaflets, m.p. 293° (dec.)-
© e
(CHalsN— CH2COO
Aspergillus oryzae, Patella vulgata, Claviceps purpurea
(Fries) Tul. and other fungi
Jacqueline Etienne-Petitfils, Bull. soc. chim. biol. 38 1315
(1956).
684 L-Methionine, CgHnOgNS, colorless crystals, m.p. '-'280° (dec.)
(sealed capillary), [aW^ —8° (c 1.0 in water).
CH3S— CH2CH2CH— COOH
I
NH2
Widely distributed.
685 L-Ornithine, C5H12O2N0, colorless crystals, m.p. 140° (subl.
120°), [alo'' +12° (c 6.5 in water).
HoN— CH2— CH2— CH2— CH— COOH
I
NH2
Widely distributed.
686 Choline Sulfate, C5H13O4NS
© 0
(CHalsN— CH2CH2— O— SO3
Aspergillus sydowi, Penicillium chrysogenum, lichens,
yeasts
Choline yields of 6000-7000 ^g. per gram of dry cell
weight are available in certain Distillers' Dried Solubles.
D. W. WooUey and W. H. Peterson, /. Biol. Chem. 122 213
(1937).
J. deFlines, J. Am. Chem. Soc. 77 1676 (1955).
687 Imidazoleacetol (Hydrochloride), CgHgOoNaHCl, white needles,
m.p. 171-174° (dec).
O
CH2— C— CH2OH
/
©r=n
HN:^ NH
©
CI
Neuorspora crassa and E. coli mutants
325 Amino Acids and Related Compounds
Bruce N. Ames, Herschel K. Mitchell and Mary B. Mitchell,
/. Am. Chem. Soc. 75 1015 (1953).
688 L-Histidine, CoHoOsNa, colorless crystals, m.p. 287° (dec),
[aln''' -39.7° "(c 1.13 in water).
CH— C— CH2— CH—COOH
I I I
N NH NH,
CH
Claviceps purpurea (Fries) Tul.
H. Heath and Jennifer Wildy, Biochem. J. 64 612 (1956).
689 6-Diazo-5-oxo-L-norleucine (DON), C6H9O3N3, pale greenish
yellow crystals, m.p. 145-155° (dec), [aW +21° (c 5.4
in water).
O
N2CH—C—CH2—CH2— CH—COOH
NH2
An unclassified streptomycete
Henry W. Dion, Salvatore A. Fusari, Zbigniew L. Jakubow-
ski, John G. Zora and Quentin R. Bartz, /. Am. Chem.. Soc. 78
3075 (1956). (Isolation and characterization)
690 Imidazoleglycerol (Hydrochloride), CeHioOgNg-HCl, colorless
crystals, m.p. 103° (dec), hW^ +13.3° (c 7.5 in water).
CH-
-CH— CH2
/l
1 1
©r=
n OH
OH OH
HN^
.NH
e
CI
Neurospora crassa mutant
Bruce N. Ames and Herschel K. Mitchell, /. Biol. Chem. 212
687 (1955).
691 L-Histidinol (Hydrochloride), CoH„ON3-2HCl, colorless crys-
tals, m.p. 194° (dec).
— 1 —
CH2-
-CH-
-CH
©
1 ©
1
HN^
NH
NH3
OH
e ~^
e
CI
CI
E. coli mutant
Henry J. Vogel, Bernard D. Davis and Elizabeth S. Mingioli,
/. Am. Chem. Soc. 73 1897 (1951).
Pfizer Handbook of Microbial Metabolites 326
692 L-Leucine, CcHj-iOMN, colorless crystals, m.p. ~295° (dec.)
(sealed tube") (subl. from 140°), [a],,-' -11° (c 2.0 in
water).
CH3
\
CH— CH2— CH— COOH
/ I
CH3 NH2
Widely distributed.
693 L-Isoleucine, CeHi.jO^N, colorless crystals, m.p. 284° (dec.)
(subl. from 160°), [a],r" +11° (c 3.0 in water).
CH3— CH2— CH— CH— COOH
1 I
CH3 NH,
Widely distributed.
694 L-a-Aminoadipic Acid, C(jHii04N, white crystals, m.p. 206°
(dec).
HOOC— CH,CH,CH,CHCOOH
NH,
Aspergillus oryzae
Also a component of several antibiotics.
Emmanuel Windsor, /. Biol. Chem. 192 595 (1951).
695 L-Lysine, C,jH,40^.No. white needles, m.p. 224°.
H,NCH,CH2CH2CH,CHCOOH
NH..
Ustilago maydis PRL 1092
The yield was 200-300 mg. per liter of free lysine in the
broth as determined by a bioassay (not isolated).
M. Richards and R. H. Raskins, Can. J. Microbiol. 3 543
(1957).
696 L-Arginine, C,jH,40oN4, colorless crystals (Dihydrate), m.p.
245° (dec.) (browning above 200°), [a],,-" +13° (c 3.5
in water).
NH
H N— C— NH— CH2— CH,— CH .— CH— COOH
I
NHs
Widely distributed.
3^7 Amino Acids and Related Compounds
697 8-Oxy-L-lysine (a.f-Diamino-8-hydroxycaproic acid), C,.H,.,0:jNo.
H .NCH,CHCH CH CHCOOH
I I
OH NH,
Mycobacterium phlei
Occurs bound in a phosphatide (yellow powder, m.p.
180-190°), molecular weight about 16,000. It is the sole
amino acid, and constitutes about 1 % of the phosphatide.
M. Barbier and E. Lederer, Biochim. et Biophys. Acta 8 590
(1952).
698 Anthranilic Acid, C^H^O.N, leaflets, m.p. 144°.
COOH
NHa
Corynebacterium diphtheriae
Detected by paper chromatography.
A. J. Woiwood and F. V. Lniggood, Intern. Congr. Biochem.,
Abstrs. of Communs. 1st Congr., Cambridge, England, 320
(1949).
Anthranilic acid has been isolated also from a pseu-
domonas culture:
Rokuro Takeda and 1. Nakanishi, /. Fermentation Technol.
37 No. 2 (1959).
It also accumulates in certain bacterial auxotrophs.
699 p-Aminobenzoic Acid, C7H7O0N, yellowish red crystals, m.p.
186°.
H2N— / V-COOH
Hansenula anomala, Mycotorula lipolytica
Yields about 1 mg. per gram of dry cells.
W. H. Peterson, "Yeasts in Feeding" Symposium, Milwaukee,
1948.
700 Trigonelline, CtH-O^.N, colorless crystals, m.p. (anhyd.) 218°
(dec.) (Picrate) m.p. 205° (dec).
0
COO
©
CH3
Pfizer Handbook of Microbial Metabolites 328
Polyporus sulfureiis
P. H. List, Planta Med. 6 424 (1958).
701 Homarine, C7H7O2N (Hydrochloride), m.p. 170-175° (dec.)
(Picrate) m.p. 155-160°.
c=o
0 I e
CH3 o
Polyporus sulfureus
P. H. List, Planta Med. 6 424 (1958).
702 Stachydrine, C7H13O2N, white monohydrated crystals, m.p.
(anhydr.) 235° (dec).
CH2 CH2
I I
CH2 CH
\ / \
N© C=0
CH3 \oe
CH3
Aspergillus oryzae, other fungi (in small yields)
R. Takata, J. Soc. Chem. Ind. Japan 32 155B (1929).
703 2,6-Diaminopimelic Acid (Both l,l- and mesa forms occur nat-
urally), C7H14O4N2, colorless needles, m.p. >305°.
HOOC— CH— CHo— CHo— CHo— CH— COOH
I I
NH2 NHo
Corynshacterium diphtheriae, Mycobacterium tubercu-
losis. Bacillus anthracis, E. coli mutants
Elizabeth Work, Biochem. J. 49 17 (1951).
H. Smith, R. E. Strange and H. T. Zwartouw, Nature 178
865 (1956).
Lester E. Casida, Jr., U. S. Patent 2,771,396 (1956).
704 /3-Methyllanthionine, C7H14O4N0S, [a]i>-° +37.6° (c 0.5 in 1 N
hydrochloric acid).
HOOC— CH— CH2— S— CH— CH— COOH
I I I
NH2 CHs NH2
Yeast
This isomer is not the same as the one isolated from
329 Amino Acids and Related Compounds
antibiotic hydrolysates. Desulfurization with Raney
nickel yields L-alanine and D-a-amino-/2-butyric acid.
Phyllis F. Downey and Simon Black, /. Biol. Chem. 228 171
(1957).
705 L-Phenylalanine, CgHnOoN, colorless crystals, m.p. 283° (dec.)
(rapid heating), [aW^ —35° (c 2 in water).
/ \— CH2— CH— COOH
NH2
Widely distributed.
706 L-Tyrosine, C9H11O3N, colorless crystals, m.p. 342-344° (sealed
capillary, preheated bath) (dec), [a]D" —10.6° (c 4 in
1 N hydrochloric acid).
HO—/ V-CHo— CH— COOH
NH2
Widely distributed.
707 Hercynine (Histidine Betaine), C9H15O2N3, white crystals, no
sharp m.p., forms mono- and dipicrates.
HC— C— CH2— CH— COO ®
N NH ©N(CH3)3
H
Amanita muscaria, Agaricus campestris, Boletus edulis
Bull., Polyporus sulfureus
Fr. Kutscher, Zentr. Physiol. 24 775 (1910).
R. Engeland and F. Kutscher, ibid. 26 569 (1912). (Syn-
thesis)
Albert Kiing, Z. phijsiol. Chem. 91 241 (1914).
708 Ergothioneine, C9H15O2N3S, colorless crystals, m.p. 290° (dec),
[a]D-M16.5°.
CH=C— CH2— CH— COO ®
I I 1
N NH N(CH3)3
I
SH
Pfizer Handbook of Microbial Metabolites 330
Claviceps purpurea (Fries), Tul. Coprinus comatus,
Mycobacterium tuberculosis
C. Tanret, J. pharm. chim. 30 145 (1909).
H. Heath and Jennifer Wildy, Biochem. J. 64 612 (1956).
(Biosynthesis)
Paul Heinz List, Arch. Pharm. 290 517 (1957).
Dorothy S. Genghof, Bad. Proc, 190 (1960).
709 L-Tryptophan, CiiHi^O^,N2, colorless crystals, m.p. 289° (dec.)
(rapid heating), [ix]i,-'^ —31.5 (c 1.0 in water).
CH2— CH— COOH
CO
NH2
H
Widely distributed.
710 Amino Acid from Lactarius helvus, CuHiyOaNo, colorless crys-
tals, yellowing near 200° and darkening to 300°. Molecu-
lar weight 251 by isothermal distillation. Adds 2 H^ and
2 Bro.
Partial structure:
HOOC— CH CH— COOH
NH,. ^ NH2
C7H10
C
\^
containing C= and C=C
/
C
Lactarius helvus
Ateushi Komamine and Artturi Virtanen, Acta Chem. Scaiid.
13 2141 (1959).
J. Casimir and A. I. Virtanen, ibid. 13 2139 (1959). (Iso-
lation )
711 Elaiomycin, C,..iHo,;0;!N._,, pale yellow oil, [a],,"' +38.4° (c 2.8 in
absolute ethanol).
O OH
T I
CH3(CH2)5CH=CH— N=N— CH— CH— CH3
CH0OCH3
Streptomyces hepaticus
33 1 Amino Acids and Related Compounds
Theodore H. Haskell, Albert Ryder and Quentin R. Bartz,
Antibiotics and Chcmotlierapy 4 141 (1954). (Isolation)
John Ehrlich, Lucia E. Anderson, George L. Coffey, William
H. Feldman, Myron W. Fisher, Arther B. Hillegas, Alfred G.
Karlson, Mildred P. Knudsen, Jean K. Weston, Anne S. You-
mans and Guy P. Youmans, ibid. 4 338 (1954).
C. L. Stevens, B. T. Gillis, J. C. French and T. H. Haskell.
;. Am. Chem. Soc. 78 3229 (1956). (Structure)
17
Polypeptides and Related Compounds
Polypeptides are often intractable, difficultly crystallizable
substances. The newer techniques of chromatography, end-
group analysis and electrophoresis have facilitated their investi-
gation.
Most of the polypeptides and related compounds listed in this
section are antibiotic isolates. Antibiosis may be a primary or
only a secondary function of these materials. Polypeptides, of
course, have hormonal and other functions in higher animals.
Among microorganisms streptomycetes and bacteria have been
the richest sources so far, perhaps in part because they have
been examined more extensively for antibiotic activity than
other microorganisms.
Special types of polypeptides have been isolated from bac-
terial cell walls by fragmentation with lysozyme or bacterio-
phage. They also tend to accumulate when bacteria are in-
hibited by certain antibiotics. Determination of their structures
is beginning to elucidate the nature of the bacterial cell wall as
well as the mode of action of the antibiotics involved.
Some attention has been given to intracellular peptides, prin-
cipally in connection with their role in protein synthesis. The
fundamental process of polypeptide and protein biosynthesis is
just beginning to yield some of its secrets. Before discussing it,
some earlier work on simpler polypeptide biosynthesis will be
reviewed.
Glutathione is a widely distributed tripeptide which has a
rapid metabolic turnover in yeast and also in mammalian tis-
sues. Partly for this reason it has been suggested as an inter-
mediate in protein biosynthesis, but because of its reversible
oxidation-reduction properties, a respiratory role also has been
proposed. In fact, it has not been proved satisfactorily that
polypeptides serve as direct precursors for protein synthesis in
333 Polypeptides and Related Compounds
microorganisms, although strepogenins (glutamic acid contain-
ing oligopeptides from the enzymic digests of certain proteins)
stimulate the growth of some bacteria. There is evidence for
the occurrence of independent uptake mechanisms for glycine
and glycine peptides in Lactobacillus casei.^
Glutathione formation takes place in two separate reactions,
each involving ATP : -
( 1 ) L-Glutamic Acid + L-Cysteine + ATP^
L-y-Glutamylcysteine + ADP + H3PO4.
(2) L-y-Glutamylcysteine + Glycine + ATP^
L-Glutathione + ADP + H3PO4.
The biosynthesis of pantothenic acid probably proceeds as
follows, the last step also being coupled with ATP cleavage, but
with different products ■.^- *
Ci unit from
CH3 O tetrahydro- CH3 O
\ II folic acid | ||
CH— C— COOH > HOCH2— C C— COOH
CH3 CH3 \ 2H
a-Ketoisovaleric Acid ^>i
CH3
I
HOCH2— C CH— COOH
CH3 OH
Pyrophosphate +
// Pantoic Acid
/3-Alanine /
CH, 0 ^ ATP
1 II
-C CH— C— NH— CH2— CH2— COOH
AMP + HOCH2-
CH3 OH
Pantothenic Acid
^ Franklin R. Leach and Esmond E. Snell, Biochim. et Biophys.
Acta 34 292 (1959).
2 John E. Snoke and Konrad Bloch, /. Biol. Chem. 199 407 (1952);
John E. Snoke, ibid. 213 813 (1955); John E. Snoke and Konrad
Bloch, ibid. 213 825 (1955); Stanley Mandeles and Konrad Bloch,
ibid. 214 639 (1955).
3 Werner K. Maas and Henry J. Vogel, /. Bacteriol. 65 388 (1953);
M. Purko, W. O. Nelson and W. A. Wood, /. Biol. Chem. 207 51
(1954); E. Nelson Mcintosh, M. Purko and W. A. Wood, ibid., 228
499 (1957).
* Werner K. Maas, /. Biol. Chem. 198 23 (1952); Akira Matsuyama,
Bull. Agr. Chem. Soc. (Japan) 21 47 (1957) and earlier papers in
this series; Herbert S. Ginoza and Robert A. Altenbern, Arch.
Biochem. and Biophys. 56 537 (1955).
Pfizer Handbook of Microbial Metabolites
334
It appears that an adenylic acid-pantoate complex is the inter-
mediate which couples with the enzyme.
NHj
sXn
o o
T T I
CH,— O— P— O— P— O— CH2— C
OH
OH
CH3 OH O
I I II
CH— C— NH— CH2— CH,— COOH
CH3
Pantothenylcysteine is a precursor of pantetheine in Lactobacil-
lus helveticus.^
The red actinomycins were the first antibiotics isolated crys-
talline from actinomycetes/' In the ensuing 20 years about a
dozen named species of streptomycetes have been found to pro-
duce actinomycins, and probably many other isolates have gone
unreported.
TABLE I
Chronological List of Microorganisms Reported to Produce Actinomycins*
Year reported
Name given to
microorganism
Actinomycin
complexf
1941
Sfrepfomyces ant/biot/cus
A
1946
Non-chromogenic species
A
1947
S. flovus
A (J)
1948
S. parvus
A
S. flavovirens
—
1949
Streptomyces sp.
B
S. chrysomallus
C
1951
S. flaveolus
A (J)
Micromonospora globosa
—
1952
Streptomyces sp.
X
5 Gene M. Brown, /. Biol. Chem. 226 651 (1957).
« S. A. Waksman and H. B. Woodruff, Proc. Soc. Exp. Biol. 45 609
(1940).
335
Polypeptides and Related Compounds
TABLE 1 -Continued
Year reported
Name given to
microorganism
Actinomycin
complexf
1954
S.
flovus
X(B)
S.
flavus
X
S.
aniibioticus
X
S.
flavus-parvus
X(B)
S.
parvullus
D
S.
cellulosae
—
S.
michiganensis
X
S.
anfibioficus
M
1956
Strepfomyces sp.
E
Sfrepfomyces sp.
F
1958
S.
fradiae
Z, X
* By courtesy of Dr. H. Boyd Woodruff, Merck, Shorpe and Dohme, and the New York
Academy of Science.
t See the discussion of nomenclature preceding the actinomycin entries.
Often these polypeptide pigments occur in closely related com-
plexes, the individual members varying only by slight changes
in the side-chains.
The chromophore, actinocinin, resembles that of the ommo-
chromes, a group of insect pigments studied by Butenandt,' and
it is similar to the pigment cinnabarin from a higher fungus.
COOH
NH,
COOH
CH3 CH3
Actinocinin
^o--^=^\
o
Xanthommatin
^ Adolph Butenandt, Ulrich Schiedt, Ernst Biekert and Pierre
Kornmann, Ann. 586 217 (1954); Adolph Butenandt, Ulrich Schiedt
and Ernst Biekert, Ann. 586 229, 588 106 (1954); Adolph Butenandt,
Ulrich Schiedt, Ernst Biekert and R. Jan. T. Cromartie, Ann. 590 75
(1954). (Structure)
Pfizer Handbook of Microbial Metabolites
336
CH3 CH3
Actinomycin C3
The dual nature of the actinomycin molecules makes it rather
obvious that they must be formed by condensation of two similar
halves. Butenandt showed that xanthommatin was derived
from tryptophan by feeding experiments with the labeled amino
acid. Similarly Katz has shown® that actinocinin is derived
from tryptophan. Thus the entire actinomycin molecule is
composed of amino acid derivatives. In the case of xanthom-
matin the intermediate is kynurenine, a known degradation
product of tryptophan. Kynurenine may also be an intermedi-
ate in actinocinin biosynthesis, although the assumed inter-
mediate, 3-oxy-4-methyl-anthranilic acid might equally well
arise through a variation in the biosynthetic route to tryptophan.
^ Edward Katz, N. Y. Acad. Sci. Conference on Actinomycins,
March 31 to April 1, 1960. (Unpublished)
337
Polypeptides and Related Compounds
CXJ
CH2— CH— COOH
1
NH,
Tryptophan
CO— CHo— CH— COOH
NHo
NHo
Kynurenine
CO— CH.— CH— COOH
I
NH,
3-Oxykynurenine
It is likely that the peptide side-chain is attached before conden-
sation to form the chromophore.
COOR
COOR
COOR
OH
CH3
3-Oxy-4-methyl-
anthranilic Acid
(R = Polypeptide
Moiety)
Actinomycins
It is interesting that methyltryptophans (a,5,6-methyls) are
inhibitory to actinomycin production. Methionine is probably
the donor of the methyl groups in N-methylvaline and sarcosine.^
In two streptomycete species D-valine inhibits actinomycin
synthesis while L-valine stimulates it, although D-vahne is the
isomer present in the side-chains.^ This behavior is reminiscent
of the results of similar earlier experiments with penicillin and
with valinomycin.
Schmidt-Kastner found that addition of a large quantity of
sarcosine to the medium caused replacement of part or all of the
side-chain proline by sarcosine. Analogously, addition of isoleu-
cine caused replacement of N-methylvaline by N-methyhsoleu-
cine.'' Since then many new actinomycins have been prepared
by addition of various amino acids to the medium. Even
^ G. Schmidt-Kastner, Naturwissenschaften 43 131 (1956).
Pfizer Handbook of Microbial Metabolites 338
pipecolic acid can be incorporated.'" It should be noted that
certain amino acid analogues can be incorporated into enzymes
and other proteins without impairing their normal functions."
Professor Hans Brockmann and his collaborators at Gottingen,
who were primarily responsible for determining the structure of
the first well-characterized actinomycin, actinomycin C^,'- have
succeeded in synthesizing this substance' ' and it should be pos-
sible now to prepare an even wider variety of actinomycins.
Valinomycin, shown opposite, can be hydrolyzed to its con-
stituents: L-valine, D-valine, D-a-hydroxyisovaleric acid and
L-lactic acid. It has been found'* that L-valine- l-C* in the
medium was incorporated to an equal extent into the D-valyl
and L-valyl portions of the molecule, to a lesser extent into the
D-a-hydroxyisovaleric acid, and not at all into the lactic acid.
D-Valine-l-C* was incorporated only to a slight extent. Similar
results have been obtained in studies on the origin of the
D-valine moieties in penicillin and in actinomycin.
The co-occurrence of valine with the biosynthetically related
-z-hydroxyisovaleric acid in several polypeptides is noteworthy.
Also conjugated with certain polypeptides are 6-methyloctanoic
CHs— CH2— CH— CH2— CH.— CH,— CH,— COOH
I
CH3
6-Methyloctanoic Acid
CH3— CH2— CH,— CHo— CH.— CH.— CH>— CH— CHo— COOH
I
OH
3-Oxydecanoic Acid
acid and 3-oxydecanoic acid. The latter substance has been
found conjugated with bacterial carbohydrates too.
10 Edward Katz and WilHam Goss, Nature 182 1668 (1958); S. A.
Waksman, E. Katz, W. A. Goss, L. H. Pugh, M. Solvtorowsky, and
N. A. Auerbach, Science 129 1290 (1959); E. Katz and W. A. Goss,
Biochem. J. 73 458 (1959); A. W. Johnson and A. B. Mauger, ibid.
73 535 (1959); WiUiam A. Goss and Edward Katz, Antibiotics and
Chemotherapy 10 221 (1960).
" E.g., Akira Yoshida and Mekoto Yamasaki, Biochim. et Biophys.
Acta 34 158 (1959).
1- H. Brockmann, G. Bohnsack, B. Franck, H. Grone, H. Muxfeldt
and C. Siiling, Angeiv. Chem. 68 70 (1956); H. Brockmann, N.
Grubhofer, H. Kalbe and W. Kass, Chem. Ber. 84 260 (1951); H.
Brockmann, Angeiv. Chem. 66 1 (1954); H. Brockmann and B.
Franck, ibid. 68 70 (1956) and other papers in this series.
1-^ H. Brockmann, W. Sunderkotter, K. W. Ohly and P. Boldt,
NatUTivissenschaften 47 230 (I960); H. Brockmann and H. Lackner,
ibid. 47 320 (1960).
"J. C. MacDonald, Can. J. Microbiol. 6 27 (1960).
339
Polypeptides and Related Compounds
CHa
\
CH
CHs
CH3
0
II
-C—
CH3
\
CH— CH
~NH^^ /
i-Valine CH
X
e
L-Lactic
Acid
CH D-Valine
NH
D-a-Hydroxy- CH
isovaleric Acid
CH
0=C
CHa
CH3
CH3
CH3
c=o
CH'
D-a-Hydroxy-
-CH isovaleric
\ Acid
NH
D-Vaiine CH /"'
CH
./
^L-Va!ine
CH^
/
CH
/ \
CHa CH3
NH
L-Lactic X O
Acid^.^0
-- C -CH'"^
" CH
Vaiinomycin
\
CHs
CH2
/
NH.
I
CH, CH3 CH3
I \ /
CHa CHa CHo CH
\ / 1 I
CH CH2 CHo CH2
I I I I
CO— NHCHCO NHCHCO NHCHCO NHCHCO— N CH2
I (l) (l) (l) (d)
CHo— CH
(l) (l) CH— CHo
(d) (l) (l) (l) I
CH2— N COCHNH COCHNH COCHNH COCHNH — CO
CH2
CH,
CH2
1
CH
/ \
CHa CHa
CH2
CH2
CH2
NH2
CH
/ \
CHa CH
Gramicidin S
Pfizer Handbook of Microbial Metabolites
340
The biosynthesis of gramicidin S has been studied. ^^ The
conclusions were: (a) The five amino acids of the cyclic de-
capeptide pass through a number of intermediates before or
during incorporation, (b) Final formation of gramicidin S is a
simple reaction not requiring free amino acids which occurs
readily in cell-free suspensions, (c) Three peptides were iso-
lated containing fragments of the amino acid sequences of the
antibiotic. These may or may not have been intermediates.
It is possible to extract intracellular peptides with suitable
solvents. This has been done with mammalian pituitary tis-
gyg 16. 17 ^fjj plant seeds^^ and with yeast^" and bacteria.-"' ^^ In
all cases cited care was taken to obviate contamination by frag-
ments of proteolysis. There is some indication that yields are
higher from rapidly growing bacteria than from resting cells.
The intracellular peptides of the torula yeast studied were
found to be predominantly acidic with glutamic acid the princi-
pal amino acid. About 40 peptides were purified in adequate
quantity to permit hydrolysis and identification of constituent
amino acids. These are tabulated below (x indicates an un-
identified ninhydrin-positive substance ) :
TABLE II
Some Intracellular Peptides of Torula Yeast
Peptide
No.
Amino acid content
Peptide
No.
Amino acid content
1
Glu, x-6, Gly, Alo, Asp, Arg,
Vol
21
22
Glo (Gly, x-3, Ala)
Glu, Gly, Cys (Glutathione)
15 J. M. Barry and Elizabeth Ishihara, Nature 181 1274 (1958).
I*' T. Winnick, R. E. Winnick, R. Acher and C. Fromageot, Biochim.
et Biophys. Acta 18 488 (1955).
" L. K. Ramachandran and T. Winnick, ibid. 23 533 (1957).
1^ H. Borriss and G. Schneider, Naturwissenschaften 42 103
(1955).
"F. Turba and H. Esser, Biochem. Z. 327 93 (1956).
2° G. E. Connell and R. W. Watson, Biochim. et Biophys. Acta 24
226 (1957).
21 R. B. Roberts, P. H. Abelson, D. C. Cowie, E. T. Bolton and R. J.
Britten, "Studies of Biosynthesis in E. coli," Carnegie Institute, Wash-
ington, D. €., 1955.
341
Polypeptides and Related Compounds
TABLE ll-Continued
Peptide
No.
Amino acid content
Peptide
No.
Amino acid content
2
3
Glu, Gly, Ala, Asp, Ser, Vol, x-7,
Arg
Glu, Gly, Asp, Ala, Thr? x-6.
23
24
Glu, Gly, Ala, His, Arg or. Cys,
x-6. Asp, Lys, Vol
Glu, Gly, Ala, x-7, x-11. Asp,
4
Arg?
Glu, Gly, Ala, Thr? Asp, Arg, His,
25
Ser, Leu, Vol, Arg, Lys
Gly, Glu, x-6, Ser, Ala, His, Vol,
Vol, x-5
Leu, Asp
5
6
Glu, Gly, Ala, His, Asp, x-4
Glu, Gly, Ala, x-5, Asp, Arg, Vol,
26
Glu, Gly, x-4, Ala, His, Lys,
Leu
7
His
Glu, Gly, His, Ala, x-5. Asp, Arg,
27
28
Gly, Ala, Glu, x-4. Vol, Arg
Glu, Gly, x-11, Ser, Ala, Arg,
8
Vol
Glu, Gly, Ala, Asp, x-4. His,
29
Thr, X-7, Asp, Vol, Lys
Glu, Gly, Ser, Ala, x-11. Asp,
9
Arg
Asp, Gly, Glu, Ala, x-5. Vol,
30
Thr, Vol, Lys, Arg, Leu
Glu, Gly, Ser, Ala, x-8. Asp, Thr,
10
Arg
Ala, Gly, Glu, x-5, x-6. Vol
31
x-11. Vol, Leu, Arg
Gly, Glu, x-4, Ser, Ala, Asp,
11
x-4, x-7, x-5, Gly, Glu, Ala,
Leu
12
Asp
Asp (Gly, Glu, Ala, x-5, x-6)
32
33
Gly, x-5, Glu, Ala, Asp, Arg
Glu, Gly, x-6, Ala, a-But, Leu
13
Glu, Gly, Ala, Asp, x-5
34
x-3, Ala, Gly, Glu, x-7, Ser, Asp,
14
Glu, Gly, Ala, x-5, x-8, Ser, Asp,
Vol, Arg, Leu
15
Vol, Arg?
Ala, Gly, Glu, x-4, x-6. Asp
35
Gly, Glu, Ala, x-7, Arg, Asp,
Vol, Leu
16
Glu, Gly, His, Ala, Cys, x-4
36
Arg? x-3, Gly, Glu, Ser., Ala,
17
Glu, Gly, Cys, x-10, Ala, Ser,
x-8, x-12. Asp, Thr, Vol, Leu
x-6. Asp, Arg, Vol, Leu
37
Gly, Glu, Ser, Ala, Asp, x-5, Arg,
18
Glu, Gly, x-9, Ser, Ala, Asp, Thr,
x-9, Thr? Vol
Cys? Arg, x-5
38
Gly, Ser, Gly, Ala, Asp, Vol,
19
Gly, Glu, x-6, Ala, Ser, Asp, Vol,
x-6, Thr, Arg, Lys, His, x-12
Leu, His
39
Gly, Glu, Ala, x-6. Leu, Vol, Thr,
20
Glu, Gly, Ala, Asp, x-7, Ser, Tyr,
Asp, x-11. His, Lys
Vol, Leu, His
40
Gly, Glu, x-5, Ala, a-But, Vol
In a similar study with the use of E. coli ten intracellular
peptides were purified in sufficient amounts to allow amino acid
determination.-- In this case the N-terminal amino acids were
^^ D. Griinberger, Jifina Cerna and F. Sorm, Experientia 16 54
(1960).
Pfizer Handbook of Microbial Metabolites
342
distinguished by formation of their dinitrophenyl derivatives.
The results are shown in the following table:
TABLE III
Some Infraceltular Peptides of Escherichia co/i
Peptide No.
Terminal amino acid
(Other amino acids)
1
Glu
(Cys, Gly, Lys)
2
Glu
(Ala, Cys, Gly, Lys)
3
Asp
(Cys, Gly, Lys)
4
Lys
(Ala, Arg, Asp, Cys, Gly, Glu, Ser)
5
Asp
(Arg, Gly, Glu, 7-NH.But, Lys, Vol)
6
Ser
(Asp, Gly, Lys)
7
Ala
(Asp, Lys)
8
Glu
(Ala, Asp, Cys, Gly, Lys, Leu, Vol)
9
Glu
(Ala, Asp, Lys, Cys, Gly)
10
Glu
(Cys, Gly)
It has been reported that gram-negative bacteria contain
much less intracellular free ninhydrin-positive substances than
do gram-positive ones.-^
A basic polypeptide has been extracted from dried cells of the
human strain of Mycobactenum tuberculosis H.jyR,, purified,
crystallized and quantitatively analyzed for amino acid con-
stituents.-' The pure peptide showed activity in the tuberculin
test at least equal to that of standard old tuberculin. The amino
acid content was as follows, subscripts indicating number of
moles :
Argio HiSi Lyso Phe, Tyr, Leu..^ Ileu^. Val-
Alag Glye Glus Pro- Ser^ Thr.{ Asp,, Tryi
The molecular weight was calculated to be 7180.
Certain polypeptides accumulate in E. coli cells grown in the
presence of chloramphenicol (a protein synthesis inhibitor).
Two of these have been isolated and purified.-^
-' Yuichi Yamamura, Seisi Morizawa, Atsushi Tanaka, and Kenji
Shojima, Proc. Jap. Acad. Sci. 35 295 (1959); Seisi Morizawa, Atsushi
Tanaka, Kenji Shojima and Yuichi Yamamura, Biochivi. et Biophys.
Acta 38 252 (1960).
-' F. Sorm and Jifina Cerna, Collection Czechoslov. Chem. Com-
muTi. 25 565 (1960).
343
Poln^eptklesandRelated Compounds
Synthesis of the cell wall mucopeptides of staphjd^^o^^
unaffected by chloramphenicol, but inhibited (at least indi-
rectly) by penicillin, bacitracin, cycloserine, novobiocin and
gentian violet. None of these inhibits protein synthesis
Penicillin-inhibited Staphylococcus aureus accumulates three
closely related uridine nucleotides.- One of these has been as-
signed the structure : '■"'■ -'■ -^
\/N
^N-Acetylmuramic Acid
CH— CH.— CHo— COOH
NH2
I
NH CH,
D-Ala D-Ala | I
HOOC-CH-NH-C-CH-NH-C-CH-CH2-CH,-CH2
I II I II L-Lys
CH3 O CH3 O
This fragment may be the repeating unit of an activated cell
wall precursor, since the ratio of muramic acid: alanine glu-
tamic acid:lysine is 1 :3:1 :1, the same ratio found in lysozyme
digests of whole bacteria. In E. coli and Corynebacterium
diphthenae the lysine in the peptide chain is replaced by its
biosynthetic precursor, meso-diaminopimelic acid.
^^ J. T. Park and N. J. Johnson, /. Biol. Chem. 179 585 (1949).
J. T. Park and J. L. Strominger, Science 125 99 (1957).
2^ J. L. Strominger, /. Biol. Chem. 234 1520 (1959).
'-ndem.. Federation Proc. 18 334 (1959); Eijl Ito and Jack L.
Strommger, J. Biol. Chem. 235 PC5 (1960).
Pfizer Handbook of Microbial Metabolites 344
There is increasing evidence that the antibiotics mentioned,
lysozyme and bacteriophages, all bring about a similar result,
the accumulation or liberation of a fundamental cell waU unit
such as the one shown. Lysozyme and bacteriophages are able
to liberate the unit from pre-formed walls, while the antibiotics
merely block wall synthesis. Also, the unit obtained by lyso-
zyme or phage action seems to contain glucosamine as well as
muramic acid, and sometimes diaminopimelic acid (a lysine
precursor) rather than lysine. There is evidence that N-acetyl-
D-glucosamine is a direct precursor of muramic acid.
COOH
I
c=o
I
CH2
I
CH— OH
I
H2N— CH
!
HO— CH
1
HC— OH
I
HC— OH
I
CH2OH
Neuraminic Acid
Several neuraminopeptides have been isolated from an E. coli
mutant culture, and one of these has been purified.-^ It is com-
posed of N-acetylneuraminic acid, glucosamine, alanine, lysine
and glutamic, acid. '^"
A model of cell wall structure in gram-positive bacteria has
been postulated :^^
P P
/ . . / .
M — r^G >M— ^-*G >M -^ G
t * M = Muramic Acid
G G = N-Acetyl-D-glucosamine
...T... P = Peptide Moiety
P P ' *' • = Lysozyme Action
/ . / : •
M — r-^G >M — j->G >M
«
29 P. J. O'Brien and F. Zilliken, Biochim. et Biophys. Acta 31 543
(1959).
^° E. Kean, Dissertation. (In press)
31 Friedrich Zilliken, Federation Proc. 18 966-973 (1959).
345 Polypeptides and Related Compounds
The spine is composed of alternating muramic acid and N-
acetylglucosamine units with branching to adjacent chains from
muramic acid, the latter bearing the peptide chain. Penicillin
(and perhaps the other antibiotics mentioned) prevents incor-
poration of M-P units, and cycloserine prevents incorporation of
the terminal two D-alanine units into the side-chain. There is
evidence that the dipeptide D-alanyl-D-alanine is preformed be-
fore attachment to the peptide chain.
A review of the chemistry of bacterial cell walls has been
published. -^^
The newer general theory of polypeptide and protein synthesis
can be sketched in only briefly here.^- It is thought that the
DNA of the cell nucleus lays out the pattern for replication of
the ribosomal RNA, and this pattern is characteristic of each
genus, species and type of organism. The ribosomal RNA in
turn serves as the template for protein construction. Smaller,
more soluble molecules, which seem to be RNA fragments end-
ing in the nucleotide adenylic acid, attach themselves at this end
to individual amino acids. This attachment requires an enzyme
specific for each of the 20 or more amino acids plus ATP. There
is also a different transfer RNA molecule for each amino acid.
These activated amino acids can be isolated and purified. In
this form the amino acid is able to fit into the proper place on
the RNA template, probably due to the unique geometry of a
short sequence of nucleotides in the chain. Once attached to
RNA, condensation of the amino acids to form polypeptides or
proteins is facilitated by the favorable arrangement and proxim-
ity of the reacting groups. This scheme is believed to be quite
general in metabolism.
A more specific discussion by E. F. Gale of current knowledge
about the incorporation of amino acids into bacterial proteins
and polypeptides has been published. ^^ It is obvious that con-
siderable differences must exist between mechanisms of polypep-
tide synthesis in microbial and mammalian metabolism in view
of the D-amino acids and other abnormal amino acids which oc-
cur in microbial polypeptides. It is apparently these differences
32 Robert B. Loftfield, Prog. Biophys., Biophys. Chem. No. 8 348
(1957); F. H. C. Crick, Symposia of the Society for Exp. Biol. No. 12
138 (1958); Mahlon B. Hoagland, Scientific American 201 55 (1959);
Alton Meister, Rev. Mod. Phys. 31 210-220 (1959); Leo Szilard, Proc.
Nat. Acad. Sci. U. S. 46 277 (1960).
33 "CIBA Lectures in Microbial Chemistry," E. F. Gale, Synthesis
and organization in the bacterial cell, John Wiley and Sons, New
York, 1959, 106 pp.
Pfizer Handbook of Microbial Metabolites 346
which are exploited by some of the more successful antibiotics.
Certain compounds listed elsewhere might have been classed
as polypeptides. Examples are: penicillins, gliotoxin, certain
ergot alkaloids, various diketopiperazines, netropsin, amicetin,
Vitamin B^. conjugate and other fohc acids.
712 DL-Fumarylyl Alanine (Fumaromono-D,L-alanide), CYHgOgN, col-
orless needles, m.p. 229° (dec).
HOOC— CH=CH— CO— NH— CH— COOH
I
CH3
Penicillium resticnlosum
John Howard Birkinshaw, Harold Raistrick and George
Smith, Biochem. J. 36 829 (1942).
713 Nocardamin, CgHi602N2, white needles, m.p. 184°, no optical
activity.
O
II
OH
. /
CH2
^N
/
\
CH2
CH2
NH
\
CH2
CH2
CH2
^CHa^^
Actinomyces buchanan
A. StoU, J. Renz and A. Brack, Helv. Chim. Acta 34 862
(1951).
R. F.jC. Brown and G. Biichi, unpublished. (Revised struc-
ture )
714 N-Succinyl-L-glutamic Acid, C9H13O7N (Monohydrate), colorless
hygroscopic crystals, m.p. 62-64°, [«]»-" —11° (c 1.07 in
water).
HOOC— CH2—CH2—CH— COOH
NH— C— CH2— CH2— COOH
II
O
Bacillus megatherium
This substance appears during the sporulating phase
before the appearance of dipicolinic acid.
347 Polypeptides and Related Compounds
Jean Paul Aubert, Jacqueline Millet, Elisabeth Pineau and
Gerard Milhaud, Compt. rend. 249 1956 (1959).
715 Lycomarasmine, CjiHi-.O-N.., white powder, m.p. 227-229 (dec).
Tentative structure :
H,N-CO-CH, CH3
HOOC— CH— NH— CO— CH,— NH— C— OH
COOH
Fusariinn lycopersici Sacc.
This is the toxin of fusarium wilt. A second compound,
C9H1.O-N0, white powder, m.p. 273-276° (dec), has been
isolated from the mother Hquors. It is produced in up to
three times the yield of lycomarasmine, but is biologically
inactive. It is also produced (with evolution of ammonia)
by boiling lycomarasmine with water.
The yield of lycomarasmine in the initial isolation was
80-110 mg. per liter.
There is still some dissatisfaction with this structure.
PI. A. Plattner and N. Clauson-Kaas, Helv. Chim. Acta 28
188 (1945). (Isolation)
D. W. WooUey, ;. Biol. Chem. 176 1291 (1948). (Struc-
ture)
M. Brenner, R. Tamm and P. Quitt, Helv. Chim. Acta 41
763 (1958). (Criticism of structure)
716 d-Pantothenic Acid, C^Hi-OsN, viscous oil, [aji,-' +37.5° (in wa-
ter).
CH3 O
HOCH2— C— CH— C— NH— CH— CHCOOH
I 1
CH3OH
Penicillin liquors yield 600-800 /xg. per gram of dry
cell weight.
Yeasts contain 150-300 fxg. per gram of dry cell weight.
D. W. WooUey, /. Am. Chem. Soc. 62 2251 (1940). (Syn-
thesis )
Leland A. Underkofier and Richard J. Hickey, "Industrial
Fermentations," Chemical Publishing Co., Inc., New York,
1954 Vol. II, J. M. Van Lanen, Production of vitamins other
than riboflavin, chap. 6, pp. 191-216.
Pfizer Handbook of Microbial Metabolites 348
717 Toxin of tobacco wild-fire disease, C10H16O6N2.
Probable structure:
NH2 OH
I I
HOOC— CH— CH.— CHo— CH— CH— C=0
I I
NH O
1 I
0=C CH— CH3
Pseudomonas tabaci
The toxin can by hydrolyzed to lactic acid and the
amino acid, tabtoxinin, C7H14O5N2, (a,e-diamino-/3-hy-
droxypimelic acid ) :
HOOC— CH— CH2— CHo— CH— CH— COOH
I II
NH2 OH NH2
D. W. Woolley, G. Schaffner and Armin C. Braun, J. Biol.
Chem. 198 807 (1952). (Isolation)
Idem., ibid. 215 485 (1955). (Structure)
718 Glutathione (Glutamylcysteinylglycine) CiyHi^OoNgS, colorless
crystals, m.p. 190-192° (dec). Unstable. [a]Hg.'' ' -9.4°
in water, —85° in 10% hydrochloric acid.
O O
II ■ II
HOOC— CH— CH2— CH2— C— NH— CH— C— NH— CH2— COOH
I I
NH2 CH2SH
Yeasts
F. G. Hopkins, Biochem. J. 15 286 (1921). (Isolation)
Charles Robert Harington and Thomas Hobson Mead, ibid.
29 1602 '(1935). (Synthesis)
719 N-Succinyl-L-diaminopimelic Acid, CnHigOjN^.
NH2
HOOC— CH—CH,CH2CH2—CH— COOH
NH— C— CH2CH2COOH
II
O
Charles Gilvarg, Biochim. et Biophys. Acta 24 216 (1957).
Lactobacillus bulgaricus Factor (Pantetheine and Pantethine),
C11H00O4N0S and C22H4.O8N4S..
349 Polypeptides and Related Compounds
720 Pantetheine: Colorless, hygroscopic, amorphous powder, [a]i,^"
+ 12.9° (in water).
CHs
I OH
HOCH,— C— CH— CO— NH— CH,— CH2— CO— NH— CH,— CH,— SH
CH3
721 Pantethine: viscous oil.
CH3
I
IHOCH2— C CH— CO— NH— CH2— CH2— CO— NH— CH2— CH2— S— 12
I I
CH3 OH
Yeasts, Ashbya gossypi, many other microorganisms
William L. Williams, E. Hoff-Jorgensen and Esmond E.
SneU, /. Biol. Chem. 177 933 (1949).
Esmond E. Snell, Gene M. Brown, Vincent J. Peters, Jean A.
Craig, E. L. Wittle, J. A. Moore, V. M. McGlohon and O. D.
Bird, J. Am. Chem. Soc. 72 5349 (1950).
Vincent J. Peters, Gene M. Brown, William L. Williams and
Esmond E. SneU, ibid. 75 1688 (1953).
Gene M. Brown and Esmond E. Snell, ibid. 75 1691 (1953).
722 Glutathione-Cysteine Disulfide, C13H22O8N4S0.
H2N— CH— CH2— CH,— CO— NH— CH— CO— NH— CH2— COOH
I 1
COOH CH2
I
S— S— CH>— CH— COOH
I
NH2
Saccharomyces cerevisiae
Glutathione itself occurs in yeasts. The disulfide above
was not isolated.
Arthur H. Livermore and Edward C. Muecke, Nature 173
265 (1954).
723 Serratamic Acid, CjaHo.-.OsN, colorless crystals, m.p. 138° (dec.),
[(x]v-° -10.2° (c 5.0 in ethanol).
O CH.OH
II I
CH3(CH2)6CHCH2C— NH— CH
I I
OH COOH
Pfizer Handbook of Microbial Metabolites 350
Serratia species
Yields as high as 8 g. per liter have been reported.
Hydrolysis gives L-serine and ( — )-3-oxydecanoic acid.
The latter acid also has been found in conjugation with
rhamnose and with other amino acids (see Viscosin).
N. J. Cartwright, Biochem. J. 60 238 (1955).
Idem., ibid. 67 663 (1957). (Structure)
724 8-(a-Aminoadipyl) cysteinylvaline, C14H25O6N3S.
CH3 CH3
\ /
CH
O CH,— SH
HOOC— CH— CHo— CHo— CHo— C— NH— CH— C— NH— CH— COOH
NH2 O
Fenicillium chrysogenum
This tripeptide was isolated from the mycelium of the
penicillin-producing mold. It may be a penicillin precur-
sor since cyclization in the proper way would yield syn-
nematin-B (cephalosporin-N) which differs from penicil-
lin only in its side-chain. Synnematin never has been
isolated from P. chrysogenum, however.
H. R. V. Arnstein, D. Morris and E. J. Toins, Biochim. et
Biophys. Acta 35 561 (1959).
725 Alazopeptin, Ci.^Ho^OeN^, no definite m.p., [a]i,-' +9.5° (c 4.7 in
water).
A peptide containing 1 mole of a-alanine and 2 moles
of 6-diazo-5-oxoaminohexanoic acid (DON) or an isomer.
Streptomyces griseoplanus
S. E. DeVoe, N. E. Rigler, A. J. Shay, J. H. Martin, T. C.
Boyd, E. J. Backus, J. H. Mowat and N. Bohonos, "Antibiotics
Annual 1956-1957," Medical Encyclopedia, Inc., New York,
p. 730.
726 Antibiotic I.C.I. 13,959.
Acid hydrolysis yielded:
a-Aminoisobutyric Acid
CH3 COOH
CH3 NH2
35 1 Polypeptides and Related Compounds
j3-Hydroxyleucine
CH3
\
CH— CH— CH— COOH
/ I !
CH3 OH NH>
as well as L-leucine, ^-alanine and y-methylproline. The
ytJ-hydroxyleucine, which had not been reported previously
as a natural product, has either the d- or L-t/zreo but not
the erythro configuration.
A Paecilomyces strain
G. W. Kenner and R. C. Sheppard, Nature 181 48 (1958).
727 Viomycin (Vinactin A, Vinactane, Celiomycin, Viocin),
CiT-isHsi-sjOsNg, Sulfate: m.p. (anhydrous) 252° (dec.)
(hydrated) 280° (dec), [a],,--' -32° (c 1 in water). Rota-
tion varies with pH.
A strongly basic polypeptide. The following compo-
nents have been identified: a,/^-diaminopropionic acid, /?-
lysine, L-serine and a guanidino compound. Salts are
neutral.
Streptomyces fioridae, S. puniceus, S. vinaceus
A. C. Finlay, G. L. Hobby, F. Hochstein, T. M. Lees, T. F.
Lenert, J. A. Means, S. Y. P'An, P. P. Regna, J. B. Routlen,
B. A. Sobin, K. B. Tate and J. H. Kane, Am. Rev. Tuberc. 63 1
(1951).
Quentin R. Bartz, John Ehrllch, James D. Mold, Mildred A.
Penner and Robert M. Smith, ibid. 63 4 (1951).
Theodore H. Haskell, Salvatore A. Fusari, Roger P. Frohardt
and Quentin R. Bartz, J. Am. Chem. Soc. 74 599 (1952).
R. L. Mayer, P. C. Eisman and E. A. Konopka, Experientia
10 335 (1954).
728 Phthiomycin, white powder.
A basic polypeptide resembling viomycin.
Streptomyces luteochromogenes n. sp.
Kenji Maeda, Yoshiro Okami, Ryozo Utahara, Hiroko Kosaka
and Hamao Umezawa, /. Antibiotics (Japan) 6A 183 (1953).
Yasushi Miyamoto and Kenji Maeda, ibid. 7A 17 (1954).
729 Streptolin A, Ci^H^iOsN,, or C.4H4,,OiiN-, m.p. 206° (dec), sul-
fate UW-' -20°.
Streptolins A and B are similar. They resemble strepto-
thricin, viomycin, geomycin and roseothricin in their acid
hydrolysates, which contain L-/;j-lysine, a-D-gulosamine,
streptolidine, ammonia and carbon dioxide.
Pfizer Handbook o£ Microbial Metabolites
352
Streptomyces spp.
R. W. Rivett and W. H. Peterson, J. Am. Chem. Soc. 69
3006 (1947). (Isolation)
Edward E. Smissman, Robert W. Sharpe, B. F. Aycock,
Eugene E. van Tamelen and W. H. Peterson, ibid. 75 2029
(1953).
Eugene E. van Tamelen and Edward E. Smissman, ibid. 75
2031 (1953).
Eugene E. van Tamelen, John R. Dyer, Herbert E. Carter,
Jack V. Pierce and Edward E. Daniels, ibid. 78 4817 (1956).
730 Noformicin* (Sulfate), Ci7H3405Nio( 804)2, m.p. (Hydrochlo-
ride) 265° (dec.).
Hydrolysis yields glutamic acid, ammonia and two other
ninhydrin-positive compounds which are not ordinary
amino acids.
Nocardia formica
Dale A. Harris and H. Boyd Woodruff, "Antibiotics Annual
1953-1954," Medical Encyclopedia, Inc., New York, p. 609.
731 Streptothricin, CooHj^qOoNs, platelets (Reineckate), m.p. 192-194°
(Hydrochloride)' [a] d'' -51.3°.
A basic polypeptide. Hydrolysis yields:
L-/3-Lysine:
H2NCH2CH2CH2CHCH2COOH
NH2
D-Gulosamine:
H— C— OH
I
H— C— NH2
I
H— C— OH
I
HO— C— H
I
H— C
Streptolidine:
CH2OH
C6H,2N403
Several structures have been proposed for this moiety.
See C. Sweeley, Ph.D. Dissertation, Univ. of Illinois, 1955.
See entry 915 for structure.
353
Polypeptides and Related Compounds
732
It may be identical with the amino acid known as roseo-
nine or ge amine.
OH
I
N CH— C— COOH
II I I
H2N— C CH2 CH2NH2
\ /
N
H
Carbon dioxide and ammonia also have been identified
in hydrolysates.
Streptomyces lavendulae and other streptomyces species
Selman A. Waksman and H. Boyd Woodruff, Proc. Soc. Exp.
Biol. Med. 49 207 (1942). (Isolation)
Herbert E. Carter, Walter R. Hearn, Edwin M. Lansford, Jr.,
A. C. Page, Jr., Norman P. Salzman, David Shapiro and W. R.
Taylor, /. Am. Chem. Soc. 74 3704 (1952). (Structure)
H. E. Carter, R. K. Clark, Jr., Paul Kohn, John W. Rathrock,
W. R. Taylor, C. A. West, George B. Whitfield and Wilham G.
Jackson, ibid. 76 566 (1954).
Koji Nakamishi, Tashito Ito and Yoshimasa Hirata, ibid. 76
2845 (1954).
Eugene E. van Tamelen, John R. Dyer, Herbert E. Carter,
Jack V. Pierce and Edward E. Daniels, ibid. 78 4817 (1956).
R. Colin, Ph.D. Dissertation, Gottingen, 1957.
Roseothricins.
A polypeptide antibiotic complex of the streptothricin
type. Acid hydrolysis of Roseothricin A yields /? -lysine
and roseonine (geamine) I in a 1:1 ratio, an isomer of
OH
I
N CH— C— COOH
HC CH2 CH2NH2
Pfizer Handbook of Microbial Metabolites 354
glucosamine, and a substance resistant to further hydroly-
sis which was assigned structure II.
Streptomyces roseochromogenes
Seigo Hosoya, Momoe Soeda, Nobuhiko Komatsu and
Susumu Imamura, J. Antibiotics (Japan) 4 79 (1951).
Y. Saburi, ibid. 6B 402 (1953).
Tashio Goto, Yosimasa Hirata, Seigo Hosoya and Nabukiko
Komatsu, Bull. Chem. Soc. Japan 30 304, 729 (1957). (Struc-
ture)
733 Pleocidin, a hygroscopic white powder.
A polypeptide resembling streptothricin.
S. lavendulae or related sp.
Jesse Charney, Wm. S. Roberts and W. P. Fisher, Antibiotics
and Chemotherapy 2 307 (1952).
734, 735 Mycothricins (A and B).
Basic polypeptides related to streptothricin. Acid hy-
drolysis yielded ^-lysine, (present in streptothricin, pleo-
cidin, geomycin and viomycin), roseonine (geamine)
present in streptothricin, geomycin and pleocidin, and
serine (present in viomycin).
Streptomyces lavendulae type
G. Rangaswami, C. P. SchafFner and S. A. Waksman, Anti-
biotics and Chemotherapy 6 675 (1956).
736 Grasseriomycin, pale yellow hydrochloride, m.p. (Reineckate)
187-190° (dec). Molecular weight 610.
A polypeptide resembling streptothricin. Negative
biuret, Millon, FeClg. Positive ninhydrin, Molisch,
Fehling.
Streptomyces lavendulae, S. griseolavendus
Kasububo Ueda, Youichiro Okimoto, Heiichi Sakai and Kei
Arima, /. Antibiotics (Japan) 8A 91 (1955).
Yusuke Sumiki, Kinichiro Sakaguchi and Takenori Asai,
Japanese Patent 6296 (1957).
737 Actinorubin (C6H14O3N0 or C9H22O4N5) (Hehanthate), reddish
orange clusters, m.p. 206-214° (dec).
A basic polypeptide related to streptothricin. Positive
biuret, reduces KMnOi, Fehlings solution. Negative
Molisch, Sakaguchi.
Streptomyces spp. resembling S. erythreus, S. fradii, S.
albosporeus
Renate Junowicz-Kocholaty and Walter Kocholaty, /. Biol.
Chem. 168 757 (1947).
355 Polypeptides and Related Compounds
738 Enniatin-B, CooH;{sO,;N._., colorless needles, m.p. 174°, [a],,"
-106.3° (c 0.695 in chloroform).
CHj
\ O
CH3 /H -N^ /
O CH \
/ \ ""■
o=c c=o
CH, \ /
\ /CH O
/" N-^r^CH^ CH.
CHa II CH^
CHj
Fusaria species
Yield about 0.5 g. per liter.
PI. A. Plattner and U. Nager, Experientia 3 325 (1947).
PL A. Plattner, U. Nager and A. Boiler, Helv. Chim. Acta 31
594 (1948).
PI. A. Plattner and U. Nager, ibid. 31 665 (1948).
739 Islanditoxin, C24H31O7N5CI0, colorless, amorphous solid, m.p.
258°.
CH2OH O
o m — <^"— -c
CHaCH.^^/ CH
c=o
^"V ^ -^ C\ CI
Penicillium islandicum Sopp.
Pfizer Handbook of Microbial Metabolites 356
Shingo Marumo and Yusuke Sumiki, /. Agr. Chem. Soc.
Japan 29 305 (1955). (Isolation)
Shingo Marumo, Bull. Agr. Chem. Soc. (Japan) 19 258
(1955).
Idem., ibid. 23 428 (1959). (Structure)
740 Enniatin-A ( Lateritiin-I ) , C24H42O6N2, colorless needles, m.p.
122°, [aW^ -91.9° (c 0.926 in chloroform).
CH3
CH,— CH
0
\
II
— c —
CH3
^ / CH3
/
0
CH \
/
\ CH3
o-c
c=o
CH2CH3 \
/
/
^ ^^
^CH
CH3 /
—c—
•\
CHs
II
CH— CH3
Fusarium orthoceras var. enniatinum, F. scirpi Lamb,
et Fautr., F. lateritium
The yield was about 1 g. per liter.
E. Gaiimann, Stephi Roth, L. Ettlinger, PI. A. Plattner and
U. Nager, Experientia 3 202 (1947). (Isolation)
PI. A. Plattner and U. Nager, ibid. 3 325 (1947).
PI. A. Plattner, U. Nager and A. Boiler, Helv. Chim. Acta 31
594 (1948).
PI. A. Plattner and U. Nager, ibid. 31 2192, 2203 (1948).
A. H. Cook, S. F. Fox and T. H. Farmer, /. Chem. Soc, 1022
(1949).
357 Polypeptides and Related Compounds
741 Enniatin-C, C.^H^.O.jNo, m.p. 123°, [aln" -83° (c 1.162 in chlo-
roform ) .
Proposed structure:
CH3
CH
\
CH'
O
/ \ II CH3 CH3
CH3^ >H--C--../ -./
N. ^CH
/
\ /Ch: \
0=9 c==o
CH3 /CH
\ /CHr \ /
CH^ \n^ CH^ CH3
CHs CH3 II CH
O \
CH3
Fusaria species
The yield was about 0.6 g. per liter.
PI. A. Plattner and U. Nager, Helv. Chim. Acta 31 2203
(1948).
742 Eulicin, C24H52O2N8, m.p. (Helianthate) 139°.
NH
II
HoN— C— NH— (CH2)8— CH— CH— (CHsls— NHo
! I
OH NH— C— (CHsJsNH- C— NH2
II II
O NH
Streptomyces sp. resembling S. parvus
An actinomycin and a basic substance also were pro-
duced.
Jesse Charney, Roy A. Machlowitz, Frank J. McCarthy,
Gertrude A. Rutkowski, Alfred A. Tytell and W. P. Fisher,
"Antibiotics Annual 1955-1956," Medical Encyclopedia, Inc.,
New York, p. 228. (Isolation)
Robert E. Harman, Edward A. Ham, William A. Bolhofer
and Norman G. Brink, /. Am. Chem. Soc. 80 5173 (1958).
(Structure)
Pfizer Handbook of Microbial Metabolites
358
PA 114 Antibiotics.
743 PA 114A,* Cor.H^iOeNa or C35H42O9N4 (proposed), colorless nee-
dles, m.p. 200° (dec), [a],,'' -207° (c 0.5 in methanol).
A neutral substance, green FeCla test. Negative ninhy-
drin, carbohydrate tests.
744 PA 114B,t C^oHeaO^oN;, (proposed), colorless crystals, m.p. 265°
(dec), [alD^-" -59.7° (c 0.5 in methanol).
A weak acid, red FeCl^ test. Negative ninhydrin, carbo-
hydrate tests, 2,4-DNPH.
Streptomyces olivaceus
Walter D. Celmer and Ben A. Sobin, "Antibiotics Annual
1955-1956," Medical Encyclopedia, Inc., New York, p. 437.
745 PA 114B-3, colorless needles, m.p. 207°, [a]i,-'' -37.2° (in
methanol).
A polypeptide antibiotic similar to PA-114B. Analysis:
C 62.77, H6.52, N 12.61.
A Streptomyces olivaceus strain
D. C. Hobbs and W. D. Celmer, Federation Proc. 18 246
(1959).
746 Streptogramin, approximate formula CocH^^O-N,, m.p. 155°,
[all, -134°.
Neutral compound.
Streptomyces gr amino faciens
Jesse Charney, W. P. Fisher, Charles Curran, Roy A.
Machlowitz and Alfred A. Tytell, "Antibiotics Annual 1953-
1954," Medical Encyclopedia, Inc., New York, p. 171.
Lateritiin Group
Several colorless compounds similar to the enniatins
were isolated from fusaria species in England. One of
these, lateritiin I, has been shown identical vsdth enniatin
A. The others are :
747
748
749
750
Name
Suggested formula
Melting point
WW
Lateritiin II
C26H46O7N0
C26H,,-,607N2
C24H«07N2
125°
139°
129°
86°
— 92°
-101°
-103°
-83°
A).
All these compounds yield D( — )-a-hydroxyiso valeric
May be identical with staphylomycin M^, E-129A (ostreogrycin
t See addendum for structure.
359 Polypeptides and Related Compounds
acid, C,H,„0,. m.p. 65', [al„''^ -21° (c 1.25 in chloroform),
and N-methyl-L-valine on acid hydrolysis.
The enniatins also uniformly contain d( — )-a-hydroxy-
isovaleric acid, but each contains a characteristic
N-methylamino acid. (cf. valinomycin, amidomycin).
A. H. Cook, S. F. Cox, T. H. Farmer and M. S. Lacey, Nature
160 31 (1947).
A. H. Cook, S. F. Cox and T. H. Farmer, ibid. 162 61 (1948).
Idem., J. Chem. Soc, 1022 (1949).
751 Chlorine-containing Peptide, C2.-,H:{,,0sN-,CL, white needles, m.p.
251° (dec), [a],/'' -92.9° (in methanol).
Positive biuret and Pauly reactions, negative Sakaguchi,
Neubauer-Rhode, ninhydrin, Millon reactions.
Acid hydrolysis yielded serine (2 to 3 moles), a-amino-
butyric acid (1 mole), ^-phenyl-/?-aminopropionic acid
( 1 mole ) and an unidentified substance yielding a posi-
tive Ehrlich reaction.
Penicilliinn islandicum Sopp.
Yoshita Kobayashi, Kenji Uraguchi, Takashi Tatsuno,
Fuminori Sakai, Michio Tsukioka, Yutaka Sakai, Osamu
Yonemitsu, Taiko Sato, Masashi Miyake, Mamoru Saito,
Makoto Enomoto, Toshio Shlkata and Toshitaka Ishlko, Proc.
Japan Acad. 34 736 (1958).
752 Pyridomycin, C26-27H32OSN4, colorless needles, m.p. 218-222°.
Apparently rather closely related to etamycin. Alka-
line fusion yields :
OH CH3 CH2CH.3
, glycine and HOOC— CHCH— COOH
COOH '^' OH
Acid hydrolysis yields :
OH
, threonine and another degradation product incor-
•-%^i;:^\ porating picoline and glycine
■COOH
Streptomyces pyridomyceticus
Kenji Maeda, J. Antibiotics (Japan) lOA 94 (1957) and
earlier papers in the series.
753 Levomycin, Co7H:^sOtoN,; (proposed), colorless crystals, m.p. 222-
224°, [a],r' -323° (c 1 in chloroform).
A polypeptide containing an aromatic group.
Streptomyces sp.
Pfizer Handbook of Microbial Metabolites 360
Herbert E. Carter, Carl P. SchafFner and David Gottlieb,
Arch. Biochem. and Biophys. 53 282 (1954).
754 Staphylomycin Mj, CosHagOsNg (probable), m.p. 165-167° (dec),
[a]D -190° ±2° (c 0.5 in ethanol).
A neutral compound. Carbonyl group present. Gly-
cine and proline liberated on acid hydrolysis. Related to
PA 114A.*
755 Staphylomycin S, C3g_39H47_4s09N6 (proposed, but see structure
below), white crystals, m.p. 240-242° [a]i, -28.0° (c 1.0
in ethanol).
A weak acid. Threonine, norvaline, a-aminobutryic
acid, phenylalanine and proline were produced on acid
hydrolysis. Related to PA 114B (or identical).
Staphylomycin Mo. This third factor has not been ob-
tained pure.
There appears to be a relationship between the staphy-
lomycin complex and streptogramin, etamycin, etc.
Streptomyces sp. resembling S. virginiae
H. Vanderhaeghe, P. Van Dijck, G. Parmentier and P. De
Somer, Antibiotics and Chemotherapy 7 606 (1957).
The probable structure of one of the staphylomycins
recently was reported to be :
HO
^r\
0 k }
-
/ L-Phenyl-
NH glycine
—
CHa /
L-Thr CH
v°
0^
/
=^C
/ L-4-Oxo-
1 pipecolic
~CH Acid
\
\
NH
CH2
0^
CH2
D-a-Amino-
butyric CH-CH,-CH,
Acid /
— cHr
C L-N-Me
^ X Phe
0 CH
/ °
L-Pro N
/ ^N
-Q-
CH2 /
11
/ CH3
/. A
0
^"^^^CHj
r\
♦Identical with PA 114A.
36i
Polypeptides and Related Compounds
H. Vanderhaege, Abstr. Biochem. Symposium, XVIIth
Internat. Congress Pure and Appl. Chem., Munich 1959.
H. Vanderhaege and G. Parmentier, Bull. Soc. Chim. beiges
68 716 (1959).
756 Phalloidin, C35H46O10NSS + SHoO.
CHs
HOCH2
:=CH— CH— NH
CHOH
Amanita phalloides
From 100 g. of fresh fungus were obtained 10 mg. of
phalloidin, 8 mg. of x-amanitin, 5 mg. of /?-amanitin and
about 0.5 mg. of y-amanitin. The amanitins have not
been characterized thoroughly, but seem to be related to
phalloidin.
Theodor Wieland, Angew. Chem. 69 44 (1957).
Theodor Wieland and Werner Schon, Ann. 593 157 (1955).
Theodor Wieland and Christoph Dudensing, ibid. 600 156
(1956).
757 Phalloin, CssH^gOgNsS, colorless needles, m.p. 250-280° (dec).
Probable structure:
CHo CHOH
CH3
CH3
C=CH— CH-
NH-
CO-
CH2
-CH— NH— CO— CH
CH2
^N"
CH3
c=o
I
NH
I
-CH
I
c=o
NH
X
-CH
CO
CH..
CO
CH— CH3
CH
:O^NH
-NH
HCOH
I
CHs
Pfizer Handbook of Microbial Metabolites 362
Amanita phalloides
Theodor Wieland and Karl Mannes, Angew. Chem. 69 389
(1957).
Idem., Ann. 617 152 (1958).
758 Valinomycin, C;jf;H(;oOi:,N4, colorless platelets, m.p. 190°, [air'"
+31° (c 1.6 in benzene).
CH3
\ II CH-CHa
^0\-—^ ^NH.^ /
O /O L-Lactic Acid CH Q
\ > L-Valine K
^"\ / \
/ CH O CHs
CH3 7 D-Valine \ /
W\\ D-a-Hydroxyisovaleric CM \
o=c c=o
^^. \ D-a-Hydroxyisovaleric /
\ CH Acid NH
/ \ D-Valine / CH3
CH3 q /CH /
C L-Vaiine L-Lactic ,C
/ \ Acid y V
CH
CH3
NH^ n -CH
c-
CH \ \
CH3 CHa
O
CH
Streptomyces fulvissimus
The yield was about 100 mg. per liter. Acid hydrolysis
gives 2 moles of L( + )-valine, 2 moles of d( — )-vahne, 2
moles of l( — )-lactic acid and 2 moles of d( — )-a-hydroxy-
isovaleric acid. (Cf. the enniatin and lateritiin groups,
and amidomycin.)
H. Brockmann and G. Schmidt-Kastner, Chem. Ber. 88 57
(1955).
Hans Brockmann and Hermann Geeren, Ann. 603 213
(1957).
759 Viscosin, C;{,.H,j,;0]„N,;, amorphous white powder, m.p. 269°
(dec), [a],r" -162°.
363 Polypeptides and Related Compounds
:H3(CH )6— CH— CH2— CO— NH CH CO— NH— CH. CO NH CH CO—
I I " I
OH CH, CHo
I 1
CH OH
/ \
CH3 CH:,
NH— CH— CO— NH— CH— CO— NH— CH— COOH
I I I
CH CHOH CH2
/ \ I I
CH3 CHa CH3 CH
/ \
CH3 CH3
Pseudomonas viscosa
Mitsuyuki Kochi, Vincent Groupe, Leonora H. Pugh and
David Weiss, Bad. Proc, 29 (1951).
Takashi Ohno, Shigeru Tajinia and Katsuyuki Toki, /. Agr.
Chem. Soc. Japan 27 665 (1953).
Doki and Ohno (unpublished). Total structure determina-
tion. Reported by S. Otani in a lecture on polypeptide anti-
biotics in 1957.
Takashi Ohno, Shigeru Tajima and Katsuyuki Toki, /. Agr.
Chem. Soc. Japan 27 665 (1953).
760 Bottromycin (B-Mycin), C3sH57_r,i07_.sN7S, white amorphous ma-
terial, [a],;--' -14.2° (c 0.5 in 96%, ethanol).
Bottromycin is a weakly basic polypeptide. Acid hy-
drolysis yields six ninhydrin-positive compounds. Two of
these are glycine and valine. Two others are new amino
acids :
a-Amino-/3-phenylbutyric Acid
CH CH— COOH
CH3 NH2
and
/3-(2-Thiazole)-/3-alanine
CH— CHo— COOH
I
NH2
Streptomyces bottropensis
Pfizer Handbook of Microbial Metabolites 364
J. M. Waisvisz, M. G. van der Hoeven, J. van Peppen and
W. C. M. Zwennis, J. Am. Chem. Soc. 79 4520 (1957). (Iso-
lation )
J. M. Waisvisz, M. G. van der Hoeven, J. F. Holscher and
B. te Nijenhuis, ibid. 79 4522 (1957).
J. M. Waisvisz, M. G. van der Hoeven and B. te Nijenhuis,
ibid. 79 4524 (1957). (Structure)
Micrococcins.
761 Micrococcin, white needles, m.p. 222-228° (dec.), [aln^^ 116°
±1° (c 5.0 in 90% ethanol), molecular weight >2000.
A Micrococcus sp.
T. L. Su, Brit. J. Exptl. Path. 29 473 (1948).
N. G. Heatley and Hazel M. Doery, Biochem. J. 50 247
(1951).
762 Micrococcin-P, white crystals, yellowing in light, m.p. 252° (dec.
from 232°), [ale"' +63.7° (c 1.19 in 90% ethanol), mo-
lecular weight '-'2200.
Two fragments have been identified as :
HOOC HOOC
C— CH2CH3 CH— CH
CH3
O NH2 CH3
2-Propionylthiazole-4- 2-(l -Amino-2-methylpropyl)
carboxylic Acid thiazole-4-carboxylic Acid
Acid-catalyzed esterification gave a dimethyl ester,
C24Ho365Nr,S4 and a base CifiHictO^N^S-^. Also threonine,
ammonia and propionic acid were isolated.
This antibiotic seems to be similar to or identical with
the earlier one, but is distinguished by the letter P until
identity is proved.
Bacillus pumilis
A. T. Fuller, Nature 175 722 (1955). (Isolation)
E. P. Abraham, N. G. Headey, P. Brookes, A. T. Fuller and
James Walker, ibid. 178 44 (1956).
P. Brookes, A. T. Fuller and James Walker, J. Chem. Soc,
689 (1957).
3^5 Polypeptides and Related Compounds
763 Esperin, CsgH^-OnN-, colorless crystals, m.p. 238° (dec ) [al,^'^
-24° (c 0.66 in methanol).
CH,CH,COOH
CHslCH.lgCHCH.CONHCHCONHCHCONHCHCONHCHCONHCHCOOH
I I I
CH CH,
O OC— CH., / \ CH- I
CHa CH3 I CH
CH /\
/ \ CH3 CH3
CH3 CH3
Bacillus mesentericus
Hiroshi Ogawa and Teiichiro Ito, ]. Agr. Chem. Soc. Japan
24 191 (1950). (Isolation)
Idem., ibid. 26 432 (1952).
Idem., Bull. Agr. Chem. Soc. (Japan) 23 536 (1959).
(Structure)
764 Actinochrysin, C4oHr.-0„N-, a brick red pigment.
Similar to but distinct from actinomycins. A weak
base with two acid groups. Molecular weight 811. Solu-
ble in acetone.
Streptomyces chrysomallus
Hans Brockmann and Arnold Bohne, German Patent 912,-
010 (1954). (Chem. Abstr. 52 12334g)
765 Grisein, C4i,H(;i02„Ni„SFe, red, amorphous powder.
Isolated from acid hydrolysate:
O H
I ll + Glutamic Acid
y^.^J^ + '^n unidentified amino acid
CH, II
3-Methyluracil
The iron is Fe'" and can be removed and readded to the
complex.
Streptomyces griseus
The Russian antibiotic, albomycin, produced by Strepto-
myces subtropicus seems to be similar to or identical with
grisein.
Pfizer Handbook of Microbial Metabolites 366
Donald M. Reynolds, Albert Schatz and Selman A. Waks-
man, Proc. Soc. Exp. Biol. 64 50 (1947). (Isolation)
Donald M. Reynolds and Selman A. Waksman, /. Bad.
55 739 (1948).
Frederick A. Kuehl, Jr., Mary Neale Bishop, Louis Chaiet
and Karl Folkers, J. Am. Chem. Soc. 73 1770 (1951).
766 Albomycin (Sulfate), red amorphous powder, molecular weight
>1300.
Partial Constitution:
Albomycin is a basic, cyclic polypeptide containing iron
(^4% by weight). Iron can be removed with acetone
(color loss) and restored with FeCl^. Hydrolysis yields:
ornithine, serine, glutamic acid, alanine, glycine, proline
and one unidentified amino acid.
Streptomyces siibtropicus n. sp.
Albomycin may be identical with grisein, produced by
Streptomyces griseus.
M. G. Brazhnikova, N. N. Lomakina and L. I. Murayeva,
Dokladij Akad. Nauk S.S.S.R. 99 827 (1954).
G. F. Gause, Brit. Med. J. 2 1177 (1955).
Yu. O. Sazykin, Mikrobiologiya 24 75 (1955).
767 Amidomycin, C4i|H,.sOi2N4, colorless needles, m.p. 192°, [a]i)^*'
+ 19.2° (c 1.2 in ethanol).
CHj CH3
\ / CH3 CH3
CH O \ /
\ It CH
^CH C — -Q /
CH3 O. /NH CH o
CH
D-Hiv
/ ^CH D-Hiv NH CH3
^ i /
o
o=c
CH3 \
rw— CH D-Val
/ \
CH3 NH
\
CH
/ \
CH3 CH:,
\
/
-CH
D-Val CH'
\
\
CHj
c=
=0
/
0
D-Hiv CH /^"^
_/ CH
D-Val
y^r.
\
^NH
1 0
CH3
— CH
\
CH
/ \
CH3 CHj
Streptomyces species (PRL 1642)
Amidomycin contains 4 moles each of d( — ) valine and
d( — ) a-hydroxyisovaleric acid. (Cf. Valinomycin, lateri-
tiins, enniatins.)
L. C. Vining and W. A. Taber, Can. J. Chem. 35 1109
(1957).
3^7 Polypeptides and Related Compounds
768 Toxin of Helminthosporium victoriae.
This toxin consists of two loosely connected moieties.
The first is a tricyclic secondary amine called victoxinine,
and the second a pentapeptide. The intact toxin shows a
negative ninhydrin test, and a molecular weight of 800
was assumed.
Victoxinine, C,-Ho,,ON (Hydrochloride), colorless nee-
dles, m.p. 172°, [a],r' -78° (c 3.2 in 95% alcohol).
Negative U.V.
Pentapeptide :
On acid hydrolysis yielded:
Aspartic acid, glutamic acid, glycine, valine and one of
the leucines.
Helminthosporiinn victoriae
Ross B. Pringle and Armin C. Braun, Nature 181 1205
(1958).
769 Telomycin, cream colored amorphous solid.
A polypeptide antibiotic, containing glycine, alanine,
threonine and aspartic acid. Molecular weight about
1000. Contains no sulfur. Negative Fehling, ninhydrin,
biuret. Similar to etamycin.
Streptomyces sp.
M. Misiek, O. B. Fardig, A. Gourevitch, D. L. Johnson, I. R.
Hooper and J. Lein, "Antibiotics Annual 1957-1958," Medical
Encyclopedia, Inc., New York, p. 852.
770 Etamycin (Viridogrisein), C44H6oOi,.N,s, white crystals, hydro-
chloride m.p. 163-170° (dec), [a]ir' conflicting reports.
HO,
O
\ ^^C -^"^CH^ /
CH3 CH ^CH
/N Sore \^
o
P NH CH,
/ \ ^ ^
CHj— CH L-Ala D-Leu CM— CH2 ^H
I 1 ^"'
NH C=o
\ I
" \ OH-Pro / CH,
CH 3,N-DIMe CH \
C\ Ch' X^ Leu Sore ^ CH"^"^
CH CH, / C- CH ^^ Au
/ ^"^ CH3 // ^"^ \ O OH
CHj o CH,
Pfizer Handbook of Microbial Metabolites
368
Streptomyces sp. resembling S. lavendulae
Cf. Pyridomycin staphylomycin, osteogrycin, PA-114,
mikamycin, streptogramin, telomycin, echinomycin.
This class of polypeptides appears to be related bi-
ogenically to the actinomycins.
B. Heinemann, A. Gourevitch, J. Lein, D. L. Johnson, M. A.
Kaplan, D. Vanas and I. R. Hooper, "Antibiotics Annual 1954—
1955," Medical Encyclopedia, Inc., New York, p. 728.
Quentin R. Bartz, Jean Standiford, James D. Mold, Doris W.
Johannessen, Albert Ryder, Andrew Maretzki and Theodore H.
Haskell, ibid., p. 777.
Theodore H. Haskell, Andrew Maretzki and Quentin R.
Bartz, ibid., p. 784.
John C. Sheehan, Hans Georg Zachau and WiUiam B. Law-
son, /. Am. Chem. Soc. 79 3933 (1957). (Structure)
771 Colistin, C4gH850ioNi3.
CH3
CH3
\
I
/
co-
NHo
CH2
I
CH2
I
-CH-
-NH.^
CHCH2 NH'
CO
/
NH
HaNCHjCrij— CH
I
CO
\
NH
i-Diamino- ^CO CH2CH2NH2
butyric Acid \^ /
CH
D-Leucine L-Diamino- \
butyric Acid \li
\
CO
l-Diaminobutyric \
Acid CH — CH0CH2NH2
NH
/
aminobutyric
Acid
CH3
L-Leucine
\
CH
CHCHf
CO.
L-Diaminobutyric
Acid
L-Threonine CO
/
CH
NH CH
OH
-NH
CO'
\
CH3
CH3
-CH-
]
CHo
I
CH2
I
NH— CO(CH2)4CHCH2CH3
I
CHs
Yasuo Koyama, Akio Kurosasa, Atsushi Tsuchiya and Kin-
suke Takakuta, J. Antibiotics (Japan) 3 457 (1950).
3^9 Polypeptides and Related Compounds
Taiichi Ito, Sadao Miyamura, Seihachiro Niwayama, Masa-
nobu Oishi, Nobuhiro Igarashi, Hiromichi Hoshino and Shozo
Muto, ibid. 7B 147 (1954).
Yasuo Kayama, Japanese Patent 1546 (1952).
Takeshi Oda, Mitsuhiro Kinoshita, Osamu Yamanaka and
Fumio Ueda, /. Pharm. Soc. Japan 74 1234 (1954).
Takeshi Oda and Fumio Ueda, ibid. 74 1246 (1954).
772 Mycobactin, C^-H^.^Oi^N-, microcrystalline white powder with
pale green fluorescence, m.p. 165-166.5°, [a],,'' -19° (c
4.9 in chloroform).
Mycobactin is a weak acid believed to have one of the
following structures:
O— CH2
/
ru C COOR OH
^"^ \ II
N— CH— CO— NH— CH— (CH2)4— N— CO— CH=CH(CH2)uCH3
trans
or
CH3
C OH COOR
\
N— CH— CO— N— (CH.)4— CH— NH— CO— CH=CH(CH2),4CH3
trans
CH2— CH,— CH2
I /
R = CH3CH2CHCHCONH— CH
I \
CH3 CO N CH2
OH
Mycobacterium phlei
The yield was about 67 g. from 41 kg. of moist cells.
G. A. Snow, J. Chem. Soc, 4080 (1954) and earlier papers
in the series.
73 Geomycin (C,jHio02N2)8-i,„ HeHanthate red platelets, m.p. 205-
215° (dec). Hydrochloride [a],,-" +16°.
A basic polypeptide. Acid hydrolysis yields: geamine,
/3-lysine, and an amino sugar, plus small amounts of
Pfizer Handbook of Microbial Metabolites
370
aspartic acid, glutamic acid, serine, threonine, glycine
and alanine.
The structural evidence has been well summarized and
a partial structure postulated by R. Colin, Ph.D. Disserta-
tion, Gottingen, 1957. The partial structure is:
NH NH2
-C— NH— R^
O
HOOC— C CH N
I I II
CH2 CH2 C
I \m/
NHo ^^
"O
NH
C— CH2-
-CH— (CH2)3-
-NH
(CHo)3
_
NH2
_
CH— NH2
1
1
CH2
c=o
NH2
NH2
Streptomyces xanthophaeus , n.sp.
Hans Brockmann and Burchard Franck, Naturwissenschaf-
ten 41 451 (1954).
Hans Brockmann and Hans Musso, Chem. Ber. 87 1779
(1954).
Idem., ibid. 88 648 (1955).
774 Lavendulin (Helianthate), C49H63O18N13S (proposed), orange
crystals, m.p. 212-220° (dec).
A basic polypeptide. Positive FeCIs, Fehhng, biuret,
KMn04. Negative Molisch, Sakaguchi.
Streptomyces sp. similar to S. lavendulae
Albert Kelner and Harry E. Morton, J. Bad. 53 695 (1947).
(Isolation)
Harry E. Morton, Proc. Soc. Exp. Biol. Med. 64 327 (1947).
775 Echinomycin (X-948),* C-,„H„„Oi2Ni^,S2, granular, nearly color-
less hygroscopic powder, m.p. 217°, [a]i> —310° (c 0.86
in chloroform).
CH-CO NH— CH— CO— N - C— CO -N— CH— CO- O CH.
/ \
S CH,
I I
CH: S
CH,— O— CO— CH— N— CO-C-N CO— CH NH-CO— CH
II II
CH CH, CH, CH,
/ \_ I
CH,
CH,
CO
* Antibiotic X-1008 (unclassified) resembles echinomycin.
371 Polypeptides and Related Compounds
Streptornyces echinatus n. sp.
R. Corbaz. L. Ettlinger, E. Gaumann, W. Keller-Schierlein,
F. Kradolfer, L. Neipp, V. Prelog, P. Reusser and H. Zahner'
Helv. Chim. Acta 40 199 (1957). (Isolation)
W. Keller-Schierlein, M. Lj. Mikhailovich and V Prelog
iWd. 42 305 (1959). (Structure)
Circulins, C-,3Hi„„Oi3Ni(5 (Sulfate), amorphous solid, m.p. 226-
228° (dec), [«]„" -61.6°.
776 Circulin A:
CHs O
I II
CH3CH2CHCH2CH2CH2CH2— C— NH
NH2 ^"- NHo*
\ ru O /
CH ^CH O
% / \
CH. C NH
CH3
CH3
CH3 /
NH
CH'
CH L-Isoleu t-Thre CH'
\ OH
c==o
0=C NH
-„.^CH D-Leu l-Dia CH
,CH2 \^ /
CH2
^CHo
/ NH C^ --KJU
CH^ L-Thre CH
CH2 N"^^ ^-Dia ^C^ \ „ ^^
CH2 o' J.^ O CH3
H2N
/
CH2
CH2
I
NHo
Bacillus circulans
Hydrolysis yields 6 moles of L-a, y-diaminobutyric acid,
2 moles of L-threonine, 1 mole of D-leucine, 1 mole of
L-isoleucine and 1 mole of ( + )6-methyloctanoic acid.
'7 Circulin B has essentially the same structure, but the 6-methyl-
j octanoic acid moiety is attached at the starred amino
Pfizer Handbook of Microbial Metabolites 372
group. There may be other similar compounds in the
complex also.
F. J. Murray, P. A. Tetrault, O. W. Kaufman, H. Koffler,
D. H. Peterson and D. R. Colingsworth, J. Bad. 57 305
(1949).
D. H. Peterson and L. M. Reineke, J. Biol. Chem. 181 95
(1949).
Tashio Kobayashi, J. E. Grady, J. L. Parsons, Henry Koffler
and P. A. Tetrault, Abstr. 133rd Meeting Am. Cheyn. Soc, 25C
(1958).
H. Koffler and T. Kobayashi, Abstr. 4th Intern. Congr.
Biochem., 9 (1958).
Henry Koffler, Science 130 1419 (1959).
778 Fungisporin, Cr.gHyoOgNg, colorless crystals, m.p. 355-360°
(dec.) (subl. from 250°), molecular weight 980.
Proposed structure:
CHs CH3
CH O
O 1 // CH3
\ X D-Valine \ / \
CH L-Phenyl- CH CH3
// alanine L-Valine \ q
NH C^
=C NH
/ '^— CH2— CH D-Phenyl- D-Phenyl- CH— CH.— '^^^
1 alanine alanine I
NH C^^
\ / °
^C NH
O^ \ L-Valine L-Phenyl- /
CH3 CH alanine CH
CH
\ / \ D-Valine _/^ \
CH NH. Xf Yh
^C-^CH—NH-^X CH.
// I o
O CH
/ \
CH3 CH3
Penicillium and Aspergillus spp.
This polypeptide was obtained by destructive distilla-
tion of spores, when it separated by sublimation.
373 Polypeptides and Related Compounds
U. Sumiki and K. Miyao, /. Agr. Chem. Soc. Japan 26 27
(1952).
Idem., Bull. Agr. Chem. Soc. (Japan) 19 86 (1955).
Kohei Miyao, ibid. 24 23 (1960).
779 Polypeptin (formerly called circulin, but not identical with the
polypeptide now known as circuHn), C^gHooOiaN,.., color-
less crystals, m.p. 176°, [a],,-" (Sulfate) -93.3° (c 3.0 in
70% isopropyl alcohol).
A basic polypeptide, containing: three a,y-diaminobu-
tyric acids, one L-threonine, one D-vaHne, one L-isoleucine,
two L-leucines and one D-phenylalanine.
Bacillus krzemieniewski, a B. circulans mucoid variant
Stacey F. Howell, /. Biol. Chem. 186 863 (1950).
Werner Hausmann and Lyman C. Craig, ibid. 198 405
(1952).
Polymyxins:
'80 Polymyxin A (Aerosporin)
'81 Polymyxin Bi
'82 Polymyxin B,
'83 Polymyxin C
'84 Polymyxin D
'85 Polymyxin E
A complex of related polypeptides produced by Bacillus
polymyxa. Initially five components, A, B, C, D and E
were separated. Then B was resolved into two compo-
nents Bi and B^, differing only in the fatty acid moiety.
All polymyxins contain L-a, y-diaminobutyric acid and
L-threonine. All but B^ apparently contain d-6-methyloc-
tanoic acid, and it contains a C-8 acid instead. Poly-
myxin A has been reported to contain D-leucine but no
phenylalanine. It is also known as aerosporin because it
is produced by Bacillus aerosporus. Polymyxin C con-
tains phenylalanine but no leucine. Polymyxin D con-
tains leucine but no phenylalanine, and it also has been
reported to contain D-serine. Polymyxin E has the same
quahtative composition as A, but is distinct.
Two alternative structures have been suggested for
polymyxin Bj as the result of degradative studies. These
structures are shown here, the amino acids being abbrevi-
ated in the following manner:
Pfizer Handbook of Microbial Metabolites
374
HjN-
Dia = a,y-Diaminobutyric Acid
Thr = Threonine
Phe = Phenylalanine
Leu = Leucine
NH2 NH,
\ I
CH, I I
).„ O O CH— OH O CHi
Jh J-,H^ /CH.-CH.MH-C-CH-NH-C-CH
CH X ''°'° l-Dia \^ I
/\/ \ c=o
CH3 CH L-Thr NH I
/ \ (CH2),
NH L-Dia CH^^"^^"^N"2
/
o=c
,CHr
CH— CH3
1 I
\ r 1""
CHo-'S" i-Dia NH ^Hj
\ y 6-Methy|.
NH o-Phe CH octanoic
\ / ^CH ^'''^
CHo O
CH2
/ ■ ^CH
NH:
CH3 CHj
NHo
Or CH2 CH3 OH
1 \ /
CH, OH O CH2 O CH
\ / " II I II I
\C O CH,— NH— C— CH— NH— C— CH
\ II / I
CH C — .^^ CH; ^.Dio L.Thr NH
a NH "^CH I „
X^/ L-Thr ,.Dia \ .O C=0
^"'--rw / \ CH-(CHo)oNH2
9" NH NH
NH i-Dia CH— CHj— CH.NH. C=0
= C C^
\ L-Dio /"°
I
(CHJ^
CH
^CH ^(l / \
/CH. \ ^ o-Phe / ^H. CH3
CH2 X. l-Leu CH ^.j^
H2N C-^ , _C^ \
^^— CH-NH--^^ "\^
CH
/ \
CH3 CH3
octanoic
Acid
375
Polypeptides and Related Compounds
Commercial polymyxin is essentially polymyxin B sul-
fate, a white powder, m.p. 228-232° (dec.), Whr' -45°
(c 0.1). The empirical formula of the free base is
CseH.tc.gsOjsNie.
G. C. Ainsworth, A. M. Brown and G. Brownlee, Nature 160
263 (1947). (Isolation)
George Brownlee, Ann. N. Y. Acad. Sci. 51 875 (1949).
(Polymyxin A)
P. H. Bell, J. F. Bone, J. P. English, C. E. Fellows, K. S.
Howard, M. M. Rogers, R. G. Shepherd and R. Winterbottom,
ibid. 51 897 (1949). (Degradations, identification of amino
acids)
Tudor S. G. Jones, ibid. 51 909 (1949). (Separations, deg-
radations, identification of amino acids)
J. R. Catch, Tudor S. G. Jones and S. Wilkinson, ibid. 51
917 (1949).
P. P. Regna, I. A. Solomons, B. K. Forscher and A. E.
Timreck, /. Clin. Invest. 28 1022 (1949). (Purification of B)
Werner Hausmann and Lyman C. Craig, J. Am. Chem. Soc.
76 4892 (1954). (Resolution of B into two parts)
Werner Hausmann, ibid. 78 3663 (1956). (Proposal of de-
tailed cyclic structures)
Gerard Biserte and Michel Dautrevaux, Bull. soc. chim. biol.
39 795 (1957). (Structure)
Gramicidins.
A mixture of polypeptides produced by Bacillus brevis
and originally called tyrothricin was separated into two
groups, the tyrocidines (about 80 "^r ) and the gramicidins
(about 20%). Each of these groups has been fraction-
ated further into pure polypeptides.
The original gramicidin consisted of a mixture of three
closely related neutral polypeptides. It was assigned an
average empirical formula of C]4SjH2io02(iN3o, colorless
platelets, m.p. 228-231°, [aW +3°.
Fraction A
Fraction B
Fraction C
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
D-Leucine
L-Trypotophon.
l-Alanine
DL- Valine
Glycine
Phenylalanine.
Tyrosine
Pfizer Handbook of Microbial Metabolites
376
RoUin D. Hotchkiss and Rene J. Dubos, /. Biol. Chem. 132
791 (1940).
Idem., ibid. 141 155 (1941). (Isolation)
Max Tishler, J. L. Stokes, N. R. Trenner and John B. Conn,
ibid. 141 197 (1941).
Rollin D. Hotchkiss, Advances in Enzymol. 4 153 (1944).
786 Gramicidin Jo, C35H56O6N8.
NH2
1
1
CH2
1
1
CH2
1
1
CH2
1
0
1
^r^ D-Orn
CH2 CH
^cC^
NH
\
L-Val CH
.CH
\ /
CHa
CH3
"N i-Pro
o=c
\
CH D-Phe
NH
/
L-Orn CH
CH2
CH2
NH
/
D-Leu
-CH^
CH2
I
CH
-NH
\
XH2
CH2
CH3
CH3
'NH2
Bacillus brevis
Shokei Otani, H. Nagano and Y. Saito, Osaka Shiritsu
Daigaku Igaku Zasshi 7 640-650 (1958). (Chem. Abstr.
12403g)
377 Polypeptides and Related Compounds
787 Gramicidin J,, C44H6.r,0-N{,.
NH2
I
CH2
I
CH2
I
CH2 o
_— -CH2 S- ^ NH CH
CH CH
/ \
CH3
/^y_CH2 y
■CH2
/ ^NH Qr^ \
CH
CH
6
-CH2
NH C ^NH2
\ / O
>\ D-Phe y
-^ ^CH ^CH^
/
CH
/ \
CH3 CH3
Bacillus brevis
Shokei Otani and Yoshitaka Saito, Proc. Japan. Acad. 30
991 (1954).
Idem., Congr. intern, biochim.. Resumes Communs., 3e
Congr., Brussels, 88 (1955).
Pfizer Handbook of Microbial Metabolites 378
788 Gramicidin S (Gramicidin C), CeoHgoOioNio, colorless needles,
m.p. 277° (dec), [2;]..'' -289° ±10° (c 0.43 in 70% etha-
nol).
NH2
CH2
CHs CHs
CH3 CHs
CHo
CH
\/
1
1
CH
CH2
CH2
CH
CH2
CO— NHCHCO— NHCHCO— NHCHCO— NHCHCO— N CHo
I (l) (l) (l) (d)
CH,— CH
[l) (l) CH— CH'2
(d) (l) (l) (l) 1
CH2— N COCHNH— COCHNH— COCHNH— COCHNH— CO
I I I 1
CH. CHo CH2 CH
I I I / \
CH CH, CHs CHs
/ \ 1
CHs CHs CH2
I
NH2
Bacillus brevis var. Gause-Brazhnikova
G. F. Cause and M. G. Brazhnikova, Am. Rev. Soviet Med.
2 134 (1944).
R. L. M. Synge, Biochem. }. 39 363 (1945). (Character-
istics)
F. Sanger, ibid. 40 261 (1946).
R. Consden, A. H. Gordon, A. J. P. Martin and R. L. M.
Synge, ibid. 40 xciii (1946).
Idem., ibid. 41 596 (1947).
Alan R. Battersby and Lyman C. Craig, /. Am. Chem. Soc.
73 1887 (1951).
R. Schwyzer and P. Sieber, Helv. Chim. Acta 40 624 (1957).
(Synthesis)
789 Gramicidin D (Gramicidin Dubos), colorless crystals, m.p. 229°
(dec).
A crystalline component of tyrothricin. A cyclic poly-
peptide composed of 4 moles of D-Leucine, 4 moles of l-
tryptophan, 2 moles of o-Valine, 2 moles of L-Valine, 2
moles of L-alanine, 1 mole of glycine and 1 mole of
ethanolamine.
Bacillus brevis
Rene J. Dubos and Rollin D. Hotchkiss, J. Exptl. Med. 73
629 (1941). (Isolation)
A. H. Gordon, A. T. P. Martin and R. L. M. Synge, Biochem.
J. 37 86 (1943).
379 Polypeptides and Related Compounds
Rollin D. Hotchkiss, Advmices in Enzymol. 4 153 (1944).
R. L. M. Synge, Biochem. J. 39 355 (1945).
T. S. Work, The relation of optical form to biological
activity in the amino acid series, Biochem. Soc. Symposia 1
61 (1948).
790 Racemomvcin B, C,;oHio>,0;,.,N..„. white, hygroscopic powder, m.p.
150°, [2W -34° (c 6.5 in water).
A basic antibiotic resembhng streptothricln. Acid
hydrolysis gives a reducing sugar and carbon dioxide,
^-lysine and roseonine in the ratio 2:3:2. Racemomycin
B occurs in a complex with two (apparently similar) sub-
stances, racemomycins A and C.
Streptomyces racemochromogemis n. sp.
Hyozo Taniyama and Shoji Takemura, J. Pharm. Soc. Ja-
pan 77 1210 (1957).
Idem., ibid. 78 742 (1958).
791 Tyrocidine A, C66Hji60i3Ni3, colorless needles or rods, m.p. 240-
242° (dec), [a]v-'' -111°. A component of the tyrothri-
cin complex.
NH,
CH2
I
I /"^
CH3 CH, o CH
I O I // / \
CH3-CH \^NH-CH-^C^ / CH3
CH i-Orn ^CH ^
X L-Val L-Leo \ /^
CH L-Tyr D-Phe CH"^ "
NH C=0
I 1
0-=C N — -CH2
^CH i-Glu i-Pro CH._ ^
CH=-^"- \ / ^"=
OC-^ NH C^
\ / %
O ^CH L-Asp ^.p,^ CH
r/ NH_ .C^ \
CH. --C^CH-NH-^ \\ CH.
OC I \ °
/ ° CH2
H2N I \ J
CH,
Pfizer Handbook of Microbial Metabolites 380
Bacillus brevis
Rollin D. Hotchkiss and Rene J. Dubos, /. Biol. Chem. 132
791 (1940). (Isolation)
R. L. M. Synge and A. Tiselius, Acta Chem. Scand. 1 749
(1947).
R. L. M. Synge, Quart. Rev. 3 245 (1949). (Review of
work to that date)
Alan R. Battersby and Lyman C. Craig, /. Am. Chem,. Soc.
74 4019, 4023 (1952). (Separation)
Alejandro Paladini and Lyman C. Craig, ibid. 76 688
(1954). (Structure)
792 Tyrocidine B, C68H88O13N14.
A component of the tyrothricin complex.
H2NOC
381 Polypeptides and Related Compounds
Bacillus brevis
T. P. King and L. C. Craig. /. Am. Chcm. Soc. 77 6627
(1955). (Final structure)
Actinomycins.
The nomenclature of the actinomycins is confused be-
cause they occur in difficulty separable complex mixtures,
several different research groups have investigated them,
and, even when pure, one substance cannot be compared
with another by techniques as simple as a mixed melting
point. This problem has been discussed by Brockmann
in a review of the actinomycins.
L. Zechmeister (editor), "Fortschritte der Chemie organis-
cher NaturstofFe" XVIII, Hans Brockmann, The actinomycins.
Springer Verlag, Vienna, 1960.
At first actinomycins A, B and C were isolated, but later
these were found to be mixtures. As such complexes
were resolved by paper chromatography, Arabic numeral
subscripts were attached to the capital Roman letter in
order of appearance on the developed chromatogram, the
origin on the paper being zero (e.g., Ci, Co, C3). When
some of the separated actinomycins were resolved even
further, a further subdivision in nomenclature was re-
quired; so a lower case Roman letter was attached to give,
^■9-, Coj, which appeared between Co and C3. When the
Xo complex at the origin was resolved, a slightly different
system was used, Greek letters being attached to the
Arabic numeral subscript, e.g., Xo^ was less polar than X,,;,.
Few series are complete because often names have been
eliminated due to duplication, further resolution, etc.
Thus, a complex designated I was resolved into Ii and L,
but these later were shown to be the same as Cj and C2
and the I names eliminated.
Still this method of nomenclature does have a ration-
ale, although it may not be readily apparent, and it is used
in Germany and in Switzerland.
Other groups continue to refer to various complexes as
A, B or D types. These consist essentially of various ratios
of actinomycin Xo and its reduction product, actinomycin
Ci, actinomycin D being nearly pure Cj.
The E and F series arose when it was discovered that
addition of certain amino acids to the medium in large
amounts caused displacement of certain other amino
acids in the peptide side-chains, thus creating new "bio-
synthetic" actinomycins.
Pfizer Handbook of Microbial Metabolites
382
Beyond historical interest there seems to be little point
in attempting to standardize the nomenclature of actino-
mycin mixtures. Waksman has proposed that a Roman
numeral be assigned to each pure actinomycin, and John-
son's group has taken up this practice, actinomycins II
and III being distinct from those characterized elsewhere,
while IV is identical with Cj or D, etc. Brockmann views
this as one more contribution to the confusion of the liter-
ature and, claiming the right of discoverer of many of the
actinomycins, has made the suggestion that no nomen-
clature system will relieve the confusion unless it makes
apparent the amino acid sequences of the side-chains.
Although this does not solve the problem of trivial
nomenclature, Brockmann uses a shorthand method of
demonstrating the structures of the actinomycins in
which a symbol < represents the actinocinin moiety,
the branches at the right symbolizing the amino and
quinonoid carbonyl groups. The abbreviated amino
acid names are then attached in proper sequence. In
most of the asymmetric actinomycins the chains in which
the differing amino acids occur have not yet been speci-
fied, and this is indicated by an E -symbol, indicating pos-
sible reversal of position.
The structure of actinomycin C3 (which has been
synthesized) is given somewhat more fully to show struc-
tural details. The custom of arrangement by empirical
formula is ignored here to permit grouping by related
structures.
The mitomycins (unclassified) may be actinomycins.
There is an apparent striking biogenetic similarity
among the etamycin, staphylomycin, etc. group of poly-
peptides on the one hand and the actinomycins on the
other.
793 Actinomycin C.^ (VII) Cc4H9oOi6N,o
235° (dec), [2W -321° ±lo"=
red crystals, m.p. 232-
383 Polypeptides and Related Compounds
Below is shown one of the peptide side-chains of actino-
mycin C3 to permit comparison with etamycin, etc.
CH,
0
CH
Point of aftachn
i
\\
/
~^CH
/
to actinocinii
CH3-CH
\
-0-
NH
/
CH
i-Thre
CH
CH, /
L-N-Me
Vol
\^^°
/
\
o=c
\ so
NH
/
re
CH.
D-0//0-
P^
\
Isoleu
/ ^
CH-CH,— CH
N
L-Pro
C
\
/
//
\
\
CH3
CH3
-CH-
0
0
CH,
CH
2
" CH..
Streptomyces antibioticus, S. chrysomallus
H. Brockmann, G. Bohnsack, B. Franck, H. Grone, H. Mux-
feldt and C. Siiling, Angew. Chem. 68 70 (1956) and preced-
ing papers. (Structure)
H. Brockmann, W. Sunderkotter, K. W. Ohly and P. Boldt,
Naturwissenschaften 47 230 (1960).
' H. Brockmann and L. Lackner, ibid., 47 230 (1960).
794 Actinomycin C^ (D,IV,Xi,Bi,Ii) C(.iHjj„Oip,Nio red prisms, m.p.
241° (235.5-236.5) (dec.) [a],r" -349° ±10° (337°).
\
^L-Thre — D-Val — L-Pro — Sar — L-Meval — O Indicates position
of lactone not
— L-Thre — D-Val — L-Pro — Sar — L-Meval — O , proved
Where
r \° NH,
N
CH3 °
Streptomyces chrysomallus, S. antibioticus; S. parvul-
lus
A. W. Johnson and A. B. Mauger, Biochem. J. 73 535
(1959).
Hans Brockmann and Hans-Sieghard Petras, Naturwis-
senschaften 46 400 (1959).
Pfizer Handbook of Microbial Metabolites
384
Hans Brockmann, P. Boldt and Hans-Sieghard Petras,
ibid. 47 62 (1960).
795 Actinomycin Co (VI) CeoHgoOieNjo red crystals, m.p. 237° (dec),
[alD^' -325° ±10°.
— L-Thre — D- Va I — L- Pro — Sa r — L-Meva I — O
-L-Thre — D-0//0 — lieu — L-Pro — Sar — L-Meval — O
\
Indicates it is not known in which chain the
two acids ore.
Streptomyces chrysomallus
A. W. Johnson and A. B. Mauger, Biochem. J. 73 535
(1959).
Hans Brockmann and Hans-Sieghard Petras, Naturwis-
senschaften 46 400 (1959).
Hans Brockmann, P. Boldt and Hans-Sieghard Petras, ibid.
47 62 (1960).
C2a C62H90O26N12 an isomer of C2 found by paper
chromatography.
Streptomyces chrysomallus
Hans Brockmann and B. Franck, ibid. 47 15 (1960).
796 Actinomycin E^, C64H960i6Ni2-
— Thre — a— lieu — Pro — Sar-
Meval — O
-Thre — a — lieu — Pro — Sar — Meileu — O
Streptomyces sp.
Giinther Schmidt-Kastner, Naturwissenschaften 43 131
(1956).
797 Actinomycin E2, C65H9„Oi6Ni2.
-Thre — a — lieu — Pro — Sar — Meileu — O
-Thre — a — lieu — Pro — Sar — Meileu — -O
Streptomyces sp.
385
Polypeptides and Related Compounds
Giinther Schmidt-Kastner, Naturwissenschaften 43 131
(1956).
798 Actinomycin Fp CngHssOieNjo.
— Thre—
Va I Sa r— Sa r Meva I — O
— Thre — a — lieu — Sar — Sar — Meva! — O
Streptomyces sp.
Giinther Schmidt-Kastner, Naturwissenschaften 43 131
(1956).
799 Actinomycin Fo, CgoHg^^OifiNis.
-Thre— Val-
Pro Sar Meva I — O
Thre — a — lieu Sar — Sar — Meval — O
Streptomyces sp.
Giinther Schmidt-Kastner, Naturwissenschaften 43 131
(1956).
800 Actinomycin F3, CsgHgoOjeNio-
I
-Thre — o — I leo — Sar — Sa r — Meva I — O
-Thre — a — lieu — Sar— Sar — Meval — O
Streptomyces sp.
Giinther Schmidt-Kastner, Naturwissenschaften 43 131
(1956).
801 Actinomycin F4, CeiHgoOieNja.
r— I
— Thre — a — lieu — |Pro — Sar — Meval — O
— ^Thre — a — lieu — Sar — Sar — Meval — O
Streptomyces sp.
Giinther Schmidt-Kastner, Naturwissenschaften 43 131
(1956).
Pfizer Handbook of Microbial Metabolites
386
802 Actinomycin Xi„ C59H87O17N]
-Thre— Val-
Oxopro — Sar — Meval — O
Thre- Vol Sar — Sar — Meval — O
Streptomyces chrysomallus, S. fradiae
Hans Brockmann and H. Grone, Chem Ber. 87 1036
(1954).
803 Actinomycin X2 (V, Bo) CeiHggOiTNio red plates, m.p. 244-246°,
[aW> -341° ±10°.
-Thre — Val — Oxopro — Sar — Meval — O
—Thre — Vol — Pro —Sar— Meval— O
Streptomyces chrysomallus, S. fradiae
Hans Brockmann and Hans Grone, Chem. Ber. 87 1036
(1954).
804 Actinomycin X3, needles.
An actinomycin X3, containing threonine, sarcosine,
proline, valine, isoleucine and N-methyl valine, also has
been isolated.
H. Brockmann and H. Grone, Chem. Ber. 87 1036 (1954).
Werner Frommer, Arch. Mikrobiol. 34 1 (1959).
805 Actinomycin -X^^ (I) C61H90O17N10 yellow needles, m.p. 245—
247, [aW -260° ±10° (c 0.22 acetone).
-Thre— Val-
Hypro — Sar — Meval — O
Thre Val Pro — Sar— Meval— O
Streptomyces chrysomallus, S. fradiae
Hans Brockmann, Gottfried Pampus and Jost H. Manegold,
Chem. Ber. 92 1294 (1959).
Hans Brockmann and H. Grone, Chem Ber. 87 1036
(1954).
387 Polypeptides and Related Compounds
806 Actinomycin X,,,, C-.gHssOieNj..
— Thre— Val-
Pro — Sar — Meval — O
— Thre — Vol — Sar — Sar — Meval — O
Streptomyces chrysomallus, S. fradiae
Hans Brockmann and Gottfried Pampus, Angew. Chem. 67
519 (1955).
H. H. Martin and Gottfried Pampus, Arch. Mikrobiol. 25
90 (1956).
807 Actinomycin X„„ Cfi4H9oOi7Ni2.
— Thre — Vol — p — Hypro — Sar — Meval — O
Thre Vol Pro— —Sar— Meval — O
Streptomyces chrysomallus, S. fradiae
Same references as Actinomycin X„.^.
Actinomycins Z.
All contain the same five amino acids on hydrolysis:
threonine, sarcosine, N-methylalanine, vaUne and N-
methylvaline.
808 Actinomycin Z,„ amorphous orange-red powder, m.p. 250° (dec. ).
Streptomyces fradiae
R. Bossi, R. Hiitter, W. Keller-Schierlein, L. Neipp and
H. Zahner, Helv. Chim. Acta 41 1645 (1958).
809 Actinomycin Z^, orange-red crystals, m.p. 256-260 (dec), [(x]v
-362° (c 0.185 in CHCI3).
Streptomyces fradiae
R. Bossi, R. Hiitter, W. Keller-Schierlein, L. Neipp and
H. Zahner, Helv. Chim.. Acta 41 1645 (1958).
Actinomycins 'L<^,'L._<^,'L\, an inseparable mixture, m.p. 256-260°
(dec), [a"]„ -246 (c 0.257 in CHCl,)-
R. Bossi, R. Hiitter, W. Keller-Schierlein, L. Neipp and
H. Zahner, Helv. Chim. Acta 41 1645 (1958).
Pfizer Handbook of Microbial Metabolites
388
810 Actinomycin Z5, short red staffs, m.p. 261-267 (dec), [<x]v
-284° (c 0.244 in CHCI3).
Streptomyces fradiae
R. Bossi, R. Hiitter, W. Keller-Schierlein, L. Neipp and
H. Zahner, Helv. Chim. Acta 41 1645 (1958).
811 Actinomycin II, Cr.^HseOigNio red plates, m.p. 215° [aln'^ -157°
(c 0.24 in CHCI3).
-L-Thre — D- Va I — Sar — Sa r — N — Meva I — O
-L-Thre— D- Va I — Sa r — Sa r — N — Meva I — O
Streptomyces chrysomallus
A. W. Johnson and A. Mauger, Biochem. }. 73 535 (1959).
WiUiam A. Goss and Edward Katz, Antibiotics and Chemo-
therapy 10 221 (1960).
812 Actinomycin III, CggHj^eOieNio red prisms, m.p. 237°, [air"
-205° (c 0.22 in CHCI3)'.
=— L-Thre — D-Vol-
Sor— Sar— N— Me— Vol O
L-Thre— D-Val—L-Pro —Sar— N — Me— Vol- O
Streptomyces chrysomallus
A. W. Johnson and A. Mauger, Biochem. J. 73 535 (1959).
William A. Goss and Edward Katz, Antibiotics and Chemo-
therapy 10 221 (1960).
389
Polypeptides and Related Compounds
813 Mycobacillin, Co.-.HssOsoNi;^. colorless needles.
O
CH-
0
\\
1
^CH,
CHj
-C
-CH—
■NH /
CHi
\
r. \ ^
NH-^
C^
^ /
CHj
v.r
Asp
'V
/ \
/C Ala
Pro 1
N 0
HOOC\ /
\^-/' .COOH
\ /CH:
CH Asp
Asp CH'^
°-/
\
^C
NH
/
NH
"°°'-"-CH,-c'h G,.
\-
01. 1-CH.-CH.-COOH
0-
T
\
NH
\
^\ ^CH Leu
CH \
h
Tyr CH^
/ CHj /f \
/ ^/ ^>— OH
c/ oA
NH \=/
/
NH
cC
\ Asp
/\)
CH
Asp
CH "
/ \
X \
CH. X,
/ q// ^NH
HOOC °
Ser
^'CH— .
/
-c
II
NH
Tyr
^CH-^
\
NH
c
CH
COOH
CH2
CHa
/
0
\
OH
OH
Bacillus subtilis
Hydrolysis yields five aspartic acids, two glutamic ac-
ids, two tyrosines, one proline, one serine, one leucine and
one alanine. (Unspecified configurations)
S. K. Majumdar and S. K. Bose, Nature 181 134 (1958).
(Isolation)
Idem., Biochem. J. 74 596 (1960). (Structure)
Pfizer Handbook of Microbial Metabolites
390
814 Bacitracin A, CeeHiogOigN^yS, white, hygroscopic, amorphous
powder, [a]i,'' +5° (±2.5°).
CH3CH:
S— CHj
\
\
CH— CH-
/ 1
/
-C
\
CHa NH2
N— CH
CH2 COOH
\ /
c=o
1
D-Asp CH
\ ^
NH
CH3
NH 0
0
/
\/
II
-Leu CH— CHr
-CH
CH
,-— C-
— -NH
^CH.
1
c=o
1
\
CH,
NH L-Asp
l-Lys CH.
CH, ^
1
NH
1
0^/
-Glu CH— CH.-
-CHi— COOH
u^ r
^C
^CH.-^CH L-His
\
1
c=o
HC 1 —
1 1
CH2
CH—
/
HN N
0 NH
V
H
NH
ic
NH-c_CH-CH-
-CH,-CH3
C^
CH3
° \ D-Phe
CH
y^^"- NH L
NH
/
L-lleu
-lleu
D-
Orn CH
r^ ^c^
"K CH'^
0 //
~CH —
/
-NH^
V \„,
0
CH
\
CH3
/
CH2
CHo
\
NH2
CH3
Bacillus subtilis, B. licheniforTnis
The bacitracins are a difficultly separable polypeptide
complex. Bacitracins A, B, C, D, E, F^, F^, F;^ and G have
been differentiated. The F series may be artifacts. The
structure of bacitracin A has received the most attention.
In certain of the other bacitracins isoleucine is replaced
by valine. The complex from B. liche7iiformis was origi-
nally called ayfivin.
I. M. Lockhart, E. P. Abraham and G. G. F. Newton,
Biochem. J. 61 534 (1955).
J. R. Weisiger, W. Hausmann and L. C. Craig, /. Am. Chem.
Soc. 77 731, 3123 (1955).
Dorothy Wrinch, Nature 179 536 (1957).
E. P. Abraham, "CIBA Lectures in Microbial Biochemistry,"
39^ Polypeptides and Related Compounds
The bacitracins, John Wiley and Sons, New York, 1957, pp.
1-30. (A review which also covers the earlier work)
815 Subtilin, amorphous white powder, [a],,-' —29° to —35°
Subtilin is a basic polypeptide, molecular weight 3188,
which yields 11 common amino acids, lanthionine:
HOOC— CH— CH2— S— CH.— CH— COOH
NH.> NH^
and a new S-amino acid, probably yS-methyllanthionine :
(0 CH3(d)
HOOC— CH— CH.— S— CH— CH— COOH
NH. NH.,
The common amino acids identified are: glycine, ala-
nine, valine, leucine, isoleucine, proline, phenylalanine,
tryptophan, lysine, asparagine and glutamic acid.
Bacillus subtilis
Eugene F. Jansen and Doris J. Hirschmann, Arch. Biochem
4 297 (1944).
A. J. Salle and Gregory J. Jann, Proc. Soc. Exp. Biol. 60 60
(1945).
W. Steenken, Jr. and E. Wolinsky, /. Bad. 57 453 (1949).
J. C. Lewis and N. S. Snell, /. Am. Chem. Soc. 73 4812
(1951).
Gordon Alderton, ibid. 75 2391 (1953).
Nisins, nearly white needles.
Consist of four active cyclic polypeptides. All contain
lanthionine and yS-methyllanthionine. These amino acids
also occur in the antibiotics, subtilin, cinnamycin and
duramycin.
816, 817, 818 Nisins A, B and C contain leucine and/or isoleucine, val-
ine, alanine, glycine, proline, aspartic acid, histidine,
lysine and methionine.
819 Nisin D contains glutamic acid, but no valine or methionine.
Nisin A has a molecular weight of --7000 and also
I contains serine.
I Streptococcus lactis, S. cremoris
N. J. Berridge, G. G. F. Newton and E. P. Abraham,
Biochem. J. 52 529 (1952).
I G. G. F. Newton and E. P. Abraham, Nature 171 606 (1953).
Pfizer Handbook of Microbial Metabolites 392
G. Cheeseman and N. Berridge, Biochem. J. 71 185 (1959).
820 Duramycin, colorless amorphous soUd, no definite m.p., Hydro-
chloride: [a]rr' -6.4° (c 3.9 in water).
Duramycin is a polypeptide, containing at least one
free amino group and several free carboxyl groups. Acid
hydrolysis yielded: lanthionine, ^-methyllanthionine, as-
partic acid, glutamic acid, glycine, valine, proline, phenyl-
alanine and possibly ornithine and hydroxyproUne. Du-
ramycin is related to, but distinct from, cinnamycin.
Streptomyces cinnamoneus f . azacoluta
Odette L. Shotwell, Frank H. Stodola, William R. Michael,
Lloyd A. Lindenfelser, Robert G. Dworschack and Thomas G.
Pridham, J. Am. Chem. Soc. 80 3912 (1958).
821 Cinnamycin.
A polypeptide containing (probably): glutamic acid,
aspartic acid, proline, phenylalanine, valine, arginine,
lanthionine and /3-methyllanthionine.
Streptomyces cinnamoneus
Robert G. Benedict, William Dvonch, Odette L. Shotwell,
Thomas G. Pridham and Lloyd A. Lindenfelser, Antibiotics
and Chemotherapy 2 591 (1952).
Robert G. Benedict, Bot. Rev. 19 229 (1953).
822 Matamycin, colorless crystals, m.p. 173° (dec), [ajn^" +36.6°
(c 0.11 in methanol).
An essentially neutral antibiotic of low solubility.
Analysis: C 43.95, H 4.06, N 14.45, S 13.57. Halogen-
free. Positive Fehlings, ToUens, permanganate, DNPH,
and (after hydrolysis) ninhydrin tests. Negative ferric
chloride and Sakaguchi tests. A hydrolysate contained:
cysteic acid, glycine, serine, alanine, arginine and two
other amino acids.
Streptomyces matensis n. sp.
P. Sensi, R. Ballotta and G. G. Gallo, Antibiotics and Chem-
otherapy 9 76 (1959).
An inactive compound, "Compound I," evidently of
analogous structure was isolated from the same culture:
823 Compound I, colorless crystals, m.p. 189° (dec), [aln'" +151.6°
(c 0.1 in dioxane).
Analysis: C 45.84, H 3.90, N 14.99, S 14.64. It may
be a dehydration product of matamycin.
393 Polypeptides and Related Compounds
824 Comirin, nearly colorless powder, m.p. 230-235° (dec.)-
A polypeptide containing the following amino acids:
serine, aspartic acid, glycine, a,y-diaminobutyric acid,
lysine, leucine, isoleucine, tyrosine and arginine. An
ether-soluble moiety also was present. Negative ninhy-
drin, positive biuret. No free amino acid groups.
Pseudomonas antimycetica
W. G. C. Forsyth, Biochem. J. 59 500 (1955).
825 Colimycin.
A crystalline polypeptide, containing mainly D-leucine
and L-threonine.
Bacillus colistinus
P. V. Forni and E. Guidetti, Minerva med. II 823 (1956).
826 Brevin.
Brevin is a polypeptide containing: aspartic acid, gly-
cine, tyrosine, serine, an unidentified basic substance
(and also a fatty acid component?).
Bacillus brevis
I Ella M. Barnes and G. G. F. Newton, Antibiotics and Chem-
otherapy 3 866 (1953).
827 Brevolin, Hydrochloride yellowish white amorphous, [ajn^*'
-18.9°.
Brevolin is a polypeptide, probably related to brevin.
Bacillus brevis
Junichi Kawamata and Yutaka Motomura, J. Antibiotics
(Japan) 7A 25 (1954).
Antibiotics from Yeast.
Two amorphous compounds have been isolated from
bakers' yeast. They have antibacterial and antifungal
effects, and seem to be cyclic polypeptides. Acid hydroly-
828 sis of one of these (Y^) gave leucine, valine, alanine,
829 glutamic acid and glycine. Acid hydrolysis of Y2 gave the
same amino acids plus y-aminobutyric acid.
■ Werner Motzel and Elton S. Cook, Nature 182 455 (1958).
F ,, .
830 Alvem.
A basic polypeptide containing arginine.
Bacillus alvei
K. Gilliver, A. M. Holmes and E. P. Abraham, Brit. J.
Exptl. Path. 30 209 (1949).
Pfizer Handbook of Microbial Metabolites 394
831 Thiostrepton, colorless crystals, m.p. 246-256° (dec), [ajo"^
—98.5° (c 1 in glacial acetic acid).
A weakly basic polypetide. Probable amino acid con-
tent: leucine (or isoleucine), valine, alanine, threonine,
proline, lysine, glycine, aspartic acid, glutamic acid,
cystine and tryptophan.
Streptomyces sp.
John Vandeputte and James D. Dutcher, "Antibiotics An-
nual 1955-1956," Medical Encyclopedia, Inc., New York, p.
560.
832 Antibiotic 899, reddish yellow amorphous powder, m.p. 115-
120°.
A neutral compound with spectra similar to those of
streptogramin.
Streptomyces sp. resembling S. virginiae
P. De Somer and P. Van Dijck, Antibiotics and Chemother-
apy 5 632 (1955).
833 Amphomycin, colorless crystals, [ajn"' +7.5° ±5 (c 1 in water
at pH 6).
An acidic (amphoteric) polypeptide, minimal molecu-
lar weight about 1500.
Streptomyces canus
Bernard Helnemann, Murray A. Kaplan, Robert D. Muir
and Irving R. Hooper, Antibiotics and Chemotherapy 3 1239
(1953).
834 Aspartocin.
An acidic polypeptide similar to amphomycin. C 53.2,
H 7.6, N 13.2, S 0.42, no halogen. Hydrolyzes to 4
moles of L-aspartic acid, 2 moles of glycine, 1 mole of
L-proline, 1 mole of L-valine, a,y8-diaminobutyric acid,
a-lL],/8-methylaspartic acid, D-a-pipecoHc acid and an un-
saturated fatty acid.
Streptomyces griseus var. spiralis, S. violaceus
Yields of 1 to 10 g. per liter were obtained.
A. J. Shay, J. Adam, J. H. Martin, W. K. Hausmann, P. Shu
and N. Bohonos, 7th Annual Symposium on Antibiotics, Wash-
ington, D. C, 1959.
J. H. Martin and W. K. Hausmann. J. Am. Chem. Soc. 82
2079 (1960).
835 Zaomycin, m.p. 242-246° (dec).
A polypeptide resembling amphomycin.
Streptomyces zaomyceticus n. sp.
395 Polypeptides and Related Compounds
Yorio Hinuma, /. Antibiotics (Japan) 7A 134 (1954>.
836 Bacillomycin (Fungocin, Bacillomycin R, Bacillomycin A), color-
less microcrystals.
An acidic polypeptide, molecular weight ~1000. Anal-
ysis: C 52.69, H 7.20, N 12.29. Contains glutamic acid,
aspartic acid, serine, threonine and tyrosine. Similar to
or identical with eumycin.
Bacillus siibtilis
Maurice Landy, Sanford B. Rosenman and George H. War-
ren, ;. Bad. 54 24 (1947).
Howard Tint and Wilhelm Relss, 7- Biol. Chem. 190 133
(1951).
Robert A. Turner, Arch. Biochem. 60 364 (1956).
837 Bacillomycin B, amorphous yellow material.
A polypeptide containing glutamic acid, aspartic acid,
proline, tyrosine and leucine.
Bacillus subtilis
Isao Shibasaki and Gyozo Terui, /. Fermentation Technol.
(Japan) 31 339 (1953).
838 Bacillomycin C.
A polypeptide containing glutamic acid, aspartic acid,
tyrosine, leucine and valine.
Bacillus subtilis
Isao Shibasaki and Gyozo Terui, /. Fermentation Technol.
(Japan) 32 115 (1954).
839 Fungistatin.
An amphoteric polypeptide, containing aspartic acid,
lysine, serine, threonine, proline, alanine, isoleucine,
valine, tryptophan, tyrosine, other unidentified amino ac-
ids. Molecular weight about 2400.
Bacillus subtilis
Gladys L. Hobby, Peter P. Regna, Nancy Dougherty and
WiUiam E. Steig, J. Clin. Invest. 28 927 (1949).
P. P. Regna, R. A. Carboni and W. E. Steig, Am. Chem. Soc.
Meeting-in-Miniature, Brooklyn (1950).
Robert L. Peck and John E. Lyons, Ann. Rev. Biochem. 20
367 (1951).
840 Bryamycin, m.p. 223-235° (dec), [«]«'' -68.5° (c 1 in chloro-
form ) .
A polypeptide containing alanine, glycine, isoleucine,
threonine, cystine and unidentified compounds.
Pfizer Handbook of Microbial Metabolites 396
Streptomyces hawaiiensis n. sp.
M. J. Cron, D. F. Whitehead, I. R. Harper, B. Heinemann
and J. Lain, Antibiotics and Chemotherapy 6 63 (1956).
841 Coliformin.
A polypetide, molecular weight 4000 ± 400, containing
glutamic acid, aspartic acid, lysine, valine, leucine, serine,
alanine and glycine. Positive Molisch. Contains traces
of phosphorus and sulfur.
An E. coli-Aerobacter aerogenes type of bacterium
Stig K. L. Freyschuss, Stig O. Pehrson and Borje Steinberg,
Antibiotics and Chemotherapy 5 218 (1955).
842 Mycosubtilin, white crystals, m.p. 256°.
A polypeptide, C 55.31, H 7.61, N 15.15.
Bacillus subtilis
Robert P. Walton and H. Boyd Woodruff, /. Clin. Invest. 28
924 (1949).
843 Grizein ( Helianthate ) homogeneous brown powder, m.p. 194-
196° (dec.) (hydrochloride) white, hygroscopic powder.
A basic polypeptide complex. Positive biuret, ninhy-
drin, glucosamine reactions. Negative maltol, histidine,
Sakaguchi tests.
Streptomyces griseus-like strains
N. A. Krasilnikov, A. N. Belozerskii, Ya. I. Rautenshtein,
A. I. Korenyako, N. I. Nikitina, A. I. Sokolova and S. O. Ury-
son, Mikrobiologiya 26 418 (1957).
Licheniformins, amorphous white powders, no m.p.
844 Licheniformin A, hydrochloride: [aln^^ —37.4° (c 1 in chloro-
form).
845 Licheniformin B, hydrochloride: [a]D^° —37.7° (c 1 in chloro-
form).
846 Licheniformin C, hydrochloride: [ajn^" —36.8° (c 1 in chloro-
form ) .
A rather high molecular weight polypeptide complex.
Negative glucosamine and Molisch. Positive Sakaguchi,
biuret.
Licheniformins A and B contain: aspartic acid, glycine,
serine, lysine, arginine, valine, proline and phenylalanine.
Bacillus licheniformis
R. K. Callow, R. E. Glover, P. D'Arcy Hart and G. M. Hills,
Brit. J. Exptl. Path. 28 418 (1947).
397 Polypeptides and Related Compounds
R. K. Callow and T. S. Work, Biochem. J. 51 558 (1952).
847 Carcinomycin, dark green, amorphous.
A polypeptide antibiotic. Sulfur-free.
Streptornyces carcinomyciciis
Shogo Hosotani and Momoe Soeda, Japanese Patent 6893
(1959). (Chem. Abstr. 54 831g)
848 Carcinocidin, [oc]u'^ —20° (c 1 in water).
A polypeptide antibiotic, containing cystine, lysine,
glycine and glutamic acid. Molecular weight >6000.
Streptornyces kitazazvaensis
This organism also produces antimycin A.
F. Okamoto, Shigeo Kubo, Takahashi Nara and Shiro Ta-
naka, Jap. Patent Appl. 6894 (1959). (Chem. Abstr. 54 832c)
849 Melanomycin (Sodium Salt), brown, amorphous powder.
A polypeptide antibiotic yielding on hydrolysis : phenyl-
alanine, leucine, valine, proline, alanine, glutamic acid
and histidine.
Streptornyces melanogenes
Fujiki Hata, Ryozo Sugawara, Akihiro Matsumae and Taka-
moto Sano, Japanese Patent 5899 (1959). {Chem. Abstr. 54
833b)
850 Notatin (Penicillin B, Penatin), buff colored powder, water sol-
uble, [ajn'" -4.8° (c 0.012 in water).
A fiavoprotein enzyme (glucose-oxidase), molecular
weight about 152,000.
PenicilliuTn notatum, other Penicillium spp.
R. Cecil and A. G. Ogston, Biochem. J. 42 229 (1948).
18.
Heterocycles
a. FURANS AND RELATED SUBSTANCES
Apparently there has been no investigation of the biosynthetic
origin of the furans listed here, but it is known that furans can
be formed in several different ways.
The relationship of furans to sugars is recognized in the desig-
nation of the five-membered ring hemi-acetal form of sugars as
the furanose form. Dilute acid converts glucose to 5-hydroxy-
methylfurfural. The latter compound may be a precursor of
Sumiki's acid, although the transformations are probably enzy-
matic. The four carbon atom sugar erythrose also is a likely
furan precursor as pointed out by Wenkert.^
The furans with carbon chains at the 2-position are obviously
terpenoid. Since they were isolated from a sweet potato me-
dium, their direct derivation from glucose cannot be assumed.
The simpler substances may arise from oxidation of the more
complex.
It is interesting to note that the lactone side-chain of digitoxi-
genin is derived from acetate rather than from mevalonic acid.^
Such lactones as well as the related tetronic acids, would seem
Digitoxigenin
HO
to be potential furan precursors.
1 Ernest Wenkert, Experientia 15 165 (1959).
^ E. Leete, Seventh Medicinal Chemistry Symposium of the Amer-
ican Chemical Society, Kingston, Rhode Island, 1960.
399 Furans and Related Substances
851 Furan-3-carboxylic Acid, C.-,H40;,, colorless crystals, m.p. 121°.
COOH
/
u
Ceratostomella fimbriata (sweet potato substrate)
Takashi Kubota and Keizo Naya, Chem. and Ind., 1427
(1954).
852 5-Hydroxymethylfuran-2-carboxylic Acid (Sumiki's Acid), CeHr,04,
colorless crystals, m.p. 164° (dec).
I J
HOCH, COOH
Aspergillus glaucus, A. clavatus, A. niger, A. oryzae, A.
wentii, Gibberella fujikuroi
Yusuke Sumiki, J. Agr. Chem. Soc. Japan 7 819 (1931).
Akira Kawarada, Nobutaka Takahashi, Hiroshi Kitamura,
Yasuo Seta, Makoto Takai and Saburo Tamura, Bull. Agr.
Chem. Soc. (Japan) 19 84 (1955).
853 Ipomeanine, CoHi.Ai, oil, b.o.ooi 74-79°, Hd'-^ 1.4975, [a]o +3.9°.
O O
II II
C— CH2— CH2— C— CHs
Ceratostomella fimbriata (sweet potato substrate)
Takashi Kubota and Nobutaka Ichikawa, Chem. and Ind.,
902 (1954).
854 Batatic Acid, C10H10O4, colorless crystals, m.p. 88.5°, [ajc^"
+ 17.5" (in ethanol).
Ceratostomella fimbriata (sweet potato substrate)
Takashi Kubota and Keizo Naya, Chem. and Ind., 1427
(1954).
Pfizer Handbook of Microbial Metabolites 400
855 Ipomeamarone, C15H20O3, colorless oil, b. 0.001 103°, ric^^ 1.4827,
[<x]u-' +28°.
-CH CH2
1 I
O CH2
U
CH3 C— CHo— CH2— CH
CH3
CH3
Ceratostomella fimbriata (sweet potato substrate)
T. Kubota and T. Matsuura, Chem. and Ind., 521 (1956).
(Synthesis)
There is a marked resemblance between ipomeamarone
and dendrolasin, an oil Ci.r.HoL.O, isolated from ants. It is
an enantiomer of ngaione, isolated from Myoporum spp.
(higher plant).
A. Quilico, F. Piozzi and M. Pavan, Tetrahedron 1 177
(1957). (Structure)
A. J. Birch, R. A. Massy-Westropp and S. E. Wright, Chem.
and Ind., 902 (1954).
Ipomeamarone is thought to be formed by the host
(sweet potato) tissue to resist invasion by Ceratostomella
fimbriata.*
b. DIBENZOFURANS AND RELATED SUBSTANCES
Dibenzofurans constitute a class of natural products
found only in lichens. Usnic acid is the most widely dis-
tributed dibenzofuran. Its structure, which was contro-
versial for some time, now has been proved by synthesis.^
The dibenzofurans are formed from 2 moles of the ace-
tate-derived resorcinolic substances typical of lichens.
Results of chemical experiments, including the method of
synthesis of usnic acid, make it quite probable that phenol
coupling of the sort mentioned in connection with dep-
sides and depsidones also is involved here.-' ^ Thus,
* T. Akazawa, Arch. Biochem. and Biophys. 90 82 (1960).
1 D. H. R. Barton, A. M. Deflorin, O. E. Edwards and J. B. Hen-
drickson, Chem. and Ind., 1670 (1955).
2 D. H. R. Barton and T. Cohen, Festschr. Arthur Stoll, 117 (1957).
^ Holger Erdtman and Carl Axel Wachtmeister, ibid., 144 (1957).
401
Dibenzofurans and Related Substances
dydymic acid would be formed by coupling of two similar
orsellinic acids:
CH3CH,CH2 ^^^^ CHaCH,CH,CH,CH, ^^^^
I COOH I COOH
+
HO
OH
HO
OH
CH3CH2CH2
P^
OH
I
CO
CH2CH2CH2CH2CH
0|0
H
COOH
OH
HvCsl^^ CaHu^QQ^
HO
H7C3
C5H11
H7C3
CsHii
COOH
HO
And in the case of usnic acid:
COOH
OH CH3O O OH
Didymic Acid
H H
O O
CH3I COCH3 CH3
+
HO I '-^ O
COCH3 H
%.
HO I OH O
COCH3 H
i
H H H H
00 00
CH3 I CH,! COCH3 CH3 I r»J COCH3
" ' — H2O ^ ' " '
COCH3
Usnic Acid
HO I O
COCH3 H
Pfizer Handbook of Microbial Metabolites
402
Formation of the monobenzofuran shown also may in-
volve phenol coupling, if not precisely as indicated at least
in the same general fashion:
Apparently, many lichens contain an enzyme system
which can promote phenolic coupling of this type. Nei-
ther the dibenzofurans nor the depsides and depsidones
are produced by molds alone (although some of their
resorcinolic precursors are), and the algal partners must
be required in the coupling process.
856 Strepsilin, C15H10O5, colorless crystals, m.p. 324°.
Cladonia strepsilis Wain.
Shoji Shibata, 7- Pharm. Soc. Japan 64 20 (1944).
ture)
( Struc-
403 Dibenzofurans and Related Substances
857 Porphyrilic Acid, C,,;H,o07, colorless needles, m.p. 280-283°
(dec).
O—CH... OH
CH.> X I
HO ' ^"3
COOH
Haematomma coccineum (Dicks.), H. porphyrium
(Pers.)
Porphyrilic acid occurs together with Z-usnic acid and
atranorin.
Carl Axel Wachtmeister, Acta Chem. Scand. 10 1404
(1956). (Structure)
858 2-(6-Hydroxy-2-inethoxy-3,4-methylenedioxyphenyl)-benzofuran,
CieHioOg, colorless crystals, m.p. 118°.
Yeast
A yield of 0.5-2.0 mg. per pound of bakers' yeast was
reported.
M. A. P. Meisinger, Frederick A. Kuehl, Jr., E. L. Rickes,
Norman G. Brink, Karl Folkers, Martin Forbes, Friederich
Zilliken and Paul Gyorgy, J. Am. Chem. Soc. 81 4979 (1959).
(Structure)
859 Pannaric Acid, CigHioO;, colorless needles, m.p. 243-245°.
OH CH3 ^^^^
COOH
COOH
Crocynea membranacea (Dicks.) Zahlbr. = Pannaria
lanuginosa Ach.
O. Hesse, /. prakt. Chem. 70 1 (1904). (Isolation)
Pfizer Handbook of Microbial Metabolites 404
Akermark H. Erdtman and C. A. Wachtmeister, Acta Chem.
Scand. 13 1855 (1959). (Structure)
860 d- and MJsnic Acid, CjsHieOj, yellow crystals, m.p. 203°, [ixW
(d-form) +492°, (Z-form) -495°. M.p. d,Z-form 195°.
CH3
Usnea, Alectoria, Ramalina, Evernia, Cetraria, Parmelia,
Cladonia, Lecanora and Haematormna species (most yel-
low lichens). Long known.
Both d- and Z-forms occur in lichens. Relatively high
yields are available from some species.
Clemens Schdpf and Friedrich Ross, Naturivissenschaften
26 772 (1938).
Idem., Ann. 546 1 (1941). (Structure)
D. H. R. Barton, A. M. Deflorin, O. E. Edwards and J. B.
Hendrickson, Chem. and Ind., 1670 (1955). (Synthesis)
861 Didymic Acid (Incrassatic Acid), C22H26O5, colorless crystals,
m.p. 172°.
C3H7 C5H11 _^_,,
I I COOH
CH3O OH
Cladonia species (occurs together with squamatic and
barbatic acids)
Yasuhiko Asahina and Masaru Aoki, /. Pharm. Soc. Japan
64 41 (1944).
C. PYRANS AND RELATED SUBSTANCES
The y-Pyrones and Patulin
The biosynthesis of patulin was discussed in the intro-
duction to the chapter on phenolic substances.
Kojic acid has long attracted interest because it is pro-
duced in such high yields by certain Aspergillus species.
Within the past few years isokojic acid and several other
related y-pyrones have been isolated from Gluconoaceto-
bacter cultures.
405 Ppans and Related Substances
The fungi are able to use pentose and triose substfates
as well as glucose, although labeling studies have shown
conversion of glucose to kojic acid without cleavage of
the 6-carbon chain. ^
Gluconoacetobacter liquefaciens seems to be more se-
lective in its substrate and uses only glucose, gluconate
and 2-ketogluconate. The variety of y-pyrones produced
is useful in deducing the kind of intermediate involved.
The foregoing considerations plus the isolation of 2,5-
diketogluconic acid from cultures of this bacterium have
led to formulation of the following biosynthetic route to
the pyrones produced by Gluconoacetobacter liquefaciens:'^
CH2OH CH2OH
I I
c — o c — o
H /I \ H H /I \
1/ H \i -2H IX H \ +H2O
c c > c c=o >
|\ OH H /| |\ OH H
HO \| 1/ OH HO \|
c — c c — c
II II
H OH H OH
Glucopyranose Gluconolactone
CH2OH
I
C— OH
H yi OH
IX H I -2H
,C c=o
^\\ OH
-2H HO \|
C—
I
H O
2-Ketogluconic Acid
H OH
Gluconic Acid
H OH
5-Ketogluconic Acid
1 H. R. V. Arnstein and R. Bentley, Biochem. J. 62 403 (1956).
^ Ko Aida, Mitsuko Fujii and Toshinobu Asai, Bull. Agr. Chem.
Soc. (Japan) 21 30 (1957).
Pfizer Handbook of Microbial Metabolites
406
HO
HO
CH2OH
I
c=o
OH
J
c — c
OH
c=o
H O
2, 5-Diketogluconic Add
o=c
CHOH
C OH
H / OH
— 2H^
— H2O
c=o
OH
C— C
OH
Enol Form
-2H,0
o=c
OH H
|- I
OH H
1 I
c=c
OH COOH
Rubiginic Acid
— CO2
OH H
I I
c=c
1 I
OH H
Rubiginol
o=c
c=c
1 1
H COOH
Comenic Acid
407
Pyrans and Related Substances
Another bacterial species, Gluconoacetobacter roseum,
studied by the Japanese, produces kojic and isokojic acids
and only from a fructose, sucrose or mannitol substrate.
The two products are always found together. The pro-
posed route by which these two pyrones are formed from
fructose by Gluconoacetobacter roseum is shown below :^
CH:OH CH2OH CHOH CHO
HOCH
HOCH
j
HCOH
HCOH
CH.OH
Mannitol
CO
2H HOCH
HCOH
HCOH
CH2OH
Fructose
COH CO
I I
HOCH — 2H HOCH
HCOH HCOH
HCOH
CH2OH
Enol Form
HCOH
CHjOH
Glucosone
CHOH
I
COH
II
COH
I
HCOH
HC
CH2OH
CH2OH
CH2OH CH2OH
Kojic Acid Isokojic Acid
Kojic acid is potentially an inexpensive chemical be-
cause of high yields from aspergilH.
862 Rubiginol, C5H4O4, colorless plates, m.p. 203.5°.
O
HO
OH
^O
Gluconoacetobacter liquefaciens
A yield of 1.2 g. of rubiginol from 140 g. of glucose sub-
strate was reported.
Ko Aida, /. Gen. and Appl. Microbiol. (Japan) 1 30 (1955).
^ Ko Aida, Mitsuko Fujii and Toshinobu Asai, Proc. Japan Acad.
32 595 (1956).
Pfizer Handbook of Microbial Metabolites 408
863 Comenic Acid, CgH^Oj, colorless plates, m.p. 276° (dec.)-
HO ?
COOH
Gluconoacetobacter liquefaciens
A yield of 1.1 g. from 140 g. of glucose has been re-
ported.
Ko Aida, Bull. Agr. Chem. Soc. (Japan) 19 97 (1955).
864 Rubiginic Acid, C6H4O6, colorless needles, m.p. 230° (dec).
)
V
HO II OH
COOH
Gluconoacetobacter liquefaciens
Ko Alda, Bull. Agr. Chem. Soc. (Japan) 19 97 (1955).
865 Kojic Acid, C6H6O4, colorless prisms, m.p. 152°.
HO ?
CH2OH
Aspergillus fiavus, A. oryzae, A. tamarii, A. glaucus,
Gluconoacetobacter roseum (fructose substrate)
High yields (45 g. or more per 100 g. of glucose sub-
strate) are produced by some aspergillus strains.
Leland A. Underkofler and Richard J. Hickey, "Industrial
Fermentations," Chemical Publishing Co., Inc., New York,
1954 Vol. "II, Lewis B. Lockwood, Ketogenic fermentation proc-
esses, chap. 1, pp. 19-20. (A review)
Andrew Bielik, Advances in Carbohydrate Chem. 11 145
(1956). (A review)
866 Isokojic Acid, C6H6O4, colorless plates, m.p. 183°.
O
HO CH2OH
409 Pyrans and Related Substances
Gliiconoacetobacter roseum (fructose substrate) -
Isokojic acid was produced together with kojic acid and
an unidentified substance.
Ko Aida, Mitsuko Fujii and Toshinobu Asai, Proc. Japan.
Acad. 32 600 (1956).
867 Patulin (Clavacin, Clavatin, Claviformin, Penicidin, Expansine,
Mycoin), C7H6O4, colorless crystals, m.p. 111°.
O
o
I
OH
Penicillium patuhnn Bainier (P. urticae), P. griseo-
fulvum, P. claviforme, P. expansum, P. melinii, P. equi-
num, P. novae-zeelandiae, P. leucopus, Aspergillus clava-
tus, A. terreus, A. giganteus, Gymrioascus spp.
H. W. Florey, E. Chain, N. G. Heatley, M. A. Jennings,
A. G. Sanders, E. P. Abraham and M. E. Florey, "Antibiotics,"
Oxford University Press, London, 1949, pp. 223-272. (Re-
views earher work)
R. B. Woodward and Gurbakhsh Singh, J. Am. Chem. Soc.
72 1428 (1950). (Synthesis)
868 5-Hydroxy-2-methylchromone, CioHgOa, yellow needles, m.p. 72-
76°.
Proposed structure :
O
CH3
Daldinia concentrica
D. C. Allport and J. D. Bu'Lock, J. Chem. Soc, 654 (1960).
869 5-Hydroxy-2-niethylchromanone, C10H10O3, pale yellow needles,
m.p. 30-33°.
OH O
CH3
Daldinia concentrica
D. C. AUport and J. D. Bu'Lock, /. Chem. Soc, 654 (1960).
Pfizer Handbook of Microbial Metabolites 410
870 Aureothin, C20H23O6N, yellow crystals, m.p. 158°.
CH3 O
OzH—^y-QH^C—CH^C CH2' '
OCH3
Streptomyces thioluteus
Aureothin occurs as a by-product in the aureothricin
fermentation.
Kenji Maeda, /. Antibiotics (Japan) 6A 137 (1953). (Iso-
lation)
Y. Hirata, H. Nakata and K. Yamada, /. Chem. Soc. Japan
79 1390 (1958) and preceding papers. (Structure)
QuiNONOiD Compounds.
This section includes a group of colored compounds,
many of which have chromophores resembling those of
quinones. These unusual substances presented some
interesting structural problems. In many cases there
was a long time interval between isolation and complete
structure determination.
The relationship between fulvic acid and citromycetin
is obvious. The relationship of both of these compounds
to fusarubin has been pointed out recently.^ This is less
obvious, but a precursor such as (I) was envisaged for all
three compounds, the formation of fusarubin involving
ring closure at the dotted line.
Penicillium griseofulvum, which is one of the producers
^ F. M. Dean, R. A. Eade, R. A. Moubasher and A. Robertson, Na-
ture 179 366 (1957).
411 Pyrans and Related Substances
of fulvic acid, also produces a variety of other metabolites,
including griseofulvin and mycelianamide. There seems
to be no close relationship between these compounds and
the three mentioned above, however.
The biosyntheses of sclerotiorin,-' citromycetin- and cit-
rinin-' -^ have been investigated by using C'^-labeled ace-
tate, formate and methionine.
The two studies of citrinin (III) were in agreement, the
results of both indicating origin from a 10-carbon atom
polyketomethylene chain in the sense of (II).
C COOH
/ \ / 11 OH
CH2 CH.2 HOOC 1 ,
+3 C-atoms \i^;^'^'^3-^^^r\
0 0 > I \ ^
ti II ^ Q
c I I o^VSAch
/ \ / \ / \ CH3 CHs ,0"
0 CH2 CH- CH3 12 13
The carbon atoms 11, 12 and 13 in (III) were contrib-
uted by methionine or formate.
Sclerotiorin also is acetate derived with contribution of
three carbon atoms by formate.
Citromycetin (V) is derived entirely from seven acetic
acid units, CH3— COOH (CH3— COOH) and yields the
labeUng pattern shown below.
It would appear that purpurogenone should also be de-
rived from seven acetate units.
- A. J. Birch, P. Fitton, E. Pride, A. J. Ryan, Herchel Smith and
W. B. Whalley, /. Chem. Soc, 4576 (1958).
^ Erwin Schwenk, George J. Alexander, Allen M. Gold and Dean F.
Stevens, ;. Biol. Chem. 233 1211 (1958).
Pfizer Handbook of Microbial Metabolites
412
871 Radicinin,* CjoHioOa, yellow crystals, m.p. 220° (dec), [aW
-217.4° (c "2.37 in pyridine).
Proposed partial structure:
— -CH3
=0 -'"
Stemphylium radicinum Sterad (formerly Alternaria
radicina)
D. D. Clarke and F. F. Nord, Arch. Biochem. and Biophys.
59 269, 285 (1955).
872 Citrinin, C13H14O5, long yellow prisms, m.p. 179° (dec), [aW
-34.5° (c 0.60 in alcohol).
HOOC
Penicillium citrinum, P. expansum, P. implicatum,
P. chrzaszszi, P. citreo-sulfuratum, P. lividum, P. phaeo-
janthinellum, Aspergillus terreus, A. candidus, A. niveus
A. C. Hetherington and H. Raistrick, Trans. Roy. Soc. (Lon-
don) B220 269 (1931). (Isolation)
D. H. Johnson, Alexander Robertson and W. B. Whalley,
J. Chem. Soc, 2971 (1950).
H. H. Warren, Gregg Dougherty and Everett S. Wallis,
J. Am. Chem. Soc. 71 3422 (1949). (Synthesis)
873 Citromycetin (Frequentic Acid), C14H10O7, lemon yeUow hy-
drated needles, m.p. 283-285° (dec).
See entry 413.
413 Pyrans and Related Substances
Peuicillium frequentans, P. roseo-purpurogenum, P. gla-
brum, P. pfefferianuvi, Citromyces strains, Corynebacte-
rium diphtheriae
A. C. Hetherington and H. Raistrick, Trans. Roy. Soc. (Lon-
don) B220 209 (1931). (Isolation)
Alexander Robertson, W. B. Whalley and J. Yates, /. Chem.
Soc, 2013 (1951). (Structure)
Michizo Asano and Hideo Takahashi, /. Pharm. Soc. Japan
65 81 (1945). (Isolation from the corynebacterium )
874 Purpurogenone, Ci4H]oO,r,, crimson prisms, m.p. 310° (dec).
OH OH
Penicillium purpurogenum StoU
Yield 8-14 g. of crude pigment from about 250 g. of dry
mycelium, which was obtained from about 70 liters of
culture solution.
Ergosteryl palmitate, m.p. 104-106°, and mannitol,
m.p. 166°, also were isolated from this fermentation.
John C. Roberts and C. W. H. Warren, ]. Chem. Soc, 2992
(1955).
875 Fulvic Acid, C14H12OS, yellow crystals, m.p. 246° (dec).
HO OH
Penicillium flexuosum, P. brefeldianum, P. griseofulvum
876 P. griseofulvum produced a nitrogen-containing com-
pound, m.p. 165°, in the same broth. P. brefeldianum,
877 produced a neutral nitrogen-containing compound, m.p.
132-135°, in the same culture.
Albert Edw. Oxford, Harold Raistrick and Paul Simonart,
Biochem. J. 29 1102 (1935). (Isolation)
F. M. Dean, R. A. Eade, R. A. Moubasher and A. Robertson,
Nature 179 366 (1957). (Structure)
Pfizer Handbook of Microbial Metabolites
414
878 Fuscin, CisHipOg, orange plates, m.p. 230°.
O
CH3
.0
HO
-^N^N CH3
CH3
879
Oidiodendron fuscum Robak
A colorless dihydrofuscin, m.p. 206°, was also produced.
S. E. Michael, Biochem. J. 43 528 (1948). (Isolation)
D. H. R. Barton and J. B. Hendrickson, J. Chem. Soc, 1028
(1956). (Synthesis)
Azaphilones.
This group of mold pigments, so named because most of
them react avidly with ammonia, includes monascorubrin,
sclerotiorin, rotiorin, rubropunctatin and monascin.
A. Powell, A. Robertson and W. Whalley, "Chemical Society
Symposia," Special Publication No. 5, The Chemical Society,
London, 1956, p. 27. (Survey of the chemistry of the azaphi-
lones to that date)
880 Rubropunctatin, C2iHo^0-,, orange needles, m.p. 156.5° (dec),
[a],. -3481° "(c 1.07 in chloroform).
CH3CH2CH,CH,CH2— C=0
I
* CH3\
CH=CH— CHa
0=Cs
Monascus rubropunctatus Sato
E. J. Haws, J. S. E. Holker, A. Kelly, A. D. G. Powell and
Alexander Robertson, /. Chem. Soc, 3598 (1959). (Structure)
A. Powell, Dissertation, Liverpool, 1954. (Isolation)
881 Sclerotiorin, CoiHooO-.Cl, yellow crystals, m.p. 206° [a]„ +500°.
CI CH3 CH3
CHs— C
CH2CH3
415
Pyrans and Related Substances
Penicilliiim sclerotiorum van Beyma, P. multicolor
G.M.P.. P. iiuplicatuui Biourgc
Timothy P. MacCurtin and Joseph Reilly, Biochem. J. 34
1419 (1940). (Isolation)
H. C. Fielding, Alexander Robertson, R. B. Traners and
W. B. WhaUey, /. Chem. Soc, 1814 (1958).
F. M. Dean, J. Staunton and W. B. Whalley, ibid., 3004
(1959). (Structure)
882 Monascin, Co,Ho,;05, yellow crystals, m.p. 142°, [a]v +544°.
Monasciis rubriginosiis Sato, M. piirpureus Wentii,
M. rubropunctatus Sato
Hidijiro Nishikawa, /. Agr. Chem. Soc. Japan 8 1007
(1932).
H. Solomon and P. Karrer, Helv. Chim. Acta 15 18 (1932).
883 Rotiorin, C23H04O-,, red needles, m.p. 246° (dec.) (sublimes),
[cz]d" +5080° (c 0.002 in chloroform).
Tentative structure:
CH0CH3
Peiiicilliuni sclerotiorum van Beyma
Eight kilograms of dry mycelium yielded 300-350 g.
of sclerotiorin and 100—150 g. of rotiorin.
G. B. Jackinan, Alexander Robertson, R. B. Traners and
W. B. Whalley, /. Chem. Soc, 1825 (1958). (Structure)
884 Monascorubrin, C03H26O-,, orange crystals, m.p. 134-136°,
[alTo,/*" -1500° (c 0.1 in ethanol).
O CH2CH2CH2CH2CH2CH2CH3
M
Monascus purpureus Wentii
Pfizer Handbook of Microbial Metabolites 416
H. Nishikawa, /. Agr. Chem. Soc. Japan 5 1007 (1932).
(Isolation)
K. Nakanishi, M. Ohashi, S. Kumasaki and S. Yamamura,
J. Am. Chem. Soc. 81 6339, 6340 (1959). (Structure)
B. C. Fielding, E. J. Haws, J. S. E. Holker, A. D. G. PoweU,
A. Robertson, D. N. Stanway and W. B. Whalley, Tetrahedron
Letters No. 5 24 (1960). (Proposed revised structure shown)
885 Novobiocin (Streptonivicin, Cathomycln, Albamycin, Sphero-
mycin, Vulcamycin, Crystallinlc Acid, Antibiotic PA-93,
Cardelmycin), C31H36O11N2, pale yellow crystals, m.p.
152-156° (dec.) and 174-178° (dec.) (polymorphic),
[aJD^* -63° (c 1 in ethanol).
HoN— C
Streptomyces spheroides, S. niveus, S. griseus
Herman Hoeksema, James L. Johnson and Jack W. Hin-
man, J. Am. Chem. Soc. 77 6710 (1955).
Jack W. Hinman, Herman Hoeksema, E. Louis Caron and
W. G. Jackson, ibid. 78 1072 (1956).
Clifford H. Shunk, Charles H. Stammer, Edward A. Kaczka,
Edward Walton, Claude F. Spencer, Andrew N. Wilson,
John W. Richter, Frederick W. HoUy and Karl Folkers, ibid.
78 1770 (1956). (Structure)
Herman Hoeksema, E. Louis Caron and Jack W. Hinman,
ibid. 78 2019 (1956). (Structure)
d. XANTHONES
886 Ravenelin, C14H10O5, yellowish crystals, m.p. 267°.
OH O OH
417 Xanthones
Helniinthosporixim ravenelii
F. F. Nord and Robert P. Mull, Advances in Enzymol. 5 194
(1945). (Synthesis)
887 Rubrofusarin, CjsHjoOg, orange-red needles, m.p. 210°.
Alternative structures :
CH3 HO I II I CH3
Or
Fusarium culmorum (W.G.Sm.) Sacc, Fusarium
graminearum Schwabe (Gibberella saubinettii)
888 Another pigment, aurofusarin,* C30H20O10, m.p. >360°
889 and a colorless compound, culmorin, CjgHoeOo, m.p. 175°,
[(x]d^^ —14.45° were isolated from the same cultures.
Julius Nicholson Ashley, Betty Constance Hobbs and Harold
Raistrick, Biochem. J. 31 385 (1937).
Robert P. Mull and F. F. Nord, Arch. Biochem. 4 419 (1944).
(Structure)
890 Asperxanthone, C^oH^^Or^, yellow needles, m.p. 203°. A 1-hy-
droxydimethoxymethylxanthone which yields nor-rubro-
fusarin on demethylation.
Aspergillus niger (mycelium)
N. A. Lund, Alexander Robertson and W. B. Whalley,
J. Chem. Soc, 2434 (1953).
891 Lichexanthone, CieHi405, yellowish crystals, m.p. 187°.
CH3 O OH
CH3O
OCH3
Parmelia formosana Zahlbr.
The yield was about V2 g. from 25 g. of lichen.
Yasuhiko Asahina and Hirashi Nogami, Bull. Chem. Soc.
Japan 17 202 (1942).
See entry 584.
Pfizer Handbook of Microbial Metabolites 418
892 Sterigmatocystin, CigHioOg, pale yellow needles, m.p. 246°
(dec), [aln"-^ -387° (c 0.424 in chloroform).
Probable structure:
Aspergillus versicolor (Vuillemin) Tiraboschi
J. E. Davies, D. Kirkaldy and John C. Roberts, J. Chem. Soc,
2169 (1960). (Structure)
Abou-Zeid, Dissertation, London, 1953. (Isolation)
J. E. Davies, John C. Roberts and S. C. Wallwork, Chem.
and Ind., 178 (1956). (Isolation)
J. H. Birkinshaw and I. M. M. Hammady, Biochem. J. 65
162 (1957). (Isolation)
Yuichi Hatsuda and Shimpei Kuyama, /. Agr. Chem. Soc.
Japan 28 989 (1954). (Chem. Abstr. 50 15,522) (Isolation)
e. COMPOUNDS RELATED TO THIOPHENE,
IMIDAZOLE, THIAZOLE
AND ISOXAZOLE.
Some of the commercially important compounds in this
section are the antibiotics cycloserine and the penicillins
and the vitamins, thiamine and biotin.
Penicillin was discovered by Fleming in 1929, and com-
mercial fermentation techniques were developed during
the second World War. Penicillins with several different
side-chains were found to be produced by various penicil-
lia and aspergilli, and hundreds of unnatural penicillins
were prepared by the addition of side-chain precursors
to fermentations.
It was not until 1959, however, that the nucleus com-
mon to all penicillins, 6-aminopenicillanic acid, was iso-
lated from fermentations.^ This discovery has made pos-
sible the preparation of a new series of penicilUns through
iRoichi Kato, /. Antibiotics (Japan) 6A 130, 184 (1953); F. R.
Batchelor, F. P. Doyle, J. H. C. Nayler and G. N. Rolinson, Nature
183 257 (1959).
419 Thiophenes, Imidazoles, Thiazoles, Isoxazoles
attachment of side-chains by the methods of organic
chemistry.
HOOC— CH N C=0 HOOC— CH N C=0
CH3 I I I CH3 I I I O
C CH CH— NH. C CH CH— NH— C— R
CH3 ^ CH3 ^
6-Aminopenicillanic Acid Penicillins
Since 6-aminopenicillanic acid can be isolated from
penicillin fermentations in good yields, it is probably an
intermediate. Also, the fact that side-chain precursors
are so readily incorporated into the molecule indicates
attachment of the side-chain to be the final step in peni-
cillin biosynthesis. This is also known to be the rate-lim-
iting step, and, even in commercial fermentations, side-
chain precursors are added routinely.
The precursors of the 6-aminopenicillanic acid nucleus
have been show^n to be (stereospecifically) L-cysteine- and
L-valine,'^ although additions of these amino acids to fer-
mentations do not cause dramatic improvements in yields
or in rates of synthesis. Degradation studies have shown
that L-cysteine occurs in the same configuration after in-
corporation into the penicillin molecule, while valine has
been converted to the o-form. Aside from the change in
configuration of valine, both amino acids are incorporated
intact.
Other substances have been considered as penicillin
precursors and intermediates. Among them are peni-
cillamine,^ y8-hydroxy valine,^ serine,- glycine,- homocys-
2H. R. V. Arnsteln and P. T. Grant, Biochem. J. 57 353, 360
(1954); H. R. V. Arnsteln and J. C. Crawhall, ibid. 67 180 (1957);
Carl M. Stevens, Edward Inamine and Chester W. Belong, /. Biol.
Chem. 219 405 (1956); H. R. V. Arnsteln and H. Margreiter, Bio-
chem. J. 68 339 (1958); F. H. Grau and W. J. Halliday, ibid. 69 205
(1957).
^H. R. V. Arnsteln and Margaret E. Clubb, ibid. 65 618 (1957);
Carl M. Stevens and Chester W. Belong, /. Biol. Chem. 230 991
(1958).
* Carl M. Stevens, Pran Vohra, Edward Inamine and Oliver A.
Rohoh, Jr., ibid. 205 1001 (1953).
Pfizer Handbook of Microbial Metabolites
420
teine,'' methionine,* glutathione* and acetate. Some of
these rejected intermediates are shown:
HO
HO— C=0
\
HOOC— CH— NH2
1
HOOC— CH— NH2 C=0
CH3
+
CH— NH2 -
■> CH3 1
\
/
\ CH2— CH— NH
c
HOCH2
c /
/\
/ \s/
CHs ^
CH3 SH
Penicillamine
Serine
(3, i3-Dimethyllantliionine
HOOC— CH— NH2
HO
1
HO— C=0
\
CH2
1
HOOC— CH— NH2 C=0
1
+
CH— NH2 -
1 1
CH2
/
CH2 CH2— CH— NH
\
HOCH2
1 /
SH
CH2— S
Homocysteine
Serine
Cystathionine
HO
HOOC— CH— NH2
HO— C=0
HOOC— CH— NH2 \
CH3
1
CH3 c=o
\
+
CH— NHo -
\ 1
C
/
C CH2— CH— NH2
/\
HS— CH2
CH3 ^
CH3 OH
/3-Hydrox
yvoline
Cysteine
j3, /S-Dimethyilanthionine
Lanthionine and /?-methyllanthionine occur in several
other polypeptide antibiotics (subtilin, duramycin, cinna-
mycin, nisins). Certain of these compounds are incor-
porated to some extent, but only indirectly.
Some evidence is being accumulated concerning the
actual peptide intermediate. The dipeptide L-cystinyl-
L-(COOH — C^*) valine is a better penicillin precursor than
L-(COOH — C'*) valine alone, while the reverse is true for
protein synthesis.*' (L-Cystine can be reduced to L-cys-
teine by the mold.)
HOOC— CH— CH2— S
I
NHo
S— CH2— CH— CO— NH— CH— COOH
I 1
NH2 CH
CHs CHs
L-CystinyI-L-(COOH— C'^) valine
^ Carl M. Stevens, Pran Vohra, Joseph E. Moore and Chester W.
DeLong, ibid. 210 713 (1954).
6 H. R. V. Arnsteln and D. Morris, Biochem. ]. 71 8p (1959).
421 Thiophenes, Imidazoles, Thiazoles, Isoxazoles
The same research group (Arnstein and collaborators)
has isolated a tripeptide from the mycelium of the com-
mercial penicillin producer, Penicillium chrysogennmJ
It is 8-(a-aminoadipyl) cysteinylvaline:
HOOC— CH— CH.— CH.— CH2— CO— NH— CH— CO— NH— CH— COOH
NH.> CH2SH CH
/ \
CH3 CH3
5-(a-Aminoadipyl) cysteinylvaline
Consistent with the above evidence, this is a cysteinyl-
valine. It is not difficult to envisage cyclization to form
synnematin B:
HOOC— CH NH C=0
CH3 1 I O
\l I II
CH CH2— CH— NH— C— CH2— CH2— CH2— CH— COOH
/ / I
CH3 S NH2
H
., — 4H
HOOC— CH NH C=0
CH3 I I I O
\l I I II
CH CH CH— NH— C— CH2— CH2— CH2— CH— COOH
CH3 ^ NH2
Interesting features of this discovery are, first, that a
side-chain is attached before cyclization to form 6-ami-
nopenicillanic acid and, second, that the side-chain is
a-aminoadipic acid, the side-chain of synnematin B (ceph-
alosporin N) which is not produced by Penicillium chrys-
ogenum. Perhaps side-chain exchange occurs after cy-
clization. The configurations of the amino acids in the
acyclic mycelial peptide have not been reported yet.
The structure of cephalosporin C, a substance related
to synnematin B, is known, but has not yet been pub-
lished.
Two reviews of the biosynthesis of penicillin are
cited.s '->
"^ H. R. V. Arnstein, D. Morris and E. Toms, Biochim. et Biophys.
Acta 35 561 (1959).
® A. L. Demain, Advances in Appl. Microbiol. 1 23 (1959).
®D. Hockenhull, Prog, in Ind. Microbiol. 1 1 (1959).
Pfizer Handbook of Microbial Metabolites 422
Cycloserine (oxamycin) appears to be a cyclized D-ser-
ine amide or hydroxamide. As mentioned elsewhere it
is known to inhibit the incorporation of D-alanyl-D-alanine
into the cell walls of certain bacteria.
Thiamine is an enzyme prosthetic group of fundamen-
tal importance, probably occurring in all living things.
Many microorganisms are capable of de novo synthesis,
although the vitamin is required in mammalian diets.
Some microorganisms incapable of total synthesis can
couple certain pyrimidine and thiazole precursors, others
require only one of the heterocycles preformed, and cer-
tain yeasts have a requirement for thiamine itself.
Beyond this little is known about the biosynthesis of
thiamine. Other naturally occurring thiazoles (e.g. those
in certain antibiotics) are known to be derivatives of
cysteine. Nakayama has proposed the general scheme :^°
Cysteine -^ Thiazolidine-4-carboxylic Acid — > 4-Methylthiazoie — >
4-Methyl-5-(2-hydroxyethyl)-thiazole
on the basis of work with mutants. Some work has been
done on the biosynthesis of other pyrimidines, but appar-
ently little on the thiamine constituent.
Bacillus subtilis incorporates formate C^* extensively
into the pyrimidine, but not the thiazole moiety of thia-
mines^ In this bacterium the pyrimidine moiety of thia-
mine restores growth and formate incorporation into
purines and thymine in amethopterin treated cultures.
The thiazole part restores thiamine synthesis, but does
not show the additional effects.
It appears now that all enzymes in which thiamine is
the active site have the function of decarboxylating a-ke-
toacids and of cleaving a-diketones or a-hydroxyketones.
These functions were illustrated in an earlier section.
Thiamine, unphosphorylated and detached from its
apoenzyme, is capable of carrying out some of its coen-
zyme functions in vitro under favorable conditions. ^-^ ^^' ^^
"Hideo Nakayama, Vitamins (Japan) 11 20, 169 (1956).
SI Martin J. Pine and Robert Guthrie, J. Bacterial. 78 545 (1959).
s- Shunzi Mizuhara and Philip Handler, /. Am. Chem. Soc. 76 571
(1954).
" Emeteria Yatco-Manzo, Frances Roddy, Ralph G. Yount and
David E. Metzler, /. Biol. Chem. 234 733 (1959).
"Ralph G. Yount and David E. Metzler, ibid. 234 738 (1959).
423 Thiophenes, Imidazoles, Thiazoles, Isoxazoles
By selective synthetic substitutions with blocking groups
at various positions in the two heterocycles, the active site
of the molecule has been located as the 2-position of the
thiazole ring.'^' '" It is here that pyruvic acid, for ex-
ample, is decarboxylated to form (still in combination
with thiamine pyrophosphate) "active acetaldehyde" and
a-ketoglutaric acid to form "active succinate." The active
acetaldehyde intermediate was shown in Section 2. It is
claimed that this intermediate has been isolated from
Escherichia coli.'^'^''
A thorough review of thiamine is available.^"
For more than 20 years biotin has been recognized as
a dietary requirement in higher animals and yeasts. It
was formerly called vitamin H, and animal deficiencies
could be induced by feeding raw egg-white. This contains
a protein, avidin, which complexes tightly enough with
biotin to cause avitaminosis.
The biochemical function and mode of action of biotin
long remained obscure. It is now known to be a cocar-
boxylase or coenzyme component for the transfer of car-
bon dioxide. Some of the reactions which it catalyzes
are:
CH3— C— COOH ^ HOOC— CHo— C— COOH is, 19, 20, 21
Pyruvic Acid Oxaloacetic Acid
HOOC— CH— CHo— CH2—CH2—NH2
I
NHo
Ornithine
HOOC— CH—CH2—CH2— CHo— NH—C—NH2 22, 23
NH2
Citrulline
"Ronald Breslow, /. Am. Chem. Soc. 79 1762 (1957); 80 3719
(1958).
^•^ Ronald Breslow and Edward McNeils, ibid. 81 3080 (1959).
i«" Gerald L. Carlson and Gene M. Brown, /. Biol. Chem. 235 PC3
(1960).
^' Paul D. Boyer, Henry Lardy and Karl Myrback (Eds.), "The
Enzymes" Academic Press, New York, 1960 Vol. II, David E. Metzler,
Thiamine coenzymes, pp. 295-337.
^* Henry A. Lardy, Richard L. Potter and C. A. Elvehjem, J. Biol.
Chem. 169 541 (1947).
Pfizer Handbook of Microbial Metabolites 424
O O
II II
CH3— C=CH— C— CoA ^ HOOC— CH2— C=CH— C— CoA 24, 25
CH3 CH3
/3-Methylcrotonyl CoA /3-Methylglutaconyl CoA
o o
II II
CH3CH2C— CoA ;:± HOOC— CH2—CH2—C— CoA
Propionyl CoA Succinyl CoA
26.27
COOH 28, 29
I
CH2 o
/N I H /-
HC^ \ CH— N— C
II CH aspartic acid | \ ^j
C\,/ — -p >COOH C-^X
/ V CO2 II CH
Ribose phosphate / N
Ribose phosphate
(Intermediates in purine biosynthesis)
O O 30
II II
CH3— C— CoA ;;::± HOOC— CH2—C— CoA
Acetyi-CoA Malonyl-CoA
1^ William Shive and Lorene Lane Rogers, ibid. 169 453 (1947).
20 Herman C. Lichstein and W. W. Umbreit, ibid. 170 329 (1947).
21 Henry A. Lardy, Richard L. Potter and R. H. Burris, ibid. 179 721
(1949).
22 Patricia R. MacLeod, Santiago Grisolia, Philip P. Cohen and
Henry A. Lardy, ibid. 180 1003 (1949).
"3 Gladys Feldott and Henry A. Lardy, ibid. 192 447 (1951 ).
2* Bimal K. Bachhawat, Wm. G. Robinson and Minor J. Coon,
;. Am. Chem. Soc. 76 3098 (1954); idem., J. Biol. Chem. 219 539
(1956).
^^ F. Lynen, J. Knappe, E. Lorch, G. Jutting and E. Ringelmann,
Angew. Chem. 71 481 (1959).
'*^ Henry A. Lardy and Robert Peanasky, Physiol. Rev. 33 560
(1953).
-' Henry A. Lardy and Julius Adler, /. Biol. Chem. 219 933 (1956).
28 Patricia R. MacLeod and Henry A. Lardy, ibid. 179 733 (1949).
2^ Albert G. Moat, Charles N. Wilkins, Jr. and Herman Friedman,
ibid. 223 985 (1956); Albert G. Moat and Floyd Nasuti, Federation
Proc. 19 313 (1960).
425 Thiophenes, Imidazoles, Thiazoles, Isoxazoles
The mode of action of biotin is known now in enough
detail to suggest the scheme outUned below. It is still un-
certain which nitrogen atom of the biotin molecule par-
ticipates.-"^
O
II
/\
HN NH
I I ATP
HC CH >
HoC CH—(CH..)4— COO— Enzyme
o
II
o o
T r
Adenosine— O—P—O—P N NH
OH OH HC CH
CH2 CH—(CH2)4— COO— Enzyme
or
O O
T T
Adenosine — O — P — O — P O
OH OH
i
O o
II II
©O N NH
R I I
R— COOH < HC CH
HN N
I I
HC CH
I I
CH2 CH—{CH2)4— COO— Enzyme
I CO2
H2C CH—{CH2)4— COO— Enzyme
^^Salih J. Wakil, Edward B. Titchener and David M. Gibson,
Biochim. et Biophys. Acta 29 225 (1958); Salih J. Wakil, /. Am.
Chem. Soc. 80 6465 (1958).
Pfizer Handbook of Microbial Metabolites 426
It is probable that biotin is attached to the enzyme in an
amide linkage, perhaps at the t-amino group of a lysine
unit. Evidence indicates that a variety of apoenzymes
can use biotin as the prosthetic group in reversible carbon
dioxide transfer just as a variety of apoenzymes can use
riboflavin in reversible hydrogen transfer.
Biocytin is a biotin-lysine conjugate isolated from con-
trolled autolysates of yeast cells. ^^' ^^
HN NH
1 1
HC CH O
1 I II
H2C CH— (CH2)4— C— NH— (CH2)4— CH— COOH
NH2
Biocytin
O
II
.Cx
o
\
HN NH C NH
CH CH CH2 CH— (CH2)5— COOH
1 I \c/
CH3 CH2— (CH2)4— COOH ^
Dethiobiotin Actithiazic Acid
It is better utilized by some microorganisms than is biotin
itself.
Actithiazic acid is a biotin antimetabolite.
The biosynthetic origin of biotin remains obscure. Pi-
melic acid is an effective precursor in biotin-producing
organisms. Dethiobiotin is produced by a Penicillium
chrysogehum mutant, and it may be an intermediate in
the biosynthetic scheme at least in this and probably in
other microorganisms.^^
^^ Lemuel D. Wright, Emlen L. Cresson, Helen R. Skeggs, Thomas
R. Wood, Robert L. Peck, Donald E. Wolf and Karl Folkers, ibid. 74
1996 (1952).
■^- Donald E. Wolf, John Valiant, Robert L. Peck and Karl Folkers,
ibid. 74 2002 (1952).
3'' E. L. Tatum, /. Biol. Chem. 160 455 (1945).
427 Thiophenes, Imidazoles, Thiazoles, Isoxazoles
Junipal appears to be related to the acetylenic* sub-
stances typical of basidiomycetes which were listed in an
earlier section. In some way sulfur seems to have been
added, in effect across two acetylenic bonds to form a
thiophene ring. It has been suggested" that junipal and
anisaldehyde, occurring in the same culture and with the
same number of carbon atoms, may be derivatives of a
common acetylenic aldehyde precursor, perhaps C7H4O:
CHO
HC = C— C = C— CH=CH— CHO
CHO
OCH
Azomycin seems to incorporate a modified guanidine
group.
893 Azomycin (2-Nitroimidazole), C3H3O2N3, white needles, m.p.
283° (dec).
N NH
I
N02
Nocardia sp. resembling N. mesenterica
Shoshlro Nakamura and Hamao Umezawa, /. Antibiotics
(Japan) 8A 66 (1955) and other papers in this series.
894 Oxamycin (Cycloserine, Orientomycin D-4-Amino-3-isoxazoli-
done, PA-94), CsHgOoNo, colorless crystals, m.p. 156°
(dec), [a]546i 25° +137° ±2° (c 5 in 2 N sodium hydrox-
ide).
CH2 CH— NH2
I I
o c=o
H
Streptomyces garyphalus, S. orchidaceus, S. lavendulae,
S. nagasakiensie nov. sp., S. K-300, etc.
^-i J. H. Birkinshaw and P. Chaplen, Biochem. J. 60 255 (1955).
Pfizer Handbook of Microbial Metabolites 428
Dale A. Harris, Myrle Ruger, Mary Ann Reagan, Frank J.
Wolf, Robert L. Peck, Hyman Wallick and H. Boyd Woodruff,
Antibiotics and Chemotherapy 5 183 (1955).
Roger L. Harned, Phil Harter Hidy and Eleanore Kropp
LaBaw, ibid. 5 204 (1955).
Charles H. Stammer, Andrew N. Wilson, Claude F. Spencer,
Frank W. Bachelor, Frederick W. Holly and Karl Folkers, J.
Am. Chem. Soc. 79 3236 (1957). (Synthesis)
895 Junipal, CgHfiOS, thick, colorless needles, m.p. 80°.
HC CH
II II
CH3— C = C— C C— CHO
Daedalea juniperina Murr.
J. H. Birkinshaw and P. Chaplen, Biochem. J. 60 255
(1955).
896 6-Methoxybenzoxazolidone, CgHyOgN, red crystals, m.p. 154°.
V
CH3O o
c=o
Ustilago maydis (spores)
The same compound has been isolated from young com
plants.
P. H. List, Arch. Pharm. 292 452 (1959).
897 6-Aminopenicillanic Acid, CgHigOgNsS, colorless crystals, m.p.
208° (dec).
HOOC— CH N C=0
CH3 1
CH3
C CH CH— NH2
Penicillium chrysogenum
F. R. Batchelor, F. P. Doyle, J. H. C. Nayler and G. N. Robin-
son, Nature 183 257 (1959).
429
Thiophenes, Imidazoles, Thiazoles, Isoxazoles
898 5-Amino-4-imidazolecarboxamide Riboside, CoHi40r,N4, colorless
crystals, m.p. 213° (dec, previous browning).
II
HOCH
OH OH
Escherichia coli (sulfonamide— inhibited)
G. Robert Greenberg and Edra L. Spilman, /. Biol. Chem.
219 411 (1956).
899 Actithiazic Acid (Acidomycin, Mycobacidin PA-95), CyHigOgNS,
colorless needles, m.p. 140°, [aJD'^ —60° (c 1 in absolute
alcohol).
o=c-
-NH
CH2
CH— CH2CH2CH2CH2CH2COOH
Streptomyces virginiae, S. cinnamonensis, S. lavendu-
lae
Yields of about 0.3 g. per liter have been reported.
Walton E. Grundy, Alma L. Whitman, Elbina G. Rdzok,
Edward J. Rdzok, Marjorie E. Hanes and John C. Sylvester,
Antibiotics and Chemotherapy 2 399 (1952).
J. R. Schenck and A. F. DeRose, Arch. Biochem. and
Biophys. 40 263 (1952).
R. K. Clark, Jr. and J. R. Schenck, ibid. 40 270 (1952).
W. M. McLamore, Walter D. Celmer, Virgil V. Bogert, Frank
C. Pennington and I. A. Solomons, /. Am. Chem. Soc. 74 2946
(1952).
B. A. Sobin, ibid. 74 2947 (1952).
W. M. McLamore, Walter D. Celmer, Virgil V. Bogert, Frank
C. Pennington, B. A. Sobin and I. A. Solomons, ibid. 75 105
(1953). (Synthesis)
Pfizer Handbook of Microbial Metabolites
430
900 Biotin, CjoHifiOaNoS, colorless needles, m.p. 230-232° (dec),
[ale" +92° (c 0.3 in 0.1 N sodium hydroxide).
HN
HC-
NH
-CH
CH2 CH— CHCHiCHoCH-COOH
Torula utilis, other yeasts (occurs also in molds and
bacteria)
Yields of 0.5-3.6 /xg. per gram of dry cell weight are ob-
tained from Torula utilis.
Leland A. Underkofler and Richard J. Hickey, "Industrial
Fermentations," Chemical Pubhshing Co., Inc., New York,
1954 Vol. II, J. M. Van Lanen, Production of vitamins other
than riboflavin, chap. 6, pp. 191-216. (A review)
901 Biotin- 1 -sulfoxide, Ci(,Hic04N2S, colorless crystals, m.p. 238-
243°, [a] I,-" -40° (in 0.1 N sodium hydroxide).
HN NH
CH CH
CH2 CH— CH2CH2CH2CH2COOH
Aspergillus iiiger
Lemuel D. Wright and Emlen L. Cresson, /. Am. Chem. Soc.
76 4156 (1954).
Lemuel D. Wright, Emlen L. Cresson, John Valiant, Don-
ald E. Wolf and Karl Folkers, ibid. 76 4160, 4163 (1954).
(Isolation and characterization)
431 Thiophenes, Imidazoles, Thiazoles, Isoxazoles
902 Dethiobiotin (Desthiobiotin, 5-Methyl-2-oxo-4-imidazolidineca-
proic Acid), C,,,H,,sO;(No, colorless needles, m.p. 156-158°,
[all,-' +10.7° (c 2.0 in water).
HN NH
CHs (CHolsCOOH
Penicillium chrysogenum
E. L. Tatum, 7. Biol. Chem. 160 455 (1945).
903 Thiamin (Vitamin B,, Aneurin) (Chloride Hydrochloride),
Ci.HjsOi\4CLS, colorless needles, m.p. ~250° (dec).
NHoHCI CHs CHoCHoOH
CHo \ /
CI®
Most yeasts, molds and bacteria
Yields of 120-200 /xg. per gram of dry primary-grown
yeast cells can be obtained. Much higher yields (600-
1200 /xg. per gram) can be obtained if all that is required
is coupling of supplied precursors.
Leland A. Underkofler and Richard J. Hickey, "Industrial
Fermentations," Chemical PubHshing Co., Inc., New York,
1954 Vol. II, J. M. Van Lanen Production of vitamins other
than riboflavin, chap. 6, pp. 191-216. (A review)
904 Cocarboxylase (Cozymase II, Vitamin Bi-diphosphate, Thiamin
diphosphate, Aneurindiphosphate) (Hydrochloride),
Ci^HisO-N^SP.-HCl, nearly colorless needles, m.p. 242-
244° (dec).
0
C— CHs O O
CH C— CH2— CH2— O— P— O— P=0
I I
OH OH
Pfizer Handbook of Microbial Metabolites 432
Yeast
K. Lohmann and Ph. Schuster, Biochem. Z. 294 188 (1937).
(Isolation)
Kurt G. Stern and Jesse W. Hofer, Science 85 483 (1937).
(Synthesis)
905 Synnematin-B (Cephalosporin N, Salmotin), C14H21O6N3S, bar-
ium salt, [xW° +187° (c 0.6 in water).
HOOC— CH N— C=0
CH3
\
C CH— CH— NH— CO— CH2— CH2— CH2— CH— COOH
/ \c/ 1
CHs ^ NH2
Cephalosporium salmosynnematum
E. P. Abraham, "CIBA Lectures in Microbiol. Biochemistry,"
Biochemistry of some peptide and steroid antibiotics, John
Wiley and Sons, New York, 1957. (A review)
Natural Penicillins. General formula:
HOOC— CH N C=0
CH3 I II O
C CH CH— NH— C— R
CHs ^
906 Penicillin G, Ci„Hi804N2S, colorless prisms, m.p. (Na salt) 215°
(dec), [aW'-' +305° (c 0.821 in water).
R = Benzyl <f \-CH2
907 Penicillin K, C16H26O4N2S, colorless prisms (Na salt), [aln"'^
+258° (c 0.43 in water).
R = n-Heptyl CHslCHzle"
908 Penicillin X, CkjHisOjNsS, colorless crystals, m.p. (Na salt)
228-235° (dec), [a]v +267° (c 0.525 in water).
R = p-Hydroxybenzyl HO— f y-CH2-
909 Gigantic Acid (Dihydro F), C14H20O4N2S (Na salt), colorless
crystals, m.p. 188° (dec), [czId'' +319° (c 1 in water).
R = n-Amyl CH3(CH2)4~
433 Thiophenes, Imidazoles, Thiazoles, Isoxazoles
910 Penicillin F (Flavicidin, Flavicin) Ci4H.o04N.,S, m.p. (Na salt)
204° (dec), [oc]v-"-' +276-316° (c 0.821 in water).
R = n-Pentenyl CH3CH,— CH=CH— CH2—
The A"-pentenyl variant is also known.
Penicillium species, especially P. chrysogenum and
P. notatum Westling, and aspergillus species, especially
A. fiaviis from which Penicillin F was obtained.
H. Clarke, J. Johnson and R. Robinson, "The Chemistry of
Penicilhn," Princeton University Press, Princeton, 1949. (A
review )
911 Cephalosporin C, proposed molecular formula CigHsiOgNgS, Na
salt: [aW +103°.
Structural features:
Acid hydrolysis yields 1 D-a-aminoadipic acid, 1 CO2
and 2 NH3. No penicillamine is produced in contrast to
cephalosporin N.
Cephalosporium salmosynnematum
G. G. F. Newton and E. P. Abraham, Biochem. J. 62 651
(1956).
912 Biocytin, C16H08O4N4S, colorless crystals, m.p. 228-230° (dec.)
(245-252°).
O
/K
HN NH
I I
CH CH
I I
CH2 CH— (CH2)4— CO— NH— (CH2)4— CH— COOH
^ NH2
Yeast
Lemuel D. Wright, Emlen J. Cresson, Helen R. Skeggs,
Thomas R. Wood, Robert L. Peck, Donald E. Wolf and Karl
Folkers, /. Am. Chem. Soc. 72 1048 (1950). (Isolation)
Robert L. Peck, Donald E. Wolf and Karl Folkers, ibid. 74
1999 (1952). (Structure)
Donald E. Wolf, John Valiant, Robert L. Peck and Karl
Folkers, ibid. 74 1002 (1952). (Synthesis)
Pfizer Handbook of Microbial Metabolites
434
f. PYRROLES, PORPHYRINS AND RELATED COMPOUNDS
Pyrroles occur rather frequently as microorganism me-
tabolites. They are constituents of porphyrins, of vitamin
B^o, of certain bacterial pigments, and of some compounds
which have been considered as antibiotics.
More has been published concerning the biosynthesis
of the complex substances because of their more general
import in biological systems, but it is tempting to specu-
late on the origins of the simpler compounds even though
little evidence is yet available.
Holomycin is the simplest of three similar substances
produced by streptomycetes, although the structures of
aureothricin and thiolutin were determined earlier. The
skeletons of glycine and cysteine are perceptible within
the holomycin molecule, and, superficially, it seems that
a biosynthetic route related to the following might take
place :
NHo
HOOC— CH— CH2 0
1 II
S C— OH
/ 1
S CH
^"2 NHo
~
CH2— NHolCOCHs)
c=o
/
HO
— H2O
Cystine
Glycine
NH2
HOOC— CH— CHo
0
S C— OH CH,— NHzlCOCHs
_ S CH C=0
XH2^ ^NH^
I
NH2
I
HOOC— CH— CH2 O
I II
S C- CH— NH2(COCH3
— H2O
/
\CH2^ \n/
CH C=0
H
II
435 Pyrroles, Porphyrins and Related Compounds
NH..
HOOC— CH— CH, O
S C CH -NHo(COCH3)
S C CO
H
III
/\
S C CH— NH—CO—CH:,
111
CH C C=0 + Serine or Alanine
\ /
H
Holomycin
A glycylcystine intermediate I is reminiscent of the pep-
tide intermediate now implicated in the biosynthesis of
penicillin.^ It is known that there has been some aca-
demic interest in the origin of these compounds, however,
and since no publications have been forthcoming, perhaps
the problem is more complicated.
Pyoluteorin, with a carbonyl group at the two position
of the pyrrole moiety, suggests an origin in the glutamate
-^ prohne pathway, perhaps from 8^-pyrroline-5-carbox-
ylic acid, although the chlorination of the ring may indi-
cate a less obvious derivation. The pyrrohdine moiety of
the plant alkaloid, nicotine, has been shown to be bio-
synthesized from glutamate.-
The origins of prodigiosin and netropsin are not obvious.
Some work has been done on prodigiosin.^ * Glycine-2-C^*
was incorporated into prodigiosin, but 5-aminolevulinic
acid-5-C^* was not.* This apparently distinguishes
the method of biosynthesis from that of the por-
phyrins. Moreover, C^ '-labeled L-proline was found to be
several times more efficient as a prodigiosin precursor in
Serratia marcescens than glycine, while the reverse is
^ H. R. V. Arnstein, D. Morris and E. Toms, Biochim. et Biophys.
Acta 35 561 (1959).
- Thomas Griffith, Kenneth P. Hellman and Richard U. Byerrum,
J. Biol. Chem. 235 800 (1960).
3R. Hubbard and C. Rimlngton, Biochem. J. 46 220 (1950).
^ Gerald S. Marks and Lawrence Bogorad, Proc. Nat. Acad. Sci. 46
25 (1960).
Pfizer Handbook of Microbial Metabolites 436
true in heme synthesis (in rats)."* The biosynthesis at
least seems to be related to the metabolism of 5-carbon
units such as proUne, ornithine and glutamic acid. It
was further proposed^ that the methoxyl group in one pyr-
role ring indicated derivation from hydroxyproHne, and
that the colorless Cjo pyrrolic substance, which is thought
to be a prodigiosin precursor/' was also probably derived
from two C-5 units and that the w-amyl side-chain also
might be a rudimentary C-5 amino acid chain. In this
connection, the isolation of a C25 "prodigiosin-like pig-
ment"' from a streptomycete should be mentioned. While
all of the proposals made are not entirely compatible with
the revised structure published since,^ the basic tenets
seem to be sound.
Orange and blue variants of prodigiosin occur. The
latter, which are less soluble, may be metal chelates.
Some work also has been done on the biosynthesis of
the pyrrolic pigments of Bacillus bruntzii, and glycylgly-
cine was found to be a better precursor than glycine and
a number of other peptides.^
It is safe to say that natural pyrroles are formed by a
variety of methods. Demonstration of the participation
of erythrose in the shikimic acid biosynthetic route has
inspired the admonition that erythrose and its 4-C-atom
derivatives should not be ignored as possible precursors
of furans and pyrroles.^"
Because of their importance in photosynthesis, in he-
moglobin, in cytochromes and peroxidases and in the
chromophore of vitamin B12, there has been much investi-
gation of the general mode of biosynthesis of porphyrins.
It is likely that a similar method is operative in all cases.
Porphyrins are present in yeasts, molds and bacteria.
= David Sherain and D. Rittenberg, J. Biol. Chem. 166 621 (1946).
^ Ursula V. Santer and Henry J. Vogel, Biochim. et Biophys. Acta
19 578 (1956).
^ F. Arcamone, A. DiMarco, M. Ghione and T. Scottl, Giom.
microbiol. 4 77 (1957).
^ Harry H. Wasserman, James A. McKeon, Lewis Smith and Peter
Forgione, J. Am. Chem. Soc. 82 506 (1960).
^ J. G. Marchal and S. Baldo, Trav. lab. microbiol. fac. pharm.
(Nancy) No. 18 187 (1956).
'"Ernest Wenkert, Experientia 15 166 (1959).
437
Pyrroles, Porphyrins and Related Compounds
The photosynthetic bacteria, grown aerobically in light,
are a rich source, and so are corynebacteria. Part of the
biosynthetic pathway to the porphyrins has been explored
in photosynthetic bacteria, and it is thought to be of gen-
eral significance:^^' ^-
-CO.
HOOC— CH>— CH>— C— COOH
a-Ketoglutaric Acid
-^ HOOC— CH.— CHo— CO— CoA
Succinyl Coenzyme A
HOOC— CHo— CHo— CO— CoA + HOOC— CH2
Succinyl Coenzyme A Glycine
-NH,
-COo
COOH
HOOC— CH2— CHo— C— CHo— NH2
6-Aminolevulinic Acid
H2N— CH2
COOH CH2
1 1
CH2 CH2
1 1
— 2H20
>
CH2 o=c
1 1
C CHo
0 H2N
5-Aminolevulinic Acid
HOOC— CH2
\
c-
c
H2N— CH2/ \
CH2— CH2-
/
— c
II
c
-COOH
H
Porphobilinogen
Pyridoxal phosphate is required as a co-factor (glycine
activator) in the glycine-succinyl-COA condensation.^^
Porphobihnogen then condenses to form coproporphyrin
and protoporphyrin. In certain photosynthetic bacteria,
" June Lascelles, Biochem. }. 62 78 (1956); idem., Abstracts of the
Gordon Conference on Metabolism, 1957.
^- Goro Kikuchi, Abhaya Kumar, Phyllis Talmadge and David
Shemin, /. Biol. Chem. 233 1214 (1958).
Pfizer Handbook of Microbial Metabolites 43S
such as Rhodopseudomonas spheroides, the following se-
quence has been shown:
— 4NH3 — 4H
4 Porphobilinogen > Uroporphyrinogen > Uroporphyrin III
— 2H
— 4CO2
— 4H
Coproporphyrinogen > Coproporphyrin III
--4H — 2CO2
— 4H
Protoporphyrinogen > Protoporphyrin IX
The reduced precursors may be the biologically active
species, and the porphyrins by-products stabilized by oxi-
dation.'^
Higher animals (as well as microorganisms) are ca-
pable of porphyrin synthesis, and, in fact, the above work
with photosynthetic bacteria was based on earUer labeling
experiments in animals,^' and porphobilinogen was first
isolated from the urine of humans with acute porphyria."
Widely occurring enzymes convert porphobilinogen to
uroporphyrins, but it is difficult to isolate and identify the
intermediates. Apparently they are quite transitory.
Some interesting speculations have been published con-
cerning their nature.'^' ^''' The Wittenberg hypothesis,
based on the known transformations of porphobilinogen
by chemicals and enzymes, the extensive labeling studies
that have been published, and on the construction of mod-
els, is outlined in the following series of equations :
'•"'David Shemin and D. Rittenberg, J. Biol. Chem. 166 621, 627
(1946); Norman S. Radin, D. Rittenberg and David Shemin, ibid. 184
745 (1950); Jonathan Wittenberg and David Shemin, ibid. 185 103
(1950); David Shemin and Jonathan Wittenberg, ibid. 192 315
(1951); Helen M. Muir and A. Neuberger, Biochem. J. 47 97 (1950);
David Shemin^ Charlotte S. Russell and Tessa Abramsky, /. Biol.
Chem. 215 613 (1954); K. D. Gibson, W. G. Lauer and A. Neuberger,
Biochevi. J. 70 71 (1958); K. D. Gibson, A. Neuberger and J. J. Scott,
ibid. 61 618 (1955); J. E. Falk, E. I. B. Dresel, A. Benson and B. C.
Knight, ibid. 63 87 (1956); E. I. B. Dresel and J. E. Falk, ibid. 63
388 (1956).
1" R. G. Westall, Nature 170 614 (1952); G. H. Cookson and C. Rim-
ington, Biochem. J. 57 476 (1954).
'^ David Shemin, Harvey Lectures 50 258 (1956).
16 Jonathan B. Wittenberg, Nature 184 876 (1959).
439
Pyrroles, Porphyrins and Related Compounds
A = -CHuCOOH
P = -CH;CH:COOH
A
P /
H,
V
/\N/
\n/
H
H
H,C „
\ H
1 C r
/Kv
2
H,
J
Bogorad found'' that the enzyme porphobilinogen de-
aminase converts porphobilinogen (A) to uroporphyrino-
gen (D). Because a second enzyme, uroporphyrinogen
isomerase, has as its only substrate (not D) a product of
the action of porphobilinogen deaminase on (A), there
must have been one or more colorless intermediates. The
intermediates must be convertible, spontaneously or under
the continuing influence of porphobihnogen deaminase.
1' Lawrence Bogorad, /. Biol. Chem. 233 501, 510, 516 (1958).
Pfizer Handbook of Microbial Metabolites 440
to (D) (reaction 5). The linear tetrapyrrole (B) shown is
the intermediate proposed by Wittenberg.
The enzyme, uroporphyrinogen isomerase, acting on
porphobihnogen, yields uroporphyrinogen III (E) as its
first detectable product. Wittenberg proposed that the
function of this enzyme is to condense 2 molecules of (B)
(reaction 2), creating the cychc octapyrrole (C). Model
studies indicate that such an intermediate could fold and
undergo rearrangement, spontaneously or under contin-
ued enzyme influence, to yield 2 molecules of uropor-
phyrinogen III (E) (reaction 4).
The over-all result of this reaction sequence would be
the interchange of the pyrrole moieties destined to form
rings D of the porphyrins between two tetrapyrroles, with
consequent reversal of the positions of the D rings rela-
tive to the other pyrrole rings of the tetrapyrroles.
This hypothesis seems to be in accord with aU other
known evidence concerning porphyrin biosynthesis, and
it would account for their pecuhar asymmetry. Many ref-
erences to related work are cited by Wittenberg. It is
notable that appropriate dipyrrome thanes were not con-
verted to porphyrinogens or porphyrins by porphobilino-
gen deaminase. ^^
Vitamin 6^2 is the only vitamin produced exclusively by
microorganisms, although not all microbes are capable
of elaborating it. Most seem to form little more than
enough for their own slight requirements, the best or-
ganisms for primary production by fermentation being:
Streptomyces olivaceus, S. griseus, Propionibacterium
shernianii and Bacillus megatherium.
The nucleus of vitamin Bj^ differs somewhat from that
of porphyrins and is called the corrin ring:^"'
17 -15. 13
Corrin
18 D. S. Hoare and H. Heath, Biochim. et Biophys. Acta 39 167
(1960).
441
Pyrroles, Porphyrins and Related Compounds
(b) COoH
CH2 CH3 \ XHi.CO^H (c)
CH2.CH2.CO2H (d)
(g) HO2C.CH2
(f) H02C.CH2.CK CH3 '-"3
CH2.CH2.CO2H (e)
Cobyrinic Acid
CONH
/
CONH2CH3 CH2 u
/ H V
CH^ *?">N^ CN/^-pl^
CH3
NH2
-CO
/ AM
NH OH
/ O©/
CH2 / /
a-(5,6-Dimethylbenzimidazolyl) cobamide Cyanide
The nucleotide-free carboxylic acid form is called co-
byrinic acid, the carboxyl groups (amides, etc.) being let-
Pfizer Handbook of Microbial Metabolites
442
tered as shown. When the aminopropanol group is in-
corporated by amide Unkage at the f-position, the name is
modified to cobinic acid ( all carboxyl groups as amides =
cobinamide), and when ribose is incorporated, the name
is modified to cobamic acid (cobamide). The name of
the heterocycle is then inserted at the beginning with the
suffix -yl. Thus, vitamin B12 is correctly named: a-(5,6-
dimethylbenzimidazolyl) cobamide cyanide.
The two principal moieties are called the planar group
and the nucleotide, and these are essentially perpendicu-
lar in relative steric arrangement.
A number of analogues of vitamin Bjo have been iso-
lated from natural sources. These sources include B12
fermentations, the rumen or the gut of various animals
and sewage sludge. The naturally occurring analogues
are listed below by trivial name, together with the charac-
teristic heterocycle of the nucleotide.
TABLE I
Naturally Occurring Vifamin 612 Analogues
Name
Nucleotide base
Reference
Vitamin Bn
5,6-Dimethylbenzimidazole
Pseudo (i/')-Vitamin B12
Adenine
19, 20, 21,
22,23
Factor A
2-Methyladenine
20, 21, 22,
23
Factor B (Etiocobalamine)
No nucleotide
21, 24, 25,
26
Factor C (Guanosine Diphos-
phate Factor B)
Guanine
21, 24, 25,
27,37
Factor D*
Unknown
21,22
Factor E*
Unknown
22
Factor F
2-Methylmercaptoadenine(?)
21,22,25
Factor G
Hypoxanthine
22
Factor H
2-Methylhypoxanthine
22
Factor 1 (B12 factorni)
5-Hydroxybenzimidazole
22, 28, 29
Factors J, K, L, M
Unknown
30
Unknown purine base (?)
2-Methylmercaptoadenine
31
32
(May be factor F)
(May be factor C)
Guanine
27
Factor "A" Ribose Phosphate
No base
33
Factor Via (Cobyrinic Acid
a, b, c, d, e, g-hexaamide)
No base
34,35
Factor Vib (Cobyrinic Acid
Pentamide)
No base
34, 35
5-Methylbenzimidazole
36
Benzimidazole
36t
*Not crysfoillne. t About 17 other cobamides were defected in this study.
443 Pyrroles, Porphyrins and Related Compounds
Besides the natural analogues, many vitamin 8,0 "var-
iants have been prepared by addition of analogues of the
1-' H. W. Dion, D. G. Calkins and J. J. Pfiffner, /. Am. Chem. Soc. 74
1108 (1952).
-"]. E. Ford, E. S. Holdsworth, S. K. Kon and J. W. G. Porter,
Nature 171 148 (1953).
-^ H. G. Heinrich (Editor), "Vitamin Bu and Intrinsic Factor, First
European Symposium, Hamburg, 1956." M. E. Coates and S. K. Kon,
Ferdinand Enke. Stuttgart, 1956, p. 72.
-- F. B. Brown, J. C. Cain, Dorothy E. Gant, T. F. J. Parker and
E. Lester Smith, Biochem. J. 59 82 (1955).
-' H. W. Dion, D. G. Calkins, and J. J. Pfiffner, /. Am. Chem. Soc.
76 948 (1954).
^S. K. Kon, Biochem. Symposium No. 13, p. 17 (1955).
^'' H. G. Heinrich (Editor), "Vitamin B,o and Intrinsic Factor, First
European, Hamburg, 1956." J. W. S. Porter, Ferdinand Enke,
Stuttgart, 1956, p. 43.
-•'J. B. Armitage, J. R. Cannon, A. W. Johnson, T. F. J. Parker,
E. Lester Smith, W. H. Stafford and A. R. Todd, /. Chem. Soc, 3849
(1953).
-" R. Barchielli, G. Boretti, P. Julita, A. Migliacci and A. Minghetti,
Biochim. et Biophijs. Acta 25 452 (1957).
-* Wilhelm Friedrich and Konrad Bernhauer, Chem. Ber. 89 2030
(1956).
-^ Wilhelm Friedrich and Konrad Bernhauer, Angew. Chem. 65 627
(1953).
'" Clifford H. Shunk, Franklin M. Robinson, James F. McPherson,
Marjorie M. Gasser and Karl Folkers, 7. Am. Chem. Soc. 78 3228
(1956).
31 G. E. W. Wolstenholm and Maeve O'Connor (Eds.), CIBA
Foundation Symposium on "The Chemistry and Biology of Purines,"
E. Lester Smith, The chemistry of neiv purines in the Bi2 series of
vitamins, Little, Brown & Co., Boston, 1957, pp. 160-168.
3- Wilhelm Friedrich and Konrad Bernhauer, Chem. Ber. 90 1966
(1957).
■'^ Hanswerner Dellweg and Konrad Bernhauer, Arch. Biochem. and
Biophijs. 69 74 (1957).
■''* Konrad Bernhauer, Hanswerner Dellweg, Wilhelm Friedrich,
Gisela Gross and F. Wagner, Z. Naturforsch. 156 336 (1960).
3^" K. Bernhauer, H. W. Dellweg, W. Friedrich, G. Gross, F. Wagner,
and P. Zeller, Helv. Chim. Acta 43 693 (1960).
^^ Konrad Bernhauer, Elisabeth Becher, Gisela Gross and Georg
Wilharm, Biochem. Z. 332 562 (1960).
3^" K. Bernhauer, F. Wagner and P. Zeller, Helv. Chim. Acta 43 696
(1960).
""Wilhelm Friedrich and Konrad Bernhauer, Chem. Ber. 91 2061
(1958).
^" G. Boretti, A. DiMarco, T. Fuoco, M. P. Marnati, A. Migliacci and
C. Spalla, Biochim. et Biophijs. Acta 37 379 (1960).
Pfizer Handbook of Microbial Metabolites 444
nucleotide base to fermentations. A review^^ lists about
50 such compounds, some of which have vitamin activity.
There seems to be a fundamental similarity in the bio-
synthetic routes to vitamin B^o and the porphyrins. C^^-
Labeled glycine or 8-aminolevuhnic acid are heavily in-
corporated.-^'* Threonine furnishes the aminopropanol
moiety as demonstrated by incorporation of the amino
acid labeled with N^^^" There seems to be no information
yet on the biosynthetic origin of the dimethylbenzimida-
zole moiety.
Red cobamide-containing polypeptides have been iso-
lated from microorganisms, and some of these can replace
cobamide in deficient microorganisms, and in the oral
treatment of pernicious anemia.*^' ^-
Cobamides have been impUcated in several metabolic
processes.*^ In Escherichia coli mutants they seem to
assist in the formation and transfer of methionine methyl
groups" (folic acid is also required). They are thought
to be involved in the reduction of disulfides to thiols.*^ In
38 D. Perlman, Advances in Appl. Microbiol. 1 87-112 (1952). (A
review)
2^ David Shemin, John W. Corcoran, Charles Rosenblum and Ian
M. Miller, Science 124 272 (1956); John W. Corcoran and David
Shemin, Biochim. et Biophys. Acta 25 661 (1957).
*° Alvin I. Krasna, Charles Rosenblum and David B. Sprinson, /.
Biol. Chem. 225 745 (1957).
" H. G. Wijmenga, J. Lens and A. Middlebeek, Chem. Weekblad 45
342 (1949); H. G. Wijmenga and B. Hurenkamp, ibid. 47 217 (1951);
H. G. Wijmenga and W. L. C. Veer, ibid. 48 33 (1952); H. G. Wij-
menga, K. W. Thompson, K. G. Stern and D. J. O'Connell, Biochim.
et Biophys. Acta 13 144 (1954); H. G. Wijmenga, J. Lens and S. J.
Geerts, Acta Haematol. 11 372 (1954).
i^K. Hausmann, Lancet 257 962 (1949); K. Hausmann and K.
MulU, Acta Haemotol. 1 345 (1952); idem.. Lancet 262 185 (1952);
K. Hausmann, Klin. Wochschr. 31 1017 (1953); K. Hausmann, L.
Ludwig and K. Mulli, Acta Haemotol. 10 282 (1953); K. Mulli and
O. J. Schmid, Z. Vitamin-, Hormon-u. Fermentforsch. 8 225 (1956);
J. G. Heathcote and F. S. Mooney, Lancet 274 982 (1958).
43R. D. Wilhams (Ed.), "The Biochemistry of Vitamin B,..," June
Lascelles and M. J. Cross, The function of vitamin B,j in microorgan-
isms. Biochemical Society Symposia No. 13, Cambridge University
Press, London, 1955, pp. 109-123.
•i^C. W. Helleiner and D. D. Woods, Biochem. J. 63 26p (1956).
■•^ J. W. Dubnoff and E. Bartroy, Arch. Biochem. and Biophys. 62
86 (1956); Chiun T. Ling and Bacon F. Chow, J. Biol. Chem. 206 797
(1954).
445 Pyrroles, Porphyrins and Related Com|>ounds
Lactobacillus leichmannii they are required for the re-
duction of formate to the methyl group of thymine by a
pathway not involving methionine nor a hydroxymethyl
intermediate.^" In the same organism they have been
reported necessary for the synthesis of deoxyribose."*^
The isolation of actual coenzyme forms of cobamides
has permitted more precise determination of some func-
tions which are known to be direct. Barker and collab-
orators found that cell-free extracts of the anaerobe Clos-
tridium tetavomorphuin metabolized glutamate in a way
different from the citric acid cycle, catalyzing the equi-
librium :
HOOC— CHo— CHo— CH— COOH ;=i HOOC— CH— CH— COOH
I I I
NH2 CH3 NH2
Glutamic Acid /3-MethyIaspartic Acid
HOOC— CH
CH3— C— COOH
Mesaconic Acid
An orange form of pseudovitamin B12 was isolated and
found to be required for the first step.*® (It is noteworthy
that /jj-methylaspartic acid occurs in the polypeptide anti-
biotic, aspartocin.) The entire nature of this coenzyme
is still unknown, but the nucleotide base is known to be
adenine. Also a second mole of adenine nucleoside is
present, bound in such a way as to affect radically the
corphyrin spectrum, and cleavable by photolysis. The
nucleoside apparently is attached to cobalt, replacing the
cyano group. It contains an unusual sugar.*''
In this isomerization there are two possible migrating
**' James L. Dinning, Barbara K. Allen, Ruth Young and Paul L.
Day, J. Biol. Chem. 233 674 (1958).
■•" Mancourt Downing and B. S. Schwelgert, /. Biol. Chem. 220 521
(1956); W. T. Wong and B. S. Schwelgert, Proc. Soc. Exptl. Biol.
Med. 94 455 (1957).
*s H. A. Barker, H. Welssbach and R. D. Smyth, Proc. Nat. Acad.
Sci. U. S. 44 1093 (1958).
■*9 H. A. Barker, R. D. Smyth, H. Weissbach, J. I. Toohey, J. N. Ladd
and B. E. Volcanl, /. Biol. Chem. 235 480 (I960); H. Weissbach,
J. N. Ladd, B. E. Volcani, R. D. Smyth and H. A. Barker, ibid. 235
1462 (I960); J. N. Ladd, H. P. C. Hogenkamp and H. A. Barker,
Biochem.. and Biophys. Res. Comms. 2 143 (1960).
Pfizer Handbook of Microbial Metabolites
446
groups as shown below. A labeling experiment has shown
that
HOOC— CH,— CH,— CO— S— CoA
CH3
®
— C— S— CoA
migration
HOOC— CH— CO— S— CoA
@ — COOH
,, migration
HOOC— CH,— CH2— CO— S— CoA
0 is the actual process.^" A free radical mechanism was
proposed in which the Co*""^ of the cobamide coenzyme
initiates the one-electron transfer:
COOH
COOH
HC— CH3
Co^±i) ^..^^^
^ CHo— CH,
s— CoA y
Cobamide
coenzyme
/ c=o
S— CoA
COOH i
J
V COOH
HC— CH2 y
1 i/
"^ Co<S) + H ®
• CH— CH2
c=o
C=0
S— CoA
S— CoA
This is analogous to a rearrangement reported earlier by
Urry and Kharasch.-^'^
The same organism (Clostridiian tetanomorphiim) was
found capable of producing coenzymes containing the
benzimidazole and dimethylbenzimidazole forms of vita-
min Bjo.'^ The dimethylbenzimidazole coenzyme has been
found'^' to promote the equilibrium reaiTangement previ-
ously known to exist:''*
5° H. Eggerer, P. Overath and F. Lynen, /. Am. Chem. Soc. 82 2643
(1960).
SI W. H. Urry and M. S. Kharasch, ibid. 66 1438 (1944).
^^ H. Weissbach, J. Toohey and H. A. Barker, Proc. Nat. Acad. Sci.
45 521 (1959).
''^ E. R. Stadtman, P. Overath, H. Eggerer and F. Lynen, Biochem.
and Biophys. Res. Comms. 2 1 (I960); Joseph R. Stern and Daniel L.
Friedman, ibid. 2 82 (I960); Shantov Gurnani, S. P. Mistry and
B. Connor Johnston, Biochim. et Biophys. Acta 38 187 (1960).
•'* Robert W. Swlck and Harland G. Wood, Proc. Nat. Acad. Sci.
U. S. 46 28 (1960).
447 Pyrroles, Porphyrins and Related Compounds
CH3
I
HOOC— CHo— CH.— CO— CoA ^ HOOC— CH— CO— CoA
Succinyl Coenzyme A Methylmalonyl Coenzyme A
The final step in the conversion of succinate to propionate
is the biotin-dependent decarboxylation : -'^
CH3
Methylmalonyl Coenzyme A Propionyl Coenzyme A
The total process can be written:
(1) Acetyl CoA + Succinate ^ Succinyl CoA + Acetate
B12 coenzyme
(2) Succinyl CoA , Methylmalonyl CoA
(3) Methylmalonyl CoA + Biotinenzyme :^ CO2 Biotinenzyme + Propionyl CoA
(4) Propionyl CoA + Acetate ^ Acetyl CoA + Propionate
Perhaps it is significant that propionibacteria are rela-
tively rich sources of vitamin Bjo and of bio tin. This
scheme also shows how propionic acid can be oxidized by
entry into the carboxylic acid cycle.
The precise mechanism by which these interesting rear-
rangements are promoted by the Bj^ coenzymes remains
to be determined. It has been pointed out^^ that, in effect,
what is accomplished is a transpropionation.
A monograph on vitamin Byj has been published. ^^
The cytochromes are heme proteins important in elec-
tron transport. The most studied is cytochrome c. The
commonest source is muscle, but yeast cytochrome c has
been crystallized.'"' Classification is made by spectrum,
and the proteins are species specific.
The prosthetic group of cytochrome c is protoporphyrin
IX bound firmly to the apoenzyme by covalent bonds be-
tween the thiol groups of cysteine and the vinyl groups of
the porphyrin.^' Four of the iron coordination bonds are
^^ E. Lester Smith, "Vitamin Bi-," John Wiley & Sons, Inc., New
York, 1960.
°^ Bunji Hagihara, Takekazu Horlo, Kazuo Okunuki, Jinpei
Yamashita and Mitsuhiro Nozaki, Nature 178 629 (1956).
^" K. Zeile and H. Meyer, Hoppe-Seylers Z. physiol. Chem. 262 178
(1939); H. Theorell, Enzymologia 6 88 (1939); Karl-Gustav Paul,
Acta Chem. Scand. 5 389 (1951).
Pfizer Handbook o£ Microbial Metabolites
448
to porphyrin nitrogen, the other two to histidyl residues
in the protein.
Proteolytic enzyme degradation of cytochrome c has
yielded the polypeptide fragment in the vicinity of the
porphyrin, and the amino acid sequence has been de-
termined. It is thought to be:'"'*
histidyl vaiyl-glutamyl-lysyl-cysteinyl
alanyl
glutamyl
iysyl-glutamyl-vaiyl-threonyi-histidyi-cysteinyl
Cytochrome c Fragment (Hemopeptide)
Bovine cytochrome c has a particle weight of about
13,000 and contains about 20 lysine and 3 or 4 histidine
residues. A helical model of the Pauling type thus prob-
ably showns the entire active region of the enzyme since
this cytochrome contains only one prosthetic group.
Cytochromes (c^ and Cr,) isolated from Azotobacter
vinelandii have a particle weight of about 12,000 and con-
tain 0.46% iron, so that superficially they resemble mam-
malian cytochrome c.^^ In a comparative study of mam-
mahan and bacterial (Pseudomonas aerugmosa) cyto-
s«Hans Tuppy and G. Bodo, Monatshefte Chem. 85 1024, 1182
(1954); Hans Tuppy and Sven Paleus, Acta Chem. Scand. 9 353, 365
(1955).
59 A. Tissieres, Biochem. J. 64 582 (1956).
449
Pyrroles, Porphyrins and Related Compounds
chrome c rather minor spectral differences were noted,
but there were gross differences in the amino acid com-
position of the protein.'"'" The prosthetic group of cyto-
chrome ao from Aerobacter aerogenes has been purified
but not crystallized/'^ Strict anaerobes such as Clostridia
seem to lack cytochromes, and some lactobacilli seem to
use flavins instead.
Reviews of the role of cytochromes in electron transport
have been published. ''-• '^- '^*' °^' This process is shown in
outline in the accompanying diagram.
TPN +
TPN— DPN
Transhy-
drogenase
TPNH
DPNH.
Succinic
Dehydrogenase-
FADH.
ELECTRON TRANSPORT
Amytal
Sensitive
i
E-FAD
T
DPNH
Dehy'
drogenase
i
E-FADH-;
Antimycin Cyanide
Sensitive Pr Sensitive
i I i
E-2-Heme-Fe++ 2-Heme-Fe+++ E-2(Cu+)Heme
T \ / \/ Fe++
Cytochrome y Cytochrome V Cytochrome
i
03
(Oxidase)
E-2Heme-Fe + + + 2-Heme-Fe++ E-2(Cu++)Heme- H2O
T I T Fe+++
CP T Pr CP
E-Cytochrome b
or
E-Coenzyme Q
E = Apoenzyme
CP = Coupled phosphory-
lation (ATP Synthesis)
Pr = Protein
The role of Hpides and quinones in electron transport
has been discussed. '''' The mechanism of coupled phos-
phorylation is not understood in detail, but can be repre-
sented as follows:
^ Martin D. Kamen and Yoshiro Takeda, Biochim. et Biophys. Acta
21 518 (1956).
«i J. Barrett, Biochem. }. 64 626 (1956).
•52 Albert L. Lehninger, The Harvey Lectures, 49 176-215 (1955);
idem.. Scientific American 202 102-118 (1960).
*^^ Britton Chance and G. R. Williams, Advances in Enzymol. 17
65-130 (1956).
*'^ Joseph S. Fruton and Sofia Simmons, "General Biochemistry,"
John Wiley and Sons, New York, 1958, pp. 284-386.
^^ David E. Green and Johan Jarnefelt, Perspectives in Biol, and
Med. 2 163-184 (1959).
««D. E. Green and R. L. Lester, Federation Proc. 18 987-1000
(1959).
Pfizer Handbook of Microbial Metabolites 450
H3P04
Inorganic Phosphate
XH2
/a reduced electron\
\ carrier /
X
/ an oxidized \
\electron carrier/
ADP H
ATP
Some electron transport poisons are shown. Many
other poisons also act by interfering somehow with the
function of the electron transport enzymes.
A lucid, if rather popularized, exposition has been pub-
lished of the energy relationships in cell respiration, as
well as the gross cell structure involved.'*^
913 Holomycin (Des-N-methylthiolutin), CyH^OoNoSo, orange-yellow
leaflets, m.p. 264-271° (dec).
O
NH— C— CH3
/
s — c=c
s I I
CH=C C
H O
Streptomyces griseus (Krainsky) Waksman et Henrici
L. Ettlinger, E. Gaunaann, R. Hiitter, W. Keller-Schierlein,
F. Kradolfer, L. Neipp, V. Prelog and H. Zahner, Helv. Chim.
Acta 42 563 (1959).
914 Thiolutin (Acetopyrrothine, Farcinicin), C8H8O0N0S2, yellow
crystals, m.p. 260-270° (dec).
0
II
NH-
II
-c-
-CH:
/
s-
-c — c
/
s
\
c=
=c c
H
1 0
CHj
«7 Albert L. Lehninger, Scientific American 202 102-117 (1960).
451 Pyrroles, Porphyrins and Related Compounds
Streptomyces albus
Walter D. Celmer, Fred W. Tanner, Jr., M. Harfenist, T. M.
Lees and I. A. Solomons, /. Am. Chem. Soc. 74 6304 (1952).
Walter D. Celmer and I. A. Solomons, ibid. 77 2861 (1955).
(Structure)
915 Noformicin, C,sHi,-ON-, Dihydrochloride m.p. 265° (dec), [a],"
+ 7.0° (c 1.0 in water).
[ ] O NH
HN H C— NH— CHo— CH.2— C— NH2
Nocardia formica
Reed A. Gray, Phytopathologij 45 281 (1955).
Robert L. Peck, Henry M. Shafer and Frank J. Wolf, U. S.
Patent 2,804,463 (1957).
916 Aureothricin ( Propiopyrrothine ) , CgHioO^N^So, yellow crystals,
m.p. 256° (dec).
NH— C— CH,— CH3
/
s — c=c
s I I
\ I I
CH=C C
I o
CH,
Streptomyces cellulofiavus n. sp.
Haruo Nishimura, Toshlaki Kimura and Masa Kuroya, /.
Antibiotics (Japan) 6A 57 (1953).
Walter D. Celmer and I. A. Solomons, J. Am. Chem. Soc. 77
2861 (1955). (Structure)
917 Pyoluteorin, CuH^OgNCL., m.p. 174° (dec).
Partial structure:
2 CI
Pfizer Handbook of Microbial Metabolites 452
Pseudomonas aeruginosa
Rokuro Takeda, J. Am. Chem. Soc. 80 4749 (1958). (Struc-
ture)
918 Netropsin (Congocidine, Sinanomycin, T1384), CigHoeOgNio,
the hydrochloride crystallizes as colorless, hygroscopic
prisms, m.p. 168-172° (dec).
NH NH
II II
H2N— C— CH2— C— NH
u
o
\ll
I C— NH
CH3
O
o o
\ll II
I C— NH— CH2— CH2— C— NH2
CH3
Streptomyces netropsis, S. chromogenes n.sp., S. ambo-
faciens n. sp.
A. C. Finlay, F. A. Hochstein, B. A. Sobin and F. X. Murphy,
J. Am. Chem. Soc. 73 341 (1951).
E. E. van Tamelen and A. D. G. Powell, Chem.. and Ind., 365
(1957). (Structure)
919 Prodigiosin, C20H25ON3, red crystals with a green reflex, m.p.
151.5-152.9° (dec).
Alternative structures : *
(CH2)4— CH3
(CH2)4— CH3
* See addendum.
453 Pyiroles, Porphyrins and Related Compounds
Serratia marcescens (Bacillus prodigiosum), S. marino-
rubriivi
Fritz Wrede and Alexander Rothhaas, Z. physiol. Chem. 226
95 (1934).
Other metabohtes which have been isolated from cul-
tures of Serratia marcescens are:
920 A "prodigiosin precursor," C10H10O0N2, colorless nee-
dles, m.p. > 250° (dec).
921 A colorless, crystalline compound, not an antibiotic,
CS4HG0O10N3, m.p. 153°.
922 An amide, C04H33O2N7.
Palmitic acid.
Three other red, one orange and one blue pigments.
A polypeptide, marcescin.
A polysaccharide.
Fritz Wrede and Alexander Rothhaas, Z. physiol. Chem. 226
95 (1934).
Ursula V. Santer and Henry J. Vogel, Biochim. et Biophys.
Acta 19 578 (1956).
O. M. Efimenko, G. A. Kuznetsova and P. A. Yakimov,
Biokhimiya 21 416 (1956).
A. J. Castro, J. F. Deck, M. T. Hugo, L. R. wmiams and
M. R. Zingg, /. Org. Chem. 23 1232 (1958).
A. J. Castro, A. H. Corwin, F. J. Waxham and A. L. Beilby,
ibid. 24 455 (1959).
Doris P. Courington and T. W. Goodwin, J. Bacteriol. 70
568 (1955).
Harry H. Wasserman, James E. McKeon, Lewis Smith and
Peter Forgione, /. Am. Chem. Soc. 82 506 (1960). (Structure
shown above)
A. Treibs and R. Galler, Angew. Chem. 70 57 (1958).
923 Celesticetin, C24H3g09N2S, hygroscopic glass, m.p. (Oxalate):
147-152°, [aU-' +126.6° (c 0.5 in chloroform), [aW*
(Oxalate) 106.6° (c 0.5 in water).
Proposed Structure:
O
CH2— CH2— O— C— '^^^
S /
HO I HO
O
0\ CH-NH-C-L^
I CH, '.. I
"o in ^"^ CH
CH3
OCHj
Pfizer Handbook of Microbial Metabolites
454
Streptoviyces celestis n. sp., resembling S. glaucus
C. DeBoer, A. Dietz, J. R. Wilkins, C. N. Lewis and G. M.
Savage, "Antibiotics Annual 1954-1955," Medical Encyclope-
dia, Inc., New York, p. 831.
Herman Hoeksema, Glen F. Crum and William H. DeVries,
ibid. p. 837.
Clarence DeBoer, Alma Dietz and Herman Hoeksema, U. S.
Patent 2,928,844 (1960). (Structure)
924 Prodigiosin-Iike Pigment, C^.-.Ha-.ON.j, orange crystals, partial
melting 147-149°, resolidification, melting 203°.
Streptomycete related to S. ruber (Krainsky, Waksman
and Henrici) and S. roseodiastaticus, Waksman and
Lechevalier
F. Arcamone, A. DiMarco, M. Ghione and T. Scotti, Giorn.
microbiol. 4 77 (1957).
925 Hematin, C34H3oO4N4Fe®OH0.
CH=CH
CH=CH2
HOOC— CH2— CH
CH2— CH2— COOH
Saccharomyces anamensis
H. Fischer and F. Schwerdtel, Z. physiol. Chem. 175 248
(1928).
926 Protoporphyrin, C34H34O4N4, deep red crystals, m.p. >300°.
CH^CH, CH3
CH=^CH2
HOOC— CH2— CH2
CHo— CH2— COOH
455 Pyrroles, Porphyrins and Related Compounds
Yeasts, Rliodopseudomonas spheroides, other photosyn-
thetic bacteria
Hans Fischer and Hermann Fink, Z. physiol. Chem. 140 57
(1924).
927 Coproporphyrin I, Cno,H3s08N4.
HOOC— CH,— CH
CHo— CH2— COOH
CH3
CH2— CH2— COOH
CH2— CH2— COOH
Saccharomyces cerevisiae, S. anamensis, other yeasts,
Aspergillus oryzae, photosynthetic bacteria
Hans Fischer and Hermann Fink, Z. physiol. Chem. 150 243
(1925).
928 Coproporphyrin III, C36H3SO8N4, dark red crystals.
CH2— CHo— COOH
CH3
CHo— CH,— COOH
HOOC— CHo— CHo
CH2— CHo— COOH
Mycobacterium tuberculosis var. hominis, Rhodopseu-
domonas spheroides, Corynebacterium diphtheriae
M. O'L. Crowe and A. Walker, Brit. J. Exptl. Path. 32 1
(1951).
C. M. Todd, Biochem. J. 45 386 (1949).
Pfizer Handbook of Microbial Metabolites 456
929 Uroporphyrin III, C40H38O16N4.
:— OH ^
CH2— C— OH
CH2— CHo— C— OH /
CH2— CH2— C— OH
CH2— C— OH
/
CH2 CHo— CHo— C— OH
Rhodopseudomonas spheroides
June Lascelles, Abstracts Gordon Research Conference,
Vitamins and Metabolism (1958). (Detection)
H. Fischer and H.-J. Hofmann, Z. physiol. Chem. 246 15
(1937); H. Fischer and A. Miiller, ibid. 246 31 (1937). (Struc-
ture)
930 Bacteriochlorophyll a, C55H740(;N4Mg, amorphous, slow decom-
position above 94°.
0=C— CH3 cHs H
C20H39— OOC CH2— CH
Phytyl H3COOC
Rhodospirillum rubrum, R. fulvum, Rhodopseudomonas
spheroides, Thiocystis violacea, other Rhodovibrio spp. and
sulfur and chlorobacteria
Hans Fischer and Robert Lambrecht, Z. physiol. Chem. 249
1 (1937).
Hans Fischer, Robert Lambrecht and Hellmuth Mittenzwei,
ibid. 253 1 (1938).
John W. Weigl, /. Am. Chem. Soc. 75 999 (1953).
A. Seybold and G. Hirsch, Naturwissenschaften 41 258
(1954.)
457
Pyrroles, Porphyiins and Related Compounds
931 Vitamin Bi^ (Cyanocobalamin, a-(5,6-Dimethylbenzimidaz0lyl)
cobamide cyanide), Ce3HssOi4Ni4PCo, dark red crystals
which blacken near 212° and do not melt below 320°,
[a]6563"^ —59 ±9° (dilute aqueous solution).
NH2COCH2 CH.CHoCONHz
CH2CONH2
CH2CH2CONH2
HOCH2
Vitamin B12 activity has been detected in fermentation
broths from many microorganisms, e.g. Streptomyces
griseus, S. antibioticus, S. roseochromogenes, Mycobacte-
rium smegmatis, Lactobacillus arabinosus, propionibacte-
ria. Crystalline material has been isolated from some of
these. For primary fermentations, Streptomyces olivaceus
is probably the best producer (3.3 mg. per liter).
Dorothy Crowfoot Hodgkin, Jennifer Kamper, Maureen
MacKay and Jenny Pickworth, Nature 178 64 (1956). (Struc-
ture)
W. H. Sebrell, Jr. and Robert S. Harris, "The Vitamins,"
Robert S. Harris, Donald E. Wolf, Karl E. Folkers, H. M.
Wuest, Thomas H. Jukes and William L. Williams, Vitamin B12,
Academic Press Inc., New York, 1954 Vol. I Chap. 3, pp. 396-
524. (A review)
Pfizer Handbook of Microbial Metabolites 458
Leland A. Underkofler and Richard J. Hickey, "Industrial
Fermentations," Chemical Publishing Co., Inc., New York,
1954 Vol. II, J. M. VanLanen, Production of vitamins other
than riboflavin, chap. 6, pp. 207-8.
932 Factor B is vitamin Bjo from which the nucleotide
moiety has been removed. It has been isolated from
fermentations, from rumen contents, from sev^^age, and
it can be prepared chemically from vitamin B^o.
E. Lester Smith, "Vitamin B12," John Wiley and Sons, Inc.,
New York, 1960, 196 pp. (A monograph)
This monograph also explains the new nomenclature
system for B^o and related compounds.
Other intermediates in the biosynthesis of vitamin B12
by Propionibacterium shermanii have been detected:
Konrad Bernhauer, Elisabeth Becher, Gisela Gross and
Georg Wilharm, Biochem. Z. 332 562 (1960).
K. Bernhauer, Hw. Dellweg, W. Friedrich, G. Gross, F.
Wagner and P. Zeller, Helv. Chim. Acta 43 693 (1960).
K. Bernhauer, F. Wagner and P. Zeller, ibid. 43 696 (I960).
g. INDOLES
The indole nucleus occurs in microorganisms in such
forms as tryptophan, one of the less abundant amino
acids, in bacterial pigments such as violacein and indigo
and in amines from higher fungi such as serotonin and
psilocybin, which have strong physiological effects in
higher animals. The indole nucleus is incorporated also
into bizarre fungal metaboUtes such as echinulin and
gliotoxin, into the mushroom poisons, such as phalloidin,
and into the ergot alkaloids listed in the following section.
One route to indole and to tryptophan was outlined in
the section on amino acids. This is the pathway discov-
ered by Yanofsky and confirmed and elaborated in his and
other laboratories.^ Anthranilic acid from the shikimic
acid route combines with ribose phosphate, cyclization oc-
curs to form the pyrrole ring, a triose phosphate is elimi-
^ C. Yanofsky, Biochim. et Biophys. Acta 16 594 (1955); idem.,
J. Biol. Chem. 223 171 (1956); F. Gibson, M. Jones and H. Taltscher,
Biochem. J. 64 132 (1956); P. A. Trudinger, ibid. 62 480 (1956);
F. Lingens and H. Hellmann, ATigew. Chem. 69 97 (1957); L. W.
Parks and H. C. Douglas, Biochim. et Biophijs. Acta 23 207 (1957);
J. Gots and S. Ross, ibid., 24 429 (1957); C. Yanofsky and M. Rach-
meier, ibid. 28 640 (1958).
459
Indoles
nated and the indole so formed combines with L-serine to
fonn L-tryptophan :
COOH
COOH
r^
NH'
CH— CH— CH— CH— CH.— O— PO3H2
' I 1
NH. OH OH
Anthranilic Acid N-(2-Carboxyphenyl)-l -aminoribose-5-phosphate
CH— CH- CH,
J
' \ I I Triose phosphate
OH OH O— POaHj ^
'OO
L-Serine
lndolyl-3-glycerol Phosphate
a?
CHo— CH— COOH
NHo
L-Tryptophan
N-Fructosylanthranilic acid has been isolated from a
yeast, and it may be another intennediate in indole syn-
thesis. In this case a tetrose would be eliminated. If
pentoses and hexoses can both be used in reactions with
anthranilic acid, perhaps tetroses can be as well. This
possibility is emphasized by Wenkert" in a discussion of
alkaloid biosynthesis. A reaction of this sort might ex-
plain the frequent occurrence in nature of indole deriva-
tives with two carbon atom side-chains in the 3-position.
In other words the indole biosynthesis could be general-
ized:
-Ernest Wenkert, Experientia 15 165 (1959).
Pfizer Handbook of Microbial Metabolites 460
H
in which R — CH — CH — CHO is any of several sugars.
OH OH
It may be that other derivatives of anthranihc acid can
participate in this route, too. For example 5-hydroxyan-
thranilic acid would give rise to the 5-oxyindole derivatives
found in nature. It is notable that this acid is a growth
promoter for an Escherichia coli mutant.^
Ascorbigen, a bound form of ascorbic acid isolated from
plants of the cabbage family, has one of the structures:*
CH2— C^=CH CH2— C=CH
oa< > CD
H
HO— C CH or H CH C— OH
/ \
CHo— CH— CH C=0 0==C CH— CH— CH2
OH OH \^/ \^/ OH OH
O
Ascorbigen
(alternate structures)
The presumptive precursor is 3-indolylacetol, analogous to
an intermediate in histidine biosynthesis, and it is interest-
ing to speculate as to whether this is an offshoot of the
biosynthetic route to tryptophan or whether it is formed by
way of tryptophan.
The mold product, echinuhn, has an unusual structure,
apparently involving the indole synthesis, terpenoid and
amino acid precursors. Gliotoxin, on the other hand, is
almost entirely derived from amino acids, and it could
have been classified as a polypeptide. C"-Labeling studies
have demonstrated the following biosynthetic pathway for
gliotoxin : ^
3H. Niemer and A. Oberdorfer, Z. physiol. Chem. 308 51 (1957).
■* Z. Prochazka, V. Sanda and F. Sorm, Coll. Czech. Chem. Comm.
22 654 (1957).
s J. A. Winstead and R. J. Suhadolnik, J. Am. Chem. Soc. 82 1644
(1960); R. J. Suhadobiik, A. Fischer and J. Wilson, Federation Proc.
19 8 (1960).
461
Indoles
H,N^\
COOH
Phenylalanine
lO]
H-iU^^
Serine
COOH Methionine
m-Tyroslne
XH3
CH2OH
''from Serine^
and
^Methionine
Dethiogiiotoxin
2S
N s
s N
,/-
CH2OH
Gliotoxin
Methionine was the most efficient source of the N-methyl
group, the ^-carbon of serine being about one third as ef-
fective. Both of the amino acid skeletons were incorpo-
j rated intact when furnished, and m-tyrosine could also be
used as a precursor.
, 933 Indole, CgHyN, colorless leaflets, m.p. 52°.
cxj
934
H
Escherichia coli mutants, yeasts, Treponema spp.
P. A. Trudinger, Biochem. J. 62 480 (1956).
Charles Yanofsky, /. Biol. Chem. 223 171 (1956).
F. Gibson, Marjorie J. Jones and H. Teltscher, Biochem. J.
64 132 (1957).
L. W. Parks and H. C. Douglas, Biochim. et Biophys. Acta
23 207 (1957).
Michel Moureau and W. Aladame, Ann. inst. Pasteur 88 231
(1955).
Indole-3-acetic Acid (Rhizopin), CioHgOoN, colorless plates, m.p.
164°.
oa
CHoCOOH
Rhizopus suinus, R. nigricans, Aspergillus niger, Peni-
Pfizer Handbook of Microbial Metabolites 462
cillium notatum, Absidia ramosa, Boletus edulls, Yeasts
Niels Nielsen, Biochem. Z. 237 244 (1931); 249 196 (1932).
Fritz Kogl and D. G. F. R. Kostermans with A. J. Haagen-
Smit and H. Erxleben, Z. phijsiol. Chem. 228 113 (1934).
Kenneth V. Thimann, /. Biol. Chem. 109 279 (1935).
Donald J. Cram and Max Tishler, /. Am. Chem. Soc. 70
4238 (1948). (Isolation)
Ryuichi Honda, Japanese Patent 603 (1950).
935 Serotonin ( 5-Hydroxytryptamine ) , C10H12ON2 (Hydrochloride),
colorless crystals, m.p. 167°.
HO CH2CH2NH2
Oj
H
Panaeolus campanulatus
Demonstrated by paper chromatography only.
Varro E. Taylor, Jr., Science 128 718 (1958).
936 Psilocin, CjsHigONs, colorless crystals, m.p. 173-176° (dec).
H
O
CH2CHoN(CH3
Psilocybe species
Psilocin is a minor constituent of the mushrooms which
contain psilocybin.
A. Hofmann and F. Troxler, Experientia 15 101 (1959).
937 Psilocybin, C12H17O4N2P, colorless crystals, m.p. 185-195°
(dec).
OH
o=p— o®
o
OJ
CH3
@/
CH2CH2N
\
CH3
463 Indoles
Psilocybe mexicana Heim, P. caerulescens Murr. var.
Mazecotorum Heim, P. aztecorum Heim, P. sempervirens
Heim et Cailleux, P. zapotecorinn Heim, Stropharia cuhen-
sis Earle
A. Hofmann, R. Heim, A. Brack and H. Kobel, Experientia
14 107 (1958).
A. Hofman, A. Frey, H. Ott, Th. Petrzilka and F. Troxler,
ibid. 14 397 (1958). (Synthesis)
938 Gliotoxin ( Aspergillin ) , Ci:^Hi403NoSo, m.p. 195° (dec), [aW-'
-290° ±10° (c 0.078 in ethanol).
/
s
O
CH3
CH2OH
Trichoderma viride, Aspergillus fumigatus, Penicillium
terlikowski Zaleski, P. cinerascens, P. jenseni, Gliocladium
fimbriatuTn
The yield of gliotoxin and its acetate from P. terlikowski
Zaleski was reported as about 100 mg. per liter.
John R. Johnson, William F. Bruce and James D. Dutcher,
J. Am. Chem. Soc. 65 2005 (1943) and other papers in this
series.
Malcolm R. Bell, John R. Johnson, Bernard S. Wildi and
R. B. Woodward, J. Am. Chem. Soc. 80 1001 (1958). (Struc-
ture)
939 Gliotoxin Acetate, Ci-.HieO-NoS^, pale yellow rhombic crystals,
m.p. 159°, [a]i,''' -197° (c 0.600 in chloroform).
^N
O
O^^CH3
CH2— O— C— CH3
Penicillium terlikowski Zaleski
John R. Johnson, Aklaq R. Kidwai and John S. Warner, /.
Am. Chem. Soc. 75 2110 (1953).
Pfizer Handbook of Microbial Metabolites 464
940 Indigo, C16H10O2N2, blue powder with a coppery luster, sublimes.
Schizophyllum commune mutant
Ammonium ion was the only nitrogen source.
Philip G. Miles, Henning Lund and John R. Raper, Arch.
Bioche7n. and Biophys. 62 1 (1956).
941 Chetomin, Ci(5Hi704N3S2 (proposed), amorphous white powder,
m.p. 218-220° (dec), [ajn'^ +360° (c 1 in chloroform).
A neutral compound. Positive indole, Hopkins-Cole,
negative biuret, Millon.
Chaetomium cochlioides
Walton B. Geiger, Jean E. Conn and Selman A. Waksman,
;. Bacterial. 48 531 (1944). (Isolation)
Walton B. Geiger, Arch. Biochem. 21 125 (1949).
942 Violacein, C20H13O3N3, violet-black microcrystals, m.p. >350°
(dec).
HO C=CH
Co
NH C
c ^1 —
O X N
O H
Chromohacterium, violaceum.
F. M. Strong, Science 100 287 (1944).
R. T. S. Beer, Angew. Chem. 69 676 (1957).
J. A. Ballantine, C. B. Barrett, R. J. S. Beer, B. G. Boggiano,
K. Clarke, Stephen Eardley, B. E. Jennings and Alexander
Robertson, /. Chem. Soc, 2222 (1957) and preceding papers
in this series.
J. A. Ballantine, R. T. S. Beer, D. J. Crutchley, G. M. Dodd
and D. R. Palmer, /. Chem. Soc, 2292 (1960). (Synthesis)
R. D. Demoss and N. R. Evans, /. Bacteriol. 79 729 (1960).
(Biosynthesis)
465 Ergot Alkaloids
943 Echinulin, CosHa^OsNg, white needles, m.p. 242°.
Probable structure:
Aspergillus glaucus types, A. echinulatus, A. chevalieri
About 200 g. of pure material were obtained from 5 kg.
of dry mycelium. Auroglaucin and flavoglaucin were
isolated from the same source.
A. Quilico and L. Panizzi, Ber. 76B 348 (1943). (Isolation)
Adolfo Quilico, Cesare Cardini and Franco Piozzi, Gazz.
Chim. ital. 86 211 (1956). (Structure)
Ziro Kitamura, Uzukiko Kurimoto and Matatsugu Yoko-
yama, 7- Pharm. Soc. Japan 76 972 (1956).
C. Cardani, G. Casnati, F. Piozzi and A. QuUico, Tetrahedron
Letters No. 16 1 (1959). (Structure)
h. ERGOT ALKALOIDS
The constituents of the sclerotia of the fungus Claviceps
purpurea (Fries) TuL, a cereal parasite, have been exten-
sively studied. Some of the alkaloids are used in medicine
for their oxytocic properties and to relieve migraine.
Ergocristine, ergokryptine and ergocornine (and their
isomers) constitute a closely related complex formerly
thought to be homogeneous and called ergotoxine. Be-
sides the alkaloids which are shown in the succeeding
Pfizer Handbook of Microbial Metabolites
466
pages, many other chemicals have been identified.
Among them are:
Ergothioneine
Histidine
Tyrosine
Betaine
ChoUne
Acetylcholine
Cadaverine
Putrescine
Agmatine
Histamine
Tyramine
Valine
Leucine
Ammonia
Methylamine
Trimethylamine
Ethylamine
n-Propylamine
iso-Propylamine
iso-Butylamine
iso-Amylamine
n-Hexylamine
ytJ-Phenylethylamine
Mannitol
Clavicepsin
Ergosterol
Oils
Lactic Acid
Succinic Acid
Oxalic Acid
Citric Acid
Formic Acid
Ethanol
Furfural
Acetaldehyde
Acetone
Ergoflavine and
other pigments
Careful work has shown that many of the alkaloids
produced in the natural state can be produced in artificial
culture as well/ -• ■' Total alkaloid yields of 1000-1500
mg. per liter of culture fluid have been obtained exclusive
of mycelial alkaloids.^
The conventional ergot alkaloids contain the lysergic
acid moiety I or isolysergic acid, the stereoisomer at posi-
tion 8.
HOOC H
^ A. Hofmann, R. Brunner, H. Kobel and A. Brack, Helv. Chim.
Acta 40 1358 (1957).
'W. A. Taber and L. C. Vining, Can. J. Microbiol. 3 55 (1957).
3 Ervin Glaz, Acta Pharm. Hung. 25 11 (1955).
I
467
Ergot Alkaloids
A number of different hypotheses have been advanced
concerning the biosynthetic origin of the ergot alkaloids.
These are outlined below:
( 1 ) van Tamelen ( 1 953 ) : *
HO
r^
;
CHo— CH— COOH
NH2
cXj
lO] o^
CH — CH— COOH
' ' I
NH2 +
I
CH3
CONHo
CHo— CH— COOH
I
NH2
CONH2
(/ N— CH3
0 V CH.-
C0NH2
^ N— CH
-CH— COOH — ^
1 H2 J\ /
kJ^N^
WH 1 ' 1 1
NM2 ' 1 1
— H2O ^^:^>^N^
H
CH>— CH— COOH
I
NHo
CONHo
CH2— COOH
©
— H2
<
CONH2
I
N— CH3
— CO2 ^
N
H
i
Lysergic Acid
(2) Harley-Mason (1954):^
Eugene van Tamelen, Experientia 9 457 (1953).
'J. Harley-Mason, Chem. and Ind., 251 (1954).
Pfizer Handbook of Microbial Metabolites
COOH
CH2O
CH2 /
468
0=C NH2
\ /
HOOC— CH2 C— COOH
\
CH2
^
COOH
NH
"^^X^
N'
COOH
)0=
NH
Lysergic Acid
HOC
(3) Wendler (1954) :«
NH2
/
^^-^\ 0 NH-
\h2 >/
/ -H2O ^ >
1" 1 ) ' 1 II
-R
COOH
1
HO— C— CH2— COOH
1
CH2
/
k;^
1 L i 1^
H H
HOOC
(Citric Acid)
- HO COOH
\l
^^^^ /C— CH2— COOH
HOOC^<: NH— R
HO-
COOH
:CH2
NH— R
Lysergic Acid
6N. L. Wendler, ExpeHentia 10 338 (1954).
469 Ergot Alkaloids
(4) Robinson (1955):^
COOH
I
CH,
/ COOH
CH, I
\ CH.
COOH /
NH— CHj CHj NH— CH3
/ \ /
CH— COOH C— CH
\ II \
CH2 O CHj
H H
lysergic Acid
(5) Feldstein (1956):«
NH,
"°°^-^( O NH,
""CH, % /
oi-Keto-
a/
f^y^ ^Si/^N glutaric Acid
H H
COOH
I
O CH,
II /
HOOC— C— C NH,
COOH
I
CH,
/
HOOC— C NH,
% / CH2O
^;?C__J> > Lysergic
f fl -CO,
^^=5iA-N-^ +CH,
^ Sir Robert Robinson, "The Structural Relations of Natural Prod-
ucts," Oxford University Press, Oxford, 1955.
8 A. Feldstein, Experientia 12 475 (1956).
Pfizer Handbook of Microbial Metabolites 470
(6) Birch (1958),^ Mothes, et aZ. (1958):"
C
Isoprene
Equiva- "
lent
C=C
c
\
c
NHCH31
"-N
J
Tryptamine — > — > — > Lysergic Acid
Equivalent
Each of these hypotheses has had its votaries, but now
experimental work is beginning to accumulate. There
have been conflicting results, partly because some experi-
menters have injected labeled precursors into infected rye
plants, while others added them to cultures grown on arti-
ficial medium.
The 5-hydroxytryptophan proposals have been criti-
cized^ because no 5-hydroxyindole analogues of lysergic
acid have been found in nature, and because (obviously
the devices of organic chemists) they suffer from some
rather improbable biological intermediates. Brady has
found that in artificial culture tryptophan was an efficient
precursor for the clavine alkaloids, while 5-hydroxytrypto-
phan was not.^^
By using parasitic cultures one group reported good in-
corporation of /;j-C^*-tryptophan,^" while another reported^-
only weak labeling of the alkaloids isolated from the
sclerotia.
By use of a cell homogenate technique, it was found
that alanine and phenylalanine were incorporated into
ergotamine and the ergotoxine complex, but not into
ergonovine, which suggests that these amino acids are
precursors of the peptide structure of the water-insoluble
^ G. E. Wolstenholme and Cecilia M. O'Connor, CIBA Foundation
Symposium on "Amino Acids and Peptides with Antimetabolic Ac-
tivity," A. J. Birch and Herchel Smith, Oxidative formation of bio-
logically active compounds from peptides, Little, Brown and Co., Bos-
ton, 1958, pp. 254-256.
'^' K. Mothes, F. Weygand, D. Groger and H. Grisebach, Z. Natur-
forsch. i;}b 41 (1958).
" Lynn Robert Brady, Dissertation Abstr. 20 2526 (1960).
'^ R. J. Suhadolnik, L. M. Henderson, J. B. Hanson and Y. H. Loo,
;. Am. Chem. Soc. 80 3153 (1958).
471 Ergot Alkaloids
ergot alkaloids.'-* Ci4-Labeled indole and serine, alone or
together, were not incorporated.
Another artificial culture study in which the Claviceps
purpurea culture was grown saprophytically on a simple
galactose, ammonium succinate, mineral salts, biotin me-
dium to which D,L-/^-C"-tryptophan was added, found that
the tryptophan was an efficient precursor.^' Labeling was
about the same throughout the range of alkaloids isolated,
thus suggesting a common biogenesis. Supplementation
with L-tryptophan increased the yield and caused the for-
mation of elymoclavine and agroclavine, which were not
formed otherwise.
Another (non-tracer) experiment in artificial culture
showed no increase in total alkaloid production on supple-
mentation with either tryptophan, hydroxytryptophan, in-
dole, 5-hydroxyindole or serotonin.^''
The consensus of the labeling experiments seems to be,
however, that tryptophan is a rather direct precursor of
the lysergic acid skeleton.
Apparently there is no good evidence yet concerning the
origin of the remainder of the skeleton. The isoprenoid
precursor hypothesis is under investigation. •'• ^"^ This pro-
posal is buttressed by the structure of the mold metabolite,
echinulin, which has an indole nucleus bearing isoprenoid
attachments.
CH3
\
C=CH— CH,
CH3 r 1^ 11 CH3 CH.OH
'CU...
H
^ C— CH=CH. C— CH3
CH3 CH2 1 /"
\ I CH3 HC NH-CH3
c=c ^
CH3 .CHv O
HN
I
^C NH
CH3
Echinulin
kJ.J
>
H
Chanoclavine
" Aro Garo Paul, Dissertation Abstr. 17 2143 (1957).
i*W. A. Taber and L. C. Vining, Chem. and Ind. 1218 (1959).
1^ Ross M. Baxter, S. I. Kandel and A. Okany, Nature 185 241
(1960).
^^ A. J. Birch, B. J. McLoughlin and Herchel Smith, Tetrahedron
Letters No. 7 1 (1960).
Pfizer Handbook of Microbial Metabolites 472
It is also supported by the structure of chanoclavine,
which seems to be not too remotely derived from such an
intermediate.
A thorough review of the chemistry of the ergot alka-
loids has been published. ^^
944 Agroclavine, CieH^gNo, colorless crystals, m.p. 210-212° (dec),
[aW -183° (c 1 in pyridine).
N— CH3
Claviceps purpurea (Fries) Tul.
A. Hofmann, R. Brunner, H. Kobel and A. Brack, Helv.
Chim. Acta 40 1358 (1957).
945 Setoclavine, CieHjgON^, colorless crystals, m.p. 229-234° (dec),
[aW° +174° (c 1 in pyridine).
946 Isosetoclavine (Triseclavine), CieHigONa (stereoisomer of seto-
clavine), colorless crystals, m.p. 234-237° (dec), [c(]u~°
-J-107° (c 1 in pyridine).
Clavicepts purpurea (Fries) Tul.
A. Hofmann, R. Brunner, H. Kobe! and A. Brack, Helv.
Chim. Acta 40 1358 (1957).
" Arthur Stoll, Fortschr. Chem. org. Naturstoffe 9 114-170 (1952).
473 Ergot Alkaloids
947 Elymoclavinc, CksHi^ONo, colorless crystals, m.p. 245-247°
(dec), hW -152° (c 1 in pyridine).
CH,OH
Claviceps purpurea (Fries) Tul.
A. Hofmann, R. Brunner, H. Kobel and A. Brack, Helv.
Chim. Acta 40 1358 (1957).
948 Penniclavine, CjoHigOoNs, colorless crystals, m.p. 222-225°
(dec), [aJD'" +153° (c 1 in pyridine).
949 Isopenniclavine, CicHi^O^No (stereoisomer of penniclavine),
colorless crystals, m.p. 163-165° (dec), [aW° +146° (c 1
in pyridine).
HOCHo
:n— CH3
Claviceps purpurea (Fries) Tul.
A. Hofmann, R. Brunner, H. Kobel and A. Brack, Helv.
Chim. Acta 40 1358 (1957).
950 Dihydroagroclavine (Festuclavine), CigHooNo, colorless crystals,
m.p. 242° (dec), [a]D-° -69° (c 0.5 in chloroform).
Pfizer Handbook of Microbial Metabolites 474
Claviceps purpurea (Fries) Tul.
Matazo Abe, Ann. Rept. Takeda Res. Lab. 10 73, 83, 90,
110, 126, 129, 145, 152, 167, 171, 179, 190, 205, 210 (1951).
Matazo Abe, Togo Yamano, Yoshiharu Kozu and Mitsugu
Kusumoto, ;. Agr. Chem. Soc. Japan 24 416, 471 (1951); 25
458 (1952); 27 18, 613, 617 (1953).
Matazo Abe ibid. 28 44, 501 (1954).
Matazo Abe, Togo Yamano, Yochiharu Kozu and Mitsugi
Kusumoto, ibid. 29 364 (1955).
Matazo Abe, Saburo Yamatodani, Togo Yamano and Mit-
sugi Kusumoto, Bull. Agr. Chem. Soc. (Japan) 19 92 (1955).
Saburo Yamatodani and Matazo Abe, ibid. 19 94 (1955).
951 Pyroclavine, CuiH^oNi., colorless crystals, m.p. 204° (dec), [(x]d-°
-90° (c 0.2 in pyridine).
and
952 Costaclavine, CjeHooNo, colorless crystals, m.p. 182° (dec),
[a] I,'-" +44° (c 0.2 in pyridine).
These are thought to be isomers of dihydroagroclavine.
Claviceps purpurea (Fries) Tul.
Matazo Abe, Saburo Yamatodani, Togo Yamano and Mit-
sugi Kusumoto, Bull. Agr. Chem. Soc. (Japan) 20 59 (1956).
953 Dihydroelymoclavine, Ci.jH.oONo, colorless crystals, m.p. 210°
(dec), [a]^'^ -167° (c 0.16 in chloroform).
H CH2OH
Claviceps purpurea (Fries) Tul.
See references under dihydroagroclavine.
475 Ergot Alkaloids
954 Chanoclavine (Secaclavine), Ci,jH^.„ON^., colorless crystals, m.p.
220-222° (dec), [a],r" -240° (c 1 in pyridine).
CH2OH
I
C— CH3
/
HC NHCH3
Claviceps purpurea (Fries) Tul.
A. Hofmann, R. Brunner, H. Kobel and A. Brack, Helv.
Chim. Acta 40 1358 (1957).
Matazo Abe, Togo Yamano, Saburo Yamatodani, Yoshiharu
Kozu, Mitsugi Kusumoto, Hajime Koinatsu and Saburo Ya-
mada. Bull. Agr. Chem. Soc. (Japan) 23 246 (1959).
955 Ergobasine (Ergometrine, Ergonovine, Ergotocine, Ergostetrine,
Ergotrate, Ergoclinine ) , Ci.,Hj;^02N.{, colorless crystals,
m.p. 162°, [a]ir" +90° (c 1 in water).
956 Ergobasinine, Ci9H2.s02N;{ (stereoisomer of ergobasine), colorless
crystals, m.p. 196°, [ajo'" +414° (c 1 in chloroform).
CH3
O NH— CH— CHoOH
\
C
N— CH3
Claviceps purpurea (Fries) Tul.
Walter A. Jacobs and Lyman C. Craig, Science 82 16
(1935). (Structure)
Pfizer Handbook of Microbial Metabolites
476
957 Ergosecalinine, C04H28O4N4, colorless crystals, m.p. 217° (dec),
[(xW^ +298° (c 0.2 in chloroform).
o=c
NHo^ H
N— CH3
Claviceps purpurea
Matazo Abe, Togo Yamano, Saburo Yamatodani, Yoshiharu
Kozu, Mitsugi Kusumoto, Hojime Komatsu and Saburo Ya-
mada, Bull. Agr. Chem. Soc. (Japan) 23 246 (1959).
958 Ergosine, C30H37O5N5, colorless crystals, m.p. 228° (dec), [<x]d^^
— 179° (c 1 in chloroform).
959 Ergosinine, C30H37O5N5 (stereoisomer of ergosine), colorless
crystals, m.p. 228° (dec), [a]D-° +420° (c 1 in chloro-
form ) .
Claviceps purpurea (Fries) Tul.
477
Ergot Alkaloids
A. Stoll, A. Hofmann and Th. Petzilka, Helv. Chim. Acta 34
1544 (1951). (Structure)
960 Ergocornine, C3iH390-,N.-,, colorless crystals, m.p. 182-184°
(dec), [a]D'" -188° (c 1 in chloroform).
961 Ergocorninine, C31H39O5N5 (stereoisomer of ergocornine), color-
less crystals, m.p. 228° (dec), [a]u'" +409° (c 1 in chloro-
form).
Claviceps purpurea (Fries) Tul.
A. Stoll, A. Hofmann and Th. Petzilka, Helv. Chim. Acta
34 1544 (1951). (Structure)
962 Ergokryptine, C30H41O5N5, colorless crystals, m.p. 212-214°
(dec), [alD'" -187° (c 1 in chloroform).
963 Ergokryptinine, CgoH^iOjNg (stereoisomer of ergokryptine) col-
orless crystals, m.p. 240-242° (dec), [aW +408° (c 1 in
chloroform ) .
Pfizer Handbook of Microbial Metabolites
478
Claviceps purpurea (Fries) Tul.
A. Stoll, A. Hofmann and Th. Petzilka, Helv. Chim. Acta
34 1544 (1951). (Structure)
964 Ergotamine, C^gH^-.Or.Nr,, colorless prisms, m.p. 212-214° (dec.)>
[<xW" -160° (c 1 in chloroform).
965 Ergotaminine, C;^;{H3-,0-,N-, (stereoisomer of ergotamine), color-
less plates, m.p. 241-243° (dec), [a],/-" +369° (c 0.5 in
chloroform ) .
Claviceps purpurea (Fries) Tul.
Walter A. Jacobs and Lyman C. Craig, /. Org. Chem. 1 245
(1936).
Arthur Stoll, Helv. Chim. Acta 28 1283 (1945).
966 Ergocristine, Cg-.HjiyOr.N-,, colorless crystals, m.p. 165-170°
(dec), [a]n-" -183° (c 1 in chloroform).
967 Ergocristinine, Cjj-.HagOr.N.- (stereoisomer of ergocristine), m.p.
226° (dec), [a],.'" +336° (c 1 in chloroform).
X^o^jAn-^
479 Pyridines
Claviceps purpurea (Fries) Tul.
A. Stoll, A. Hofmann and Th. Petzilka, Helv. Chim. Acta
34 1544 (1951). (Structure)
i. PYRIDINES
Few pyridines are listed, but two of these, nicotinic acid
and pyridoxine, are vitamins. Fusaric acid is a wilt toxin,
and 2,6-dipicolinic acid appears in conspicuous quantities
in bacterial spores.
Dipicolinic acid' - ' ' probably is formed by cyclization
of ci;,€-diaminopimelic acid, a lysine precursor and cell wall
constituent of some bacteria:
HOOC — k J — COOH /^^,,
NH> NH.. / N'
HOOC COOH
Diaminopimelic Acid 2,6-Dipicolinic Acid
The metaboHc significance, if any, is unknown. In Bacil-
lus sphaericus diaminopimelic acid is present in spores
and not in vegetative cells, but in many bacteria it is pres-
ent in both.
Fusaric and dehydrofusaric acids are by-products of the
gibberellin fermentation and are produced by fusarium
types. These include plant pathogens, and fusaric acid
solutions sprayed on healthy plants of the usual host
cause wilting typical of infection. Apparently no study
has been made of the mode of biogenesis.
Nicotinic acid in its coenzyme forms occurs in all living
cells where it is essential in hydrogen and electron trans-
port. It is used by a variety of apoenzymes as the pros-
thetic group for various dehydrogenase reactions. It is
much less tightly bound to the protein than, for example,
flavine adenine dinucleotide, perhaps to facilitate move-
ment of the available supply among the apoenzymes in
need of it.
Some of the many microbial reactions known to require
diphosphopyridine nucleotide (DPN) or triphosphopyri-
dine nucleotide (TPN) are:
1 Joan F. Powell, Biochem. ]. 54 210 (1953).
-J. J. Perry and J. W. Foster, J. Bacteriol. 72 295 (1956).
■^ William K. Harrell and Emil Mantini, Can. J. Microbiol. 3 735
(1957).
^ Joan F. Powell and R. E. Strange, Biochem. J. 65 700 (1957).
Pfizer Handbook of Microbial Metabolites 480
CH3CH2OH ;=i CH3CHO (in yeast)
R— CHO ^ R— COOH (in yeast)
Glutathione — SH ;^ Glutathione — S — S — Glutathione (in yeast)
Isocitrate :?^ Oxalosuccinate (bacteria, yeast)
D-Glucopyranose-6-phosphate :?^ 6-Phospho-D-gluconolactone (yeast)
L-GIutamate ;=i a-Ketoglutarate + NH4 (bacteria)
D-Glyceraldehyde-3-phosphate + Phosphate ;=i D-l,3-Diphosphoglyceric
Acid (yeast)
Some of these reactions occur quite generally. Oc-
casionally DPN and TPN are interchangeable, although
one or the other is used more efficiently.
Direct transfer of hydrogen between the substrate and
the 4-position of the nicotinamide moiety of DPN (in the
presence of yeast alcohol dehydrogenase) has been dem-
onstrated, and the stereochemistry of this reaction studied
in exquisite detail by means of deuterated substrate : ^ ®
CONH2
H D
\/ CONH2
fY
+ CH3CD2OH ^ 0 11 -f CH3CDO + H®
1 ®
1
R
R
(R = the rest of the DPN molecule)
"w" CONH.
CONH. H
/ 1
(ill + CH3— CHO + H ® ;=i (T^Y + CH3— C— OH
1
1© D
1
R
R
In the second equation the deuterium atom is removed
exclusively, leaving deuterium-free DPN. This indicates
a marked- steric effect, since the deuterium atom projects
from one side of the molecule. Moreover, a single stereo-
isomer of deuterated ethanol is produced.
Speculations have been made concerning the precise
nature of the coenzyme-apoenzyme-substrate-metal ion
complex. One model' is shown below:
^ Harvey F. Fisher, Eric E. Conn, Birgit Vennesland and F. H.
Westheimer, J. Biol. Chem. 202 687 (1953).
^ H. Richard Levy, Frank A. Loewus and Birgit Vennesland, J. Am.
Chem. Soc. 79 2949 (1957).
^Kurt Wallenfels and Horst Sund, Biochem. Z. 329 59 (1957).
48i
Pyridines
0*-P— OH
0<-P— OH
The fact that alcohol and lactic acid dehydrogenases all
have been found to contain 2 or 4 DPN molecules has also
inspired the hypothesis that hydrogen transfer might re-
quire a pair of adjoining prosthetic groups in a scheme
such as :
in which a deuterated substrate is shown for clarity.* A
more detailed discussion has been pubUshed of the stereo-
^ Jan van Eys, Anthony San Pietro and Nathan O. Kaplan, Science
127 1443 (1958).
Pfizer Handbook o£ Microbial Metabolites
482
chemistry of microbiological reactions with emphasis on
those promoted by dehydrogenases. °
The biosynthesis of nicotinic acid has been studied in
several different biological systems. In neurospora (and
in mammals) tryptophan is the source with 3-oxyanthra-
nilic acid a proved intermediate.^" "• ^^' " ^*' ^^ The re-
maining stages of this route are obscure, although a-
aminomethyl-a,/i^-trarzs-y,8-cis-muconic acid may be an in-
termediate.^'^ It has been shown to be a precursor of
nicotinic acid for the bacterium Xanthomonas pruni. If
it proves to be generally significant, then the following
scheme can be written:
O NH2
CH,
-CH— COOH
NHo —
~7^
o,
Tryptophan
NH2
C— CH,— CH— COOH
CHO
^NH-^^
N-Formylkynurenine
NH2
CO:
[O]
CO— CH,— CH— COOH
NHo
Kynurenine
CO— CHj— CH— COOH
NH.
3- Hydroxy kynurenine
»G. E. W. Wolstenholme and Cecilia M. O'Connor (Eds.), CIBA
Foundation Study Group No. 2, "Sterlc Course of Microbiologi-
cal Reactions," Little, Brown and Company, Boston, 1959, 115 pp.
" W. A. Krehl, L. J. Teply, P. S. Sarma and C. A. Elvehjem, Science
101 489 (1945).
" Fred Rosen, Jesse W. Huff and William A. Perlzweig, /. Biol.
Chem. 163 343 (1946).
'- G. S. Beadle, H. K. Mitchell and J. F. Nye, Proc. Nat. Acad. Sci.
33 155 (1947).
'^ Francis A. Raskins and Herschel K. Mitchell, ibid. 35 500
(1949).
1* Irving L. Miller and Edward A. Adelberg, /. Biol. Chem. 205 691
(1953).
I'^WiUiam B. Jakoby and David M. Bonner, ibid. 205 699, 709
(1953).
"J. O. Harris and F. Binns, Nature 179 475 (1957).
483
Pyridines
COOh
HO .^^^
V M if
\
COOH"
H,0
CH;r
-cIh— COOH WA
1 1 NH,
NH, OH
1 ^NH..
_ 0
3-Hydroxy- Keto-form
anthranilic Acid
H
C
/\
HC CH CO,
II 1 -^
HC CH — NH,
r COOH"
H,
\
COOH
_ H
a-Aminomethyl-a,
0-trans-y, 5-cis-
muconic Acid
T(
ni
jtrahydro-
:otinic Acid
COOH'
^N
H
Dihydro-
nicotinic Acid
COOH
H2
Nicotinic
Acid
A different method of biosynthesis exists in Escherichia
coli and Bacillus suhtilis since tryptophan is not used. In-
vestigation of this route has not progressed so far, but
glycerol is capable of supplying all carbon atoms, as are
glyceric acid and dihydroxy acetone (but not pyruvate).
Succinate, malate, fumarate and oxaloacetate also were
used. Ribose and adenine were required, which suggests
direct synthesis of the coenzyme. ^^
^' Manuel V. Ortega and Gene M. Brown, /. Am. Chem. Soc. 81
4437 (1959).
Pfizer Handbook of Microbial Metabolites 484
The various forms of pyridoxine
are:
CH20H
"O. 1 /CH2OH
HO f
CH3
HO CH2NH2
CH2OH j^Q^j. HO 1 CH2OH
5^/ amination r^l
CH3
if^
CH3
Pyridoxine
Pyridoxal
Pyridoxamine
• If
CH2OH
"O 1 CH2OPO3H2
1
HO y"° CH2OPO3H2
^^ CH2NH2
HO 1 CH2OPO3H2
CH3
CH3
CH3
Pyridoxine Phosphate
Pyridoxal Phosphate
Pyridoxamine Phosphate
Virtually nothing is known concerning the biogenesis of
pyridoxine. Since catabohsm often furnishes clues useful
in the study of biosynthesis, it should be noted that oxida-
tive bacteria degrade pyridoxine as follows : ^*
CH2OH
CH2OH CH2OH
HO I ' CH2OH HO I CHO HO COOH
CH3' CH3 CH3
Pyridoxine Isopyridoxal 5-Pyridoxic Acid
(Pyridoxol) (Lactone)
CH2-O
HO ' ^
O
CH3
i
18 Victor W. Rodwell, Benjamin E. Volcani, Miyoshi Ikawa and
Esmond E. Snell, /. Biol. Chem. 233 1548 (1958); Miyoshi Ikawa,
Victor W. RodweU and Esmond E. SneU, ibid. 233 1555 (1958).
485 Pyridines
i
CH2OH
I
HOOC C
o II
COOH
CH
CH3
^NH"
a-Hydroxymethyl-a'-
(N-acetylaminomethylene)-
succinic Acid
Acid hydrolysis converts the acychc product to paraconic
acid.
Functions of the vitamin are better understood. The
names pyridoxine or vitamin B^ commonly are used in a
general sense to refer to the group. Pyridoxal 5-phosphate
is the actual prosthetic group in most enzymic reactions.
It is a component of transaminases, amino acid decar-
boxylases, tryptophan synthetase, amino acid racemases,
threonine synthetase (homoserine isomerase), S-amino-
levulinate synthetase, phosphorylase and various other
enzymes which manipulate amino acids. More thorough
discussions of functions of this important vitamin can be
found in reviews. ^^' ^°
Some pyridoxal-catalyzed reactions can be carried out in
aqueous solution without the apoenzymes if heat and the
proper metal ions (Al^"^*, Fe**, Cu++) are supplied. Mech-
anisms which have been proposed for three such reactions
are outhned in the following equations:-^' ^-- ^^- ^*
^^ Esmond E. Snell, Vitamins and Hormones 16 77 (1958).
-"Paul D. Boyer, Henry Lardy and Karl Myrback, (Eds.) "The
Enzymes," Alexander E. Braunstein, Pyridoxal phosphate, Academic
Press, New York, 1960, pp. 113-184.
-^ David E. Metzler, Mlyoshi Ikawa and Esmond E. Snell, /. Am,.
Chem. Soc. 76 648 (1954).
"J. B. Longenecker and Esmond E. Snell, ibid. 79 142 (1957).
23 W. Terry Jenkins and Irwin W. Sizer, ibid. 79 2655 (1957).
-* D. S. Hoare and Esmond E. Snell, Proc. Internat. Sympos. Enz.
Chem., Tokyo and Kyoto, Pergamon Press, London, 1957, p. 142.
Pfizer Handbook of Microbial Metabolites
486
HOCH;
CHO
OH
4- CH,— COOH
CH3 NH,
® \X 2H®
HC C--0
II i
HOCHo HC M
J' .0
N'
H CH3
CH2O
H©
NH2
HOCH2— CH— COOH
+ HOCH2— C C
CHO _.. H'
H
HOCH2
OH ^N^ jO
H.,o HOCH2 HC M
HOCHo— C— COOH
+
NHo
CH.
HOCH2 I " OH
2H©
H2O
CH3
i®
CH3
HOCH — C CO
li 1
HOCH. HC M
.0
H"^ CH3
N'
H CH3
CH3— C— COOH
+
NHa
H.O
NH2
CH2=C— COOH.
+
CHO
HOCH2 I OH 2H®
H2O
CH3
OH©
H2C-=C C=-0
HOCH. HC M
,0
H® CH3
M = Metal: (T),(2) = Aldol formation and cleavage
Ql® — Transamination
(3), (5) = «. d-Elimination
487 Pyridines
Attachment to the apoenzyme in vivo was assumed to
be at the pyridine nitrogen atom. Spectral data from such
model systems, however, when applied to purified en-
zymes, indicate that pyridoxal phosphate is bound to the
apoenzyme as a Schiff base in glutamate-aspartate amino-
pherase'-'* and in homoserine deaminase-cystathionase.^^
In crystalline muscle phosphorylase pyridoxal is bound to
the apoenzyme, probably at a lysine e-amino group, as an
aldamine, involving an additional side-chain of the protein
(perhaps — SH).-'' -'
Protein
Protein HN X ^
o© \ / o®
,N^ XH
CH.
H' ^CH (-H_o_p_OH ®0 I ' CHo— O— P— OH NaBH4
o
CH3 CH3 H®
O
Schiff Base Aldamine (X = S?)
Protein
HN XH
O©
CH I
©O I ' CH.— O— P— OH
i
o
Reduced Enzyme
Glutamate-aspartate aminopherase contains 2 moles of
bound pyridoxal phosphate and muscle phosphorylase 4.
It is rather surprising to find the vitamin in an enzyme,
such as the latter, unrelated to its ordinary function.
Doubt has been cast on its function as a prosthetic group
in phosphorylase by several experiments, one of them the
reduction shown, which should have inactivated the
pyridoxal, but which did not inactivate the enzyme.-'^ It
-^ Yoshihiko Matsuo and David M. Greenberg, /. Biol. Chem. 230
545, 561 (1958); idem., ibid. 234 507, 516 (1959).
-° Alan B. Kent, Edwin G. Krebs and Edmond H. Fischer, /. Biol.
Chem. 232 549 (1958).
-" Barbara Illingworth, Hendrlk S. Jansz, David H. Brown and
Carl F. Cori, Proc. Nat. Acad. Sci. 44 1180 (1958).
■-** Edmond H. Fischer, Alan B. Kent, Eloise R. Snyder and Edwin G.
Krebs, /. Am. Chem. Soc. 80 2906 (1958).
Pfizer Handbook of Microbial Metabolites 488
may be that it serves a structural or other function here.
D-Cycloserine has been reported to inhibit aspartate
aminopherase, indole synthetase and D-alanine-D-gluta-
mate aminopherase in some bacteria.-^' ^° Aspartic ana-
logues, such as diaminosuccinic acid and hydroxyaspartic
acid also are effective inhibitors of the first enzyme
above. ^^
It has been suggested that pyridoxine may be impli-
cated in the active transport of amino acids across cell
walls. ^^
968 2, 6-Dipicolinic Acid, C7H5O4N, colorless needles, m.p. 236°
(dec).
HOOC COOH
Bacillus megatherium, B. cereus var. terminalis, B.
sphaericus types
Occurs as the calcuim salt in spores.
Joan F. Powell, Biochem. J. 54 210 (1953).
William K. Harrell and Emil Mantini, Can. J. Microbiol. 3
735 (1957).
Joan F. Powell and R. E. Strange, Biochem. J. 65 700
(1957).
969 Pyridoxal-5'-phosphate CgHioOgNF
O
OH
HO I CH2— O— P=0
OH
>N
CH3
Yeasts, molds, bacteria (widely distributed)
29Takakazu Aoki, Kekkaku 32 544, 605 (1957). (Chem. Ahstr. 52
7427g).
30 N. K. Kochetkov, R. M. Khomutov, M. J. Karpeiskii, E. I. Budov-
skii and E. S. Severin, Doklady Akad. Nauk S.S.S.R. 126 1132 (1959).
3^ Mario Garcia-Hernandez and Ernest Kun, Biochim. et Biophys.
Acta 24 78 (1957).
3- Halvor N. Christensen, Thomas R. Riggs and Barbara R. Coyne,
J. Biol. Chem. 209 413 (1954); Halvor N. Christensen and Thomas R.
Riggs, ibid. 220 265 (1956).
489 Pyridines
I. C. Gunsalus, W. D. Bellamy and W. W. Umbreit, /. Biol.
Chem. 155 685 (1944).
Dorothea Heyl, Eileen Luz, Stanton A. Harris and Karl
Folkers, ;. Am. Chem. Soc. 73 3430 (1951). (Synthesis)
970 Pyridoxine (Vitamin B,j), CsHuOyN, colorless needles from
acetone, m.p. 160° (sublimes).
CH.OH
HO I CH2OH
CH3
Yeasts, molds.
Yields of 82-114 ^g. per gram (dry basis) have been
reported from penicillin broth filtrates.
Yields of 23-100 ^g. per gram of dry cells have been
reported from brewers' yeast.
Leland A. Underkofler and Richard J. Hickey, "Industrial
Fermentations," Chemical Publishing Co., Inc., New York,
1954 Vol. II, J. M. VanLanen, Production of vitamins other
than riboflavin, Chap. 6, pp. 191-216. (A review)
971 Ethyl Hydrogen 2, 6-DipicoIinate, C9H9O4N, colorless crystals,
m.p. 121.5°.
HOOC COOC2H5
Bacillus cereus var. mycoides (spores)
J. J. Perry and J. W. Foster, J. Bacteriol. 72 295 (1956).
972 Dehydrofusaric Acid, C10H11O2N, colorless crystals, m.p. 118°
CH2=<:H— CH2— CH2
COOH
Gibberella fujikuroi Saw.
Ernst Gaumann, Phytopathology 47 342 (1957).
C. A. Stoll and J. Renz, Phytopathol. Z. 27 380 (1957).
John Frederick Grove, P. W. Jeffs and T. P. C. Mulholland,
J. Chem. Soc, 1236 (1958).
Pfizer Handbook of Microbial Metabolites
490
973 Fusaric Acid, C10H13O2N, colorless crystals, m.p. 100°.
CH3CH2CH2CH0
COOH
Gibberella fujikuroi (Saw.) Wr., Fusarium heterospo-
rum Nees, F. bulbigenum Cke. et Mass. var. lycopersici
(Bruchi) Wr. et Rg., F. vasinfectum Atk., F. orthoceras
App. et Wr., Nectria cinnabarina (Tode) Fr.
Yields of about 0.5 g. per liter have been reported.
Teijiro Yabuta, Katsuji Kambe and Takeshi Hayashi, /. Agr.
Chem. Soc. Japan 10 1059 (1934).
John Frederick Grove, P. W. Jeffs and T. P. C. MulhoUand,
J. Chem. Soc, 1236 (1958).
974 Coenzyme III (Nicotinamide Ribose 5'-Diphosphate), CnHieOn-
NoPo.
O
II
C— NH2
o© o
I II
0=P— O— P— O— CHo
&
OH
OH
OH OH
Yeast
Nicotinic acid nucleotides also have been isolated from
yeast.
Thomas P. Singer and Edna B. Kearney, Biochim. et
Biophys. Acta 11 290 (1953).
491
Pyridines
975 Diphosphopyridinenuclcotide (DPN), C2iH^,70,4N7P^..
NH,
c.r.>
OH OH
Yeasts, molds (widely distributed)
H. von Euler, P. Karrer and B. Brecker, Helv. Chim. Acta
19 1060 (1936). (Structure)
G. A. LePage, /. Biol. Chem. 168 623 (1947).
976 Triphosphopyridinenucleotide (TPN, Codehydrase II), C.>iH<,g-
OitNtPs.
NH,
OH
O©
^V CHo— O— P— O— P— O— CM
oh\ II II
^^ O o
OH OH
Yeasts, molds, etc.
Otto Warburg, Walter Christian and Alfred Griese,
Biochem. Z. 279 143 (1935); 282 157 (1935). (Isolation)
Pfizer Handbook of Microbial Metabolites
492
H. von Euler and F. Schlenk, Z. physiol. Chem. 246 64
(1937). (Structure)
Arthur Kornberg and W. E. Pricer, Jr., /. Biol. Chem. 186
557 (1950).
;. QUINOLINES
Quinolines are produced by bacteria and molds, but ap-
parently none has been reported from streptomycetes or
lichens. A complex of seven related 4-oxyquinolines is
elaborated by the oxidative bacterium Pseudomonas aeru-
ginosa (Bacillus pyocyaneus). These are commonly
called "pyo" compounds.
Evidently no investigations have been made on the
mode of biosynthesis of microbial quinolines. The isola-
tion of anthranilic acid and of 2-n-heptyl-3-oxy-4-quino-
lone from "pyo" fermentation broths is suggestive, how-
ever.^ It seems probable that the "pyo" compounds could
COOH
NH2
Anthranilic
Acid
OH
N'
H CH2CH2CH2CH2CH2CH2CH3
2-n-Heptyl-3-oxy-4-quinolone
be formed essentially by condensation of anthranilic acid
or a biosynthetic precursor with a fatty acid or a fatty
acid precursor:
O
II
C— OH
COOH
+
NH2
H2C
c
/\
O R
O
/ CH
COOH
.C— OH
1. Oxidative
decarboxylation
2. Dehydration
OH
IH]
iRokuro Takeda, J. fermentation Technol. 37 59 (1959).
493
Quinolines
Oxidative decarboxylation would then yield an inter-
mediate of the type isolated, and a one-stage reduction the
4-oxyquinolines. The N-oxides might be formed later by
post-oxidation. Quinolines are known to be quite suscep-
tible to N-oxidation by peroxides or oxygen.
The structure of the mold product, viridicatin, has been
verified by synthesis, while that of cyclopenin is still un-
certain. It would appear that these substances are also
derivatives of anthranilic acid. In this case, condensa-
tion probably occurs with an earlier member of the shiki-
mic acid pathway, perhaps prephenic acid or phenyl-
pyruvic acid:
H2C
COOH c=0
-CO2
NH,
Anthranilic
Acid
c
O OH
CH
y \
/ c=o
\
//
OH
Phenylpyruvic
Acid
Viridicatin
Such condensations have been suggested to explain the
origin of certain oxyquinoUne plant alkaloids. -
There is, of course, a possibility for 4-oxyquinoLine for-
mation by way of tryptophan and kynurenine :
O
C
\
CH.
1
NH2 CH— NH2
transamination,
dehydration
COOH
COOH
Kynurenine
This seems to be an unnecessarily indirect route, but all
of the schemes shown here await experimental test.
Ernest Wenkert, Experientia 15 165 (1959).
Pfizer Handbook of Microbial Metabolites 494
977 Viridicatin, Ci-.H^O^N, colorless needles, m.p. 268°.
Penicillium viridicatum Westling, P. cyclopium West-
ling
See under cyclopenin.
A. Bracken, Anna Pocker and H. Raistrick, Biochem. J. 57
587 (1954). (Synthesis)
978 2-n-Heptyl-4-oxyquinoline, CjcHoiON, colorless crystals, m.p.
146°.
OH
CH2CH2CH2CH2CH.CH2CH3
Pseudoinonas aeruginosa
These quinoline derivatives are called "pyo" compounds.
Ibert C. Wells, /. Biol. Chem. 196 331 (1952). (Synthesis)
979 2-n-HeptyI-3-oxy-4-quinolone, CieH.iO.N.
O
H CH,CH2CH.CH2CHnXH2CH3
Pseudomonas aeruginosa strain T-359
The other "pyo" compounds were isolated as well as
anthranilic acid, pyoluteorin, pyocyanine, phenazine-1-
carboxylic acid and oxychlororaphine.
Rokuro Takeda, /. Fermentation Technol. 37 59 (1959).
495 Quinolines
980 2-n-Heptyl-4-oxyquinoline N-oxide, CicH^iOoN, colorless leaflets,
m.p. 158-160°.
i CH,CH,CH,CH2CH,CH,CH3
O
Pseudomonas aeruginosa
J. W. Cornforth and A. T. James, Biochem. J. 63 124
(1956). (Synthesis)
981 Cyclopenin, CiyHj^O^N., colorless tablets, m.p. 207°, [a],r"
-306° (c 1.0 in ethanol).
Proposed structures :
OH
N— CHs
H OH
Penicillhnn cyclopium Westling
Usually viridicatin is produced by the same organism.
Palitantin and frequentin are also produced by P. cyclo-
pium
A. Bracken, Anna Pocker and H. Raistrick, Biochem. J. 57
587 (1954).
982 2-(n-A'-Nonenyl)-4-oxyquinoline, Ci,t;Ho;,ON, colorless crystals,
m.p. 153°.
CH=CHCH2CH2CH2CH2CH2CH2CH3
Pseudomonas aeruginosa
Ibert C. Wells, /. Biol. Chem. 196 331 (1952). (Synthesis)
Pfizer Handbook of Microbial Metabolites 496
983 2-n-Nonyl-4-oxyquinoline, CigHogON, colorless crystals, m.p.
139°.
CH2CH2CH2CH0CH0CH2CH2CH2CH3
Pseudomonas aeruginosa
Ibert C. WeUs, J. Biol. Chem. 196 331 (1952). (Synthesis)
984 2-n-Nonyl-4-oxyquinoline N-Oxide, C18H25O2N, colorless leaflets,
m.p. 148°.
OH
i CHzCHsCHzCHzCHjCHzCHzCHiCHj
O
Pseudomonas aeruginosa
J. W. Cornforth and A. T. James, Biochem. J. 63 124
(1956). (Synthesis)
985 2-n-Undecyl-4-oxyquinoline N-Oxide, C20H09O2N, colorless leaf-
lets, m.p. 148.5°.
i CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3
O
Pseudomonas aeruginosa
J. W. Cornforth and A. T. James, Biochem. }. 63 124 (1956).
(Synthesis)
k. PYRAZINES, DIKETOPIPERAZINES
Diketopiperazines are produced by molds, yeasts and
lichens, but none has been reported from bacteria. Be-
sides those listed in this section, others are classified else-
where, for example, echinulin and gliotoxin under indoles.
Flavacol and pulcherriminic acid seem to be derived
497
Pyrazines, Diketopiperazines
from leucine, the echinulin moiety from leucine and ala-
nine, aspergillic acid from leucine and isoleucine, the
mvcelianamide moiety from tyrosine and alanine, picroro-
cellin from phenylalanine, and gliotoxin from phenyl-
alanine and serine. It might be mentioned that we have
isolated from a Rhizopus nigricans culture a diketopipera-
zine which is a derivative of isoleucine and valine (un-
published).
Dehydration, dehydrogenation, oxidation and N- or
O-methylation sometimes occur to obscure the origin to
some degree. Aromatization to a pyrazine has taken place
in flavacol and pulcherriminic acid, aspergillic acid, a
dihydropyrazine, representing an intermediate oxidation
state. Formation of pulcherriminic acid might be repre-
sented as follows:
OH H2N
CH3
CH3
\
CH— CH2— CH
I \
CH— CH2— CH C= O CH3
/ \ /
CH3 NH2 HO
H
-H2O
CH3
CH3
\
O [\ CH3
CH3 C CH— CH2— CH H2O
\ II \ —
CH— CH2— CH C=0 CH3
/ \ \
CH3 NH2 OH
CH3 "—
CH— CH2— CH
CH— CH2— CH C=0
H
CH3
CH3
CH3
\
HO— C C— CH2— CH — H2
CH3
CH— CH2
C C— OH
H
CH3
Pfizer Handbook of Microbial Metabolites 498
CH3
HO CH.— CH O.
CH3 f i CH3
CH— CH2 OH
CH3
CH3
O /
HO T CH2— CH
CH3 'I I ^^^
K^
CH— CH, i OH
/ O
CH3
The addition of sulfur across the diketopiperazine ring
in gliotoxin is interesting.
986 Flavacol, CjoH^oONo, colorless needles, m.p. 147-149°.
CH3
/
CH2— CH
K
CH3 II J C"'
CH— CH 2 Oh
/
CH3
Aspergillus flavus
George Dunn, G. T. Newbold and F. S. Spring, /. Chem. Soc.
2586 (1949). (Synthesis)
987 Aspergillic Acijcl, CjoHooOoN^, pale yellow needles, m.p. 97-99°,
[a]D-" +13.4° (c 1 in ethanol).
CHs
/
H CH2— CH
CH3
CH3— CH.
CH i OH
/ O
CH3
Aspergillus flavus
499 Pyrazines, Diketopiperazines
James D. Butcher, /. Biol. Chem. 232 785 (1958).
988 Granegillin, C,oHo„OoNo, pale yellow needles, m.p. 99-100°,
optically inactive, the crystals have a characteristic odor
(as does Aspergillic Acid).
The only important difference in properties between
granegillin and aspergillic acid is the lack of optical activ-
ity in the former, and the two compounds may be identical.
A mold resembling Aspergillus flavus
A. Csillag, Acta Microbiol. (Hungary) 1 321 (1954); Abstr.
in Bull. Hijg. 30 159 (1955).
989 Hydroxyaspergillic Acid, Ci2H2„0;iN2, nearly colorless needles,
m.p. 148-150°, [a],r' +36° (c 1 in ethanol).
CH3
/
CH.— CH
CH3 I ^"•■'
CH:, CHo— CH \ OH
I O
OH
Aspergillus flavus
James D. Butcher, J. Biol. Chem. 232 785 (1958).
990 Neohydroxyaspergillic Acid, C10H20O3N2, colorless crystals, m.p.
164-166°, [alo'' -58° (c l".01 in ethanol).
Aspergillus sclerotiorum
A yield of about 300 mg. per liter was obtained.
Ulrich Weiss, Frieda Strelitz, Helen Flon and Igor N. Ashe-
shov, Arch. Biochem. and Biophys. 74 150 (1958).
991
iminic Acid,
Cx
2H20O4N0,
m.p.
173°
CH3
\
0
CH-
-CH2
T
OH
/
CH3
\
.N^
<
/
-N^'\
HO
i
0
CH2
— CH
CH3
CHa
Candida pulcherrima (Lindner) Windisch
This compound was isolated as a red, iron-complexed
Pfizer Handbook of Microbial Metabolites 500
pigment called pulcherrimin, which probably has the
structure :
CH3 III
\ O - Fe
CH— CH2 T 1
CHa f J CHa
I III i CH2 — CH
Fe - O \
CHs
The yield was 30 mg. of pulcherrimin per gram of dry
cells.
A. J. Kluyver, J. P. van der Walt and A. J. van Triet, Proc.
liat. kcad. Sci. U. S. 39 583 (1953).
A. H. Cook and C. A. Slater, J. Chem. Soc, 4130, 4133,
(1956). (Structure)
992 Picrorocellin, C20H22O4N2, colorless prisms, m.p. 192-194°, [ajn
+ 12.5°.
CH3 O
\ /
N-C
CH— CH CH— CH-
I Vnh I
OCH3/ OH
O
Roccella fuciformis Ach.
Martin Onslow Forster and William Bristow Saville,
J. Chem. Soc, 816 (1922).
993 Mycelianamide, CooHogOgNs, colorless leaflets, m.p. 170-172°
(dec), [a]546i'' -217° (c 0.869 in chloroform).
HO O
\ /
O^N-C
-CH=C CH— CH3
c-n'
O OH
Penicillium griseofulvum
I
50I Phenazines and Phenoxazones
A. J. Birch, R. A. Massy-Westropp and R. W. Rickards,
;. Chem. Soc, 3717 (1956).
A. J. Birch, Proc. Chem. Soc, 233 (1957).
/. PHENAZINES AND PHENOXAZONES
The phenazine bacterial pigments have been known for
many years. Pyocyanine was probably isolated in the
early 1860's, and oxychlororaphine was synthesized in
1930. New pigments of this type continue to be reported,
usually from pseudomonas species, but also from strepto-
mycetes. Pyocyanine is responsible for the blue-green
color of pus, since Pseudomonas aeruginosa is a skin para-
site, and certain other blue or green stains on natural ma-
terials have been identified with phenazine pigments.
The phenazine bacterial pigments have been reviewed,^
and this introduction will be confined to a few remarks on
biosynthesis. Actually, there is as yet little to be said on
this subject. Several studies have been made concerning
medium requirements and improvements for optimum
pigment production in both growing- and stationary cul-
tures.* In growing cultures a yield of 231 mg. of pyocya-
nine per liter was obtained on a medium containing glyc-
erol, D,L-alanine, L-leucine and magnesium, calcium, phos-
phate, sulfate and ammonium ions.
In resting cultures glutamic acid and y-aminobutyric
acid were found to be the best substrates, yielding about
250 mg. of pyocyanine per liter. Pigment production was
slow and inhibited by respiratory poisons (cyanide, azide)
but not by fluoride.
These results are not very helpful in speculations on
the biosynthetic intermediates.
Viewed in aggregate there is a noticeable recurrence of
either hydroxyl or carboxyl groups at the 1-position, the
9-position or the 6-position of the phenazine nucleus.
^ G. A. Swan and D. G. I. Felton, "Phenazines," Interscience Pub-
lishers, Inc., New York, 1957, pp. 174-191.
- M. O. Burton, J. J. R. Campbell and B. A. Eagles, Can. J. Res.
26C 15 (1948); M. O. Burton, B. A. Eagles and J. J. R. Campbell,
ibid. 25C 121 (1947); G. Young, /. Bacteriol. 54 109 (1947); Esther
HeUinger, J. Gen. Microbiol. 5 633 (1951).
^ N. Grossowicz, Peyuta Hayat and Y. S. Halpern, /. Gen. Microbiol.
16 576 (1957).
Pfizer Handbook of Microbial Metabolites 502
This is reminiscent of the phenoxazones such as cinna-
HOCH, COOH OCH3 COOH
I /NH2 I
HO— CH2— C— O— CH2
Phenazine Cinnabarin Griseolutein A
barin and actinocinin. The analogy perhaps can be de-
veloped farther, since a streptomycete pigment has been
found with an amino group in the 2-position.
The resemblance is sufficient to suggest anthranilic acid
or related substances as intermediates in the biosynthesis
of phenazines. Oxidative decarboxylations of aromatic
acids to phenols are not unknown among obligate aerobes
of the type that produce phenazines. Also 3-oxyanthra-
nilic acid might account for some of the phenolic hydroxyl
groups.
As for the coupling reaction, perhaps something akin
to phenolic-free radical coupling takes place. Photoirra-
diation of aniline at low temperatures has been reported
to produce phenazine.* Also tetraphenylhydrazine heated
to 90° apparently dissociates to a free radical which re-
arranges to (among other things) a dihydrophenazine.^
NHo
light ^;;?=\^N^
low temperature ^-^'^^N
// \ ^ // \ // %
_/ Heat \_/\... r^^^^^f^^^
N— N ^ N-
// \\/ \r\ r\^
'A. N. Terenin, Acta Physicochim. S.S.S.R. 1.-5 1 (1940); Chem.
Abstr. 35 1701 (1941).
■'"' G. W. Wheland, "Advanced Organic Chemistry," John Wiley
and Sons, Inc., New York, 1949, pp. 727-728.
503 Phenazines and Phenoxazqnes
Atmospheric oxidation is enough to cause phenazine
formation from 3,4-diaminoguaiacol.'' This is a favor-
able case for free radical stabilization.
^^"^NH.- HO ?^"^ ?^"^NH.
\ ^ .M^ O.
NHo NH, NH2
This argument of course is speculative.
994 1-Phenazinol (1-Hydroxyphenazine, Hemipyocyanine ) , Cj^Hg-
ON2, orange crystals, m.p. 157° (sublimes).
OH
Pseudomonas aeruginosa
Fritz Wrede and E. Strack, Z. physiol. Chem. 177 177
(1928).
G. M. Badger, R. S. Pearce and R. Pettit, /. Chem. Soc.
3204 (1951).
Walter S. Moos and John W. Rowen, Arch. Biochem. and
Biophijs. 43 88 (1953).
995 1,6-Dihydroxyphenazine, CioH^OmN:,, golden yellow prisms, m.p.
274°.
OH
I
HO
Streptomyces thioluteus
Hideshi Akabori and Michikazu Nakamura, /. Antibiotics
(Japan) 12A 17 (1959).
<^Fr. Fichter and Julius Schwab, Ber. 39 3339 (1906).
Pfizer Handbook of Microbial Metabolites 504
996 lodinin (l,6-Phenazmediol-5,10-dioxide), C12H8O4N2, purple
crystals with a coppery glint, m.p. 236° (dec.)-
? OH
T I
HO
i
O
Chromobacterium iodinum
G. R. Clemo and A. F. Daglish, J. Chem. Soc, 1481 (1950).
997 Phenazine-1-carboxylic Acid, CigH^O^N^, greenish yeUow needles,
m.p. 242°.
COOH
Pseudomonas aureofaciens Kluyver, Streptomyces misa-
kiensis, Calonectria
Yields of about 1 g. per liter have been mentioned. The
streptomycete produced another phenazine, C17H16N0O2,
called tubermycin A. A pigment closely related to phena-
zine-1-carboxylic acid was also isolated by Kluyver from
the pseudomonas organism.
A. J. Kluyver, J. Bacteriol. 72 406 (1956).
Wm. C. Haynes, Frank H. Stodola, Joan M. Locke,
Thomas G. Pridham, Howard F. Conway, Virgil E. Sohns and
Richard W. Jackson, ibid. 72 412 (1956).
Kiyoshi Isono, Kentaro Anzai and Saburo Suzuki, /. Anti-
biotics (Japan) llA 264 (1959).
998 Oxychlororaphine, C13H9ON3, yellow needles, m.p. 237° (sub-
limes in" the absence of O^, giving yellow crystals, m.p.
241°).
CONH2
Pseudomonas chlororaphis
Fritz Kogl and J. J. Postowsky, Ann. 480 280 ( 1930). (Syn-
thesis )
505 Phenazines and Phenoxazones
999 Chlororaphine, green crystals, m.p. (in the absence of Oo) 225°
(dec.) (in the presence of Oo sublimes at 210°, giving a
yellow sublimate).
Chlororaphine in the crystalline state is a molecular
compound of phenazine-1-carboxamide and its dihydro
derivative in the ratio of 3 : 1.
CONHo CONHo
:xb - cc
H
Charles Dufraisse, Andre Etienne and Edmond Toromanoff,
Compt. rend. 235 920 (1952).
But in solution in the pH range 1.75-10.85 (particularly
at lower pH) chlororaphine exists largely in the semi-
quinone form:
CONH2
CONH2
H 1
HO
/N\^^ <-
^f^
^/Nx.
© i J
k/
!l © I
H©
H
Carlo Cattaneo, Guido Sartori and M. Morellinl, Gazz. chim.
ital. 77 381 (1947).
Pseudomonas chlororaphis
Fritz Kogl and J. J. Postowsky, Ann. 480 280 (1930).
1000 Pyocyanine, CjgHisNoO, dark blue needles, m.p. 133°, decom-
poses to 1-phenazinol on standing in light and air.
O©
I®
CHs
Pseudomonas aeruginosa (Bacillus pyocyaneus), Cya-
nococcus chroma spirans
Heinz HUleman, Ber. 7 IB 46 (1938). (Structure)
G. Farber, Sbornik Ceskoslov. Akad. Zemedelske 23 355
(1951); Chem. Abstr. 45 9605 (1951).
Pfizer Handbook of Microbial Metabolites 506
1001 Cinnabarin (Polystictin), C14H10O5N2, red needles, m.p. : dec.
>320°.
HOCH
Coriolus sanguineus Fr. [= Polyporus cinnabarinus
Ft. = P. sanguineus Fr. = P. coccineus Fr. = P. puniceus
Kalch. = Poly stictus cinnabarinus (Jacq.) = P. sanguin-
eus L. = P. semisanguineus Lloyd = Trametes cinnabarina
(Jacq.)Fr.]
About 100 mg. of red pigment were obtained from 55 g.
of mycelium.
Jarl Gripenberg, Acta Chem. Scand. 5 590 (1951).
G. W. K. Cavill, B. J. Ralph, J. R. Tetaz and R. W. Werner,
J. Chem. Soc, 525 (1953).
Jarl Gripenberg, Acta Chem. Scand. 12 603 (1958). (Struc-
ture)
The same phenoxazone chromophore which occurs in
cinnabarin and the actinomycins has been found in cer-
tain insect pigments called ommatins, e.g. xanthommatin :
HOOC— CH— CH, ^^ ^^^^
I I HO COOH
NH.. C=0
I
N
\
O
Adolf Butenandt, Ulrich Schledt, Ernst Bickert and R. Jan.
T. Cromartie, Ann. 590 75 (1954).
1002 Pigment A, C14H11O2N3 -21120, red crystals, dec. without melting.
Tentative structure:
CH3
\e 0OH NH2- HCI
.N^ /^ / V —COOH
Yield 12-20 mg. per liter
and
507 Phenazines and Phenoxazones
'003 Pigment B, C,r,H,-,0,iN:iS (may also be hydrated), red crystals,
dec. without melting.
An acidic pigment similar to A in structure, but with
an additional methyl group and a sulfo group. Yield
30-40 mg. per liter.
Both produced by a red strain of Pseudomonas aerugi-
nosa.
F. G. Holliman, Chem. and Ind., 1668 (1957).
1004 Griseoiutein A, Ci7Hi40,5No, reddish yellow needles, m.p. 193°
(dec).
Streptomyces griseoluteus
Shoshiro Nakamura, Chem. and Pharm. Bull. (Japan) 6
547 (1958).
1005 Griseoiutein B, Ci^HieOgNo, pale yellow crystals, darkening from
150°, dec. above 220°. Griseoiutein B is a phenazine with
the following proposed structure :
COOH OCH3
ocxp
CH.— O— CH— CH2
OH OH
Streptomyces griseoluteus n. sp.
Hamao Umezawa, Selki Hayano, Kenji Maeda, Yasuo Ogata
and Yoshiro Okami, J. Antibiotics (Japan) 4 34 (1951).
Teisuke Osato, Kenji Maeda and Hamao Umezawa, ibid.
7A 15 (1954).
Shoshiro Nakamura, Kenji Maeda, Teisuke Osato and Ha-
mao Umezawa, ibid. lOA 265 (1957).
Shoshiro Nakamura, Chem. and Pharm.. Bull. (Japan) 6
547 (1958).
Pfizer Handbook of Microbial Metabolites 508
m. PYRIMIDINES
Pyrimidines are fundamental components of living
cells. They have long been recognized as constituents of
nucleic acids, and more recently other functions have
been discovered.
Microorganisms are rather rich in nucleoproteins.
Yeast, which has been a common experimental source,
contains about 4 percent of its dry weight in nucleic
acids, and bacteria up to 15 percent. Bacteriophages are
largely nucleoprotein, and certain plant viruses entirely.
By contrast, thymus gland, one of the richer animal tissue
sources, contains only about 3 percent.
The protein moieties often are relatively low in molecu-
lar weight, some of them qualifying as large peptides, and
they generally seem to be rich in basic amino acids. The
total nucleoprotein molecular weights, however, are very
high — often running to many millions. The complexity
of the nucleic acid moiety varies wdth the complexity of
the species. Since the DNA carries the genetic informa-
tion, it might be expected to be more complex and higher
in molecular weight for the human species than, for ex-
ample, in a simple plant virus.
Two types of nucleic acids have been distinguished,
both widely distributed. Ribose nucleic acid (RNA) and
deoxyribose nucleic acid (DNA) have been mentioned
earlier in connection with their roles in protein synthesis
and genetics.
Neither of these substances has been obtained entirely
pure, but newer techniques such as electrophoresis and
paper chromatography have permitted refinements. The
important purine and pyrimidine components of RNA are
adenine, "guanine, cytosine and uracil. In DNA thymine
takes the place of uracil, and 5-methylcytosine is a minor
NH
V Hn"T\ N^l HN
H HoN H O H O H
Adenine Guanine Cytosine Uracil
(6-amino- (2-amino-6- (2-oxy-6-amino- (2,6-dioxy-
purine) oxypurine) pyrimidine) pyrimidine)
component in some species.
509
Pyrimidines
CH3
NH2
CH3
NH,
CH2OH
) H
Ai
Thymine
(2,6-dioxy-5-
methylpyrimidine)
O H
5-Methyl
cytosine
(2-oxy-5-methyl-
6-aminopyrimidine)
N II N
An
O H
5-Hydroxymethyl
cytosine
(2-oxy-5-hydroxy-
methyl-6-amino-
pyrimidine)
In some Escherichia coli bacteriophages the 5-methyl-
cytosine is replaced by 5-hydroxymethylcytosine. A sub-
stance believed to be 5-ribosyluracil has been isolated in
considerable quantities from yeast RNA.
The united pyrimidine and ribose moieties are called
nucleosides, and the phosphorylated nucleosides are called
nucleotides.
NH2
O
T
HOCH2 /^\ HO— P— O— CH2 /
I ^
OH
OH OH OH
Cytidine Cytidyiic Acid
(a nucleoside) (a nucleotide)
The nucleic acids are, then, polymeric nucleotides, a free
phosphoric acid function being esterified by a free pen-
tose alcohol group.
In neither RNA nor DNA are the four main heterocy-
chc components present in equimolar quantities, and,
moreover, there is of course species variation. For ex-
ample, yeast DNA contains more adenine and thymine
than guanosine and cytosine, while the reverse is true
for some bacteria. The molar sum of the purines gener-
ally equals that of the pyrimidines, and, more specifically,
the number of moles of adenine present equals the num-
ber of moles of thymine, and the cytosine (and methyl-
cytosine) equals the guanine.
There is good evidence now that most DNA is composed
Pfizer Handbook of Microbial Metabolites 510
of a helical coil of paired strands, the strands and coils
being associated by hydrogen bonding, e.g., between the
amino group of adenine and the carbonyl group of thy-
mine.^ This structure is supported by roentgen ray dif-
fraction data, by acid-base titration studies and by light-
scattering measurements on solutions. There are some
recent indications, however, that single-stranded DNA
does exist in some cases.
Tobacco mosaic virus, a crystalline substance which
has been investigated extensively, consists of a single
strand of RNA coiled within a protein sheath. The de-
gree of organization (non-covalent bonding) in the nu-
cleic acid moieties of nucleoproteins has been studied. -
In some instances the nucleic acids seem to be less organ-
ized in the intact protein than in the free state.
Pyrimidine nucleotides also serve as coenzymes in a
number of biological reactions. Thus uridine nucleotide
is important in the enzymic manipulation of sugars. In
recent years, uridine-5'-diphosphate sugar esters have
been isolated from a variety of animal, plant and mi-
crobial sources.
Confining our attention to microorganisms, uridine di-
phosphate glucose, UDP-galactose, UDP-acetylglucosa-
mine as well as uridine triphosphate (UTP) and uridine-
diphosphate (UDP) have been isolated from yeast. ^' * •''
The same substances have been isolated from Peiiicillium
chrysogenum mycelium." Other free nucleotides identi-
fied from the mold were: diphosphophyridine nucleotide
(DPN), cytidine-5'-monophosphate (CMP), adenosine-5'-
monophosphate (AMP), triphosphopyridine nucleotide
(TPN), guanosine-5'-monophosphate (CMP), inosine-5'-
monophosphate (IMP), uridine-5'-monophosphate (UMP),
1 J. D. Watson and F. H. C. Crick, Nature 171 737, 964 (1953).
- F. Bonhoeffer and H. K. Schachman, Biochem. and Biophys. Res.
Comms. 2 366 (1960).
• R. Caputto, Luis F. Leloir, C. E. Cardini and A. C. Paladinl,
J. Biol. Chem. 184 333 (1950); E. Cabib, Luis F. Leloir and C. E.
Cardini, ibid. 203 1055 (1953).
■' S. H. Lipton, S. A. Morell, Alexander Frleden and Robert M. Bock,
;. Am. Chem. Soc. 75 5449 (1953).
•^Hanns Schmitz, Biochem. Z. 325 555 (1954).
'• A. Ballio, C. Casinovi and G. Serlupi-Crescenzi, Biochim. et
Biophys. Acta 20 414 (1956).
511 Pyrimidines
adenosine-5'-diphosphate (ADP), guanosine-5'-diphos-
phatc mannose (GDPM), adenosine-5'-triphosphate (ATP)
and guanosine-5'-triphosphate (GTP).
The UTP is an intermediate in the formation of the
diphosphate: '• ""
UTP + Sugar-l-phosphate ;=i UDP-Sugar + Pyrophosphate
Once in the form of UDP esters, sugars are susceptible
to a variety of enzymic transformations, some of which
were mentioned in the section on polypeptides. For ex-
ample, 4-epimerization may be caused : '• '■'
UDP-Glucose :;=± UDP-Galactose
and
UDP-D-Xylose ;=± UDP-L-Arabinose
Since there is a DPN requirement in these reactions, it
is likely that the 4-hydroxyl group of the sugar is oxidized
to a ketone, then reduced stereospecifically. Isotope work
supports this hypothesis.^"' ^^' ^- UDPG can be oxidized
also to UDP-glucuronate : '^' ^*
2DPN 3H^
UDP-GIucose — ^ { >UDP-Glucuronic Acid
H.O 2DPNH
A yeast enzyme catalyzes the reaction : ^^- ^^
UDP-GIucose + Glucose-6-phosphate > Trehalose Phosphate + UDP
Similarly, di- and polysaccharides seem to be formed
' Paul E. Trucco, Arch. Biochem. and Biophys. 34 482 (1951).
^ Agnete Munch-Petersen, Herman M. Kalckar, Enrico Cutolo and
Evelyn E. B. Smith, Nature 172 1036 (1953).
•'Luis F. Leloir, Arch. Biochem. aiid Biophys. 33 186 (1951).
'" Arthur Kowalsky and Daniel E. Koshland, Biochim. et Biophys.
Acta 22 575 (1956).
" Laurens Anderson, Aurora M. Landel and Donald F. Diedrich,
ibid. 22 573 (1956).
1- Herman M. Kalckar and Elizabeth S. Maxwell, ibid. 22 589
(1956).
^■■' V. Ginsburg, E. F. Neufeld and W. Z. Hassid, Proc. Nat. Acad.
Sci. U. S. 42 333 (1956); V. Ginsburg, /. Biol. Chem. 232 55 (1958).
^* Evelyn E. B. Smith, Agnete Munch-Petersen and George T. Mills,
Nature 172 1038 (1953).
^^E. Cabib and Luis F. Leloir, J. Biol. Chem. 231 259 (1958).
'•^Luis F. Leloir and E. Cabib, /. Am. Chem. Soc. 75 5445 (1953).
Pfizer Handbook of Microbial Metabolites 512
in this way. Involvement in chitin (Neurospora crassay
and cellulose (Acetobacter xylinumy^ biosynthesis has
been shown with labeled UDP-acetylglucosamine and
UDP-glucose, respectively, and work with tritium-labeled
substrates and cell-free extracts of group A streptococci
has shown involvement in hyaluronate biosynthesis.^^
Other evidence indicates involvement in glucuronide-°' ^^
and glycogen--' -^ formation in animals, and glucoside-*' ^^
formation in plants. UMP,-« UDP, UTP-'' -^ and UDP-
glucose-^' •" have been synthesized chemically.
Several cytidine nucleotides have been isolated from nat-
ural sources. •■'^' ^-' ^^ CDP-Choline and CDP-ethanolamine
have been isolated from animals, ^^ plants and yeasts^*
^' Luis Glaser and David H. Brown, Biochim. et Biophys. Acta 23
449 (1957); idem., J. Biol. Chem. 228 729 (1957).
^® Luis Glaser, Biochim. et Biophys. Acta 25 436 (1957); idem., J.
Biol. Chem. 232 627 (1958).
^" Alvin Markovitz, J. A. Cifonelli and Albert Dorfman, Biochim.
et Biophys. Acta 28 453 (1958).
-" Evelyn E. B. Smith and George T. Mills, Biochim. et Biophys.
Acta 13 386 (1954).
21 G. J. Button and I. D. E. Storey, Biochem. J. 57 275 (1954); 59
279 (1955).
" Luis F. Leloir and C. E. Cardini, /. Am. Chem. Soc. 79 6340
(1957); L. F. Leloir, J. M. Olavarria, Sara H. Goldemberg and H. Car-
minatti, Arch. Biochem. and Biophys. 81 508 (1959).
"•^ P. W. Bobbins, B. B. Traut and F. Lipmann, Proc. Nat. Acad.
Sci. U. S. 45 6 (1959).
-* G. Jacobelli, M. J. Tabone and D. Tabone, Bull. soc. chim.. biol.
40 955 (1958).
-> C. E. Cardini and L. F. Leloir, Nature 182 1446 (1958).
-•^Alexander B. Todd, "Methods in Enzymology" (S. P. Colowick
and N. O. Kaplan, Editors) Academic Press, New York, 1957 3 p. 811.
-' B. B. Hurlbert, ibid., p. 785.
2« G. W. Kenner, A. B. Todd and F. J. Weymouth, /. Chem. Soc,
3675 (1952); N. Annand, V. M. Clark, B. H. Hall and A. B. Todd,
ibid., 3665 (1952).
29 G. W. Kenner, A. B. Todd and B. F. Webb, ibid., 2843 (1954).
■'" Bobert Warner Chambers, J. G. MofFatt and H. G. Khorana,
7. Am. Chem. Soc. 79 4240 (1957); J. G. Moffatt and H. G. Khorana,
ibid. 80 3756 (1958).
^^ Bolf Bergquist and Adam Deutsch, Acta Chem. Scand. 7 1307
(1953).
■" Hanns Schmitz, Bobert B. Hurlbert and Van B. Potter, /. Biol.
Chem. 209 41 (1954).
•'•' Eugene P. Kennedy and Samuel B. Weiss, J. Am. Chem. Soc. 77
250 (1955); idem., J. Biol. Chem. 222 193 (1956).
^* Irving Lieberman, L. Berger and W. Theodore Gimenez, Science
124 81 (1956).
513 Pyrimidrnes
and seem to be nearly ubiquitous, although so far they
have not been reported from other microorganisms.
CDP-Glycerol and CDP-ribitol have been isolated only
from lactobacilU,''' but probably such substances will be
found elsewhere.
CDP-Choline and CDP-ethanolamine are coenzymes es-
sential to the biosynthesis of lecithin and phosphotidyl-
ethanolamine.'^ The stages in the biosynthesis of lecithin
may be outlined :
2R— CO— S— CoA
HOCH2CH2N®(CH3)3
ATP^
r^ADP
POCH2CH2N©(CH3)3
Cyt— P— P— p«->jr
ppHI
Cyt— P— P— OCH2CH2N ® (CHsls
Cytidine— P + CH2— OCOR
I
RCOO— CH O
I T
CH2O— P— O— CH2CH2N ® (CHsla
The cytidine monophosphate can then be rephosphoryl-
35 J. Baddiley and A. P. Mathias, /. Chem. Soc, 2723 (1954);
J. Baddiley, J. G. Buchanan, B. Cares, A. P. Mathias and A. R. San-
derson, Biochem. J. 64 599 (1956).
Pfizer Handbook of Microbial Metabolites 514
ated to the triphosphate by ATP, making the process a
catalytic one.
The function of the CDP-ribitol and CDP-glycerol in
Lactobacillus arabinosus seems to be to donate these two
reduced sugar phosphates in the formation of polymers.
These ribitol-glycerol-phosphate polymers are components
of the cell walls of bacteria. Several references are given
in Appendix A to structural studies on these substances.
Biosynthesis of the pyrimidines seems to take a similar
course in microorganisms and in higher animals. So
many workers have contributed to our knowledge of this
scheme that referencing cannot be included, but in out-
line what is now believed to be the important pathway is
shown below:
Carbamyl Phosphate
O
II
H2N— C— OPO3H2 H3PO4
HOOC— CH2— CH— COOH -^^ ^- — ►
I aspartic transcarbamylase
NHo
L-Aspartic Acid
O
II
HO— C
\ H2O
H2N CH2 ^ »
I I dihydro-
C CH orotase
O JJ COOH
N-Carbamyl-l
aspartic Acid
(Ureidosuccinic Acid)
O
'^\ DPN® DPNH + H®
HN CHo
C CH dihydroorotic
^ \.Ki/^ \ dehydrogenase
O 'J COOH
n
L-Dihydroorotic
Acid
515
Pyrimidities
5-PRPP PR
HN
/^^N^ \ orotidylic
O H COOH pyrophosphorylase
Orotic Acid
COOH
OH OH
Orotidine -5 -phosphate
P— P— P— OCH2 /O
lOI
OH OH
Uridine-5'-
triphosphote
CO,
HN
n
'K^J
ATP
orotidylic
decarboxylase POCH.. ,0
OH OH
Uridine-5'- phosphate
HN^l]
L-glutamine L-glutamate
AMP
ATP ADP + P
NH3 H,0
cytidylic
deaminase
P— P— P— O— CHo ^O
CMP <
OH OH
Cytidine-5'-
triphosphate
The biosynthesis of the deoxyribonucleotides may pro-
ceed similarly as far as uridine-5'-phosphate. Direct
transfer into the deoxyribose series (i.e. removal of the
2'-hydroxyl from the ribose moiety) can then occur, or
hydrolysis to the pyrimidine base and subsequent reaction
with 2-deoxyribose-l -phosphate can take place.
There has been much interest in the origin of the
5-methyl group in thymine (5-methyluracil). The oc-
currence of 5-hydroxymethylcytosine in some species sug-
gested donation (in that series) by a tetrahydrofolic acid
derivative. Isotope experiments indicate that the a-C-
Pfizer Handbook of Microbial Metabolites 516
atom of glycine, the /3-C-atom of serine and the C-atom
of formate can all serve as donors at least indirectly.^*'' ^^
There is a vitamin Bio requirement for the conversion of
formate to the thymine methyl group in Lactobacillus
leichmannii, and the pathway does not involve methionine
or a hydroxymethyl group. ^^ It has been suggested that
since vitamin Bj2 coenzymes are required to promote the
equilibrium
HOOC— CH2— CH2— CH— COOH ^ HOOC— CH— CH— COOH
I 1 I
NHo CH3 NH2
Glutamic Acid j3-Methylaspartic Acid
/3-methylaspartic acid may replace aspartic acid as an
intermediate in thymine biosynthesis.^''
An alternate pathway of pyrimidine biosynthesis in-
volving dihydrouracil, a member of the catabolic route,
has been suggested. *°
O O
It II /"^
An/* /-h\
OH O H NH2
4,5-Dihydrouracil 4,5-Diaminouracil
The entire subject of the enzymic synthesis of pyrim-
idines has been reviewed.^^
4,5-Diaminouracil has been detected as a metabolite of
Eremothecium ashbyii and suggested as an intermediate
in riboflavin biosynthesis. ^-
■^'^ David Elwyn and David B. Sprinson, 7. Biol. Chem. 207 467
(1954); idem., J. Am. Chem. Soc. 72 3317 (1950).
•"J. R. Totter, Elliott Volkin and C. E. Carter, J. Am. Chem. Soc.
73 1521 (1951); J. R. Totter and Audrey N. Best, Arch. Biochem.
and Biophys. 54 318 (1955).
■^^ James S. Dinning, Barbara K. Allen, Ruth Young and Paul L.
Day, J. Biol. Chem. 233 674 (1958).
■^^ H. D. Isenberg, E. Seifter and J. I. Berkman, Biochim.. et Biophys.
Acta 39 187 (1960).
^" Lewis C. Mokrasch and Santiago Grisolia, Biochim,. et Biophys.
Acta 27 227 (1958).
•" Peter Reichard, Advances in Enzymology 21 263-294 (1959).
*-T. W. Goodwin and D. H. Treble, Biochem. J. 67 lOp (1957).
5 1 y Pyrimidines
1006 Uracil, C4H4O2N2, colorless needles, m.p. ^-'335° (dec.)-
O
II
O H
Agaricus nehularis, yeasts
Nils Lofgren, Bjorn Liining and Harry Hedstrom, Acta
Chem. Scand. 8 670 (1954).
1007 Cytosine, C4H5ON3, large colorless crystals, m.p. ^320° (dec).
NH2
N
O H
Agaricus nehularis
Nils Lofgren, Bjorn Liining and Harry Hedstrom, Acta
Chem. Scand. 8 670 (1954).
1008 4,5-Diaminouracil, C4H6O2N4, has been shown to be a metabolite
of Eremothecium ashbyii by trapping with diacetyl.
HN
O'
O H
NH,
NH2
T. W. Goodwin and D. H. Treble, Biochem. J. 67 lOp (1957).
1009 Uridine, CgHjoOgNs, colorless crystals, m.p. 165°, [a]D^° +6.4°
(10°) (in water).
HOCH2
"O
/^N-^
O
OH OH
Pfizer Handbook of Microbial Metabolites
518
Yeast
Hellmut Bredereck, Annelise Martini and Friedrich Richter,
Ann. 74 694 (1941).
Hubert S. Loring and James McT. Ploeser, /. Biol. Chem.
178 439 (1949).
1010 Cytidine, C9Hi30riN3, colorless needles, m.p. 225-230° (dec),
[alo'" +29.6° (in water).
HOCH
OH OH
Yeast
HeUmut Bredereck, Annelise Martini and Friedrich Richter,
Ann. 74 694 (1941).
1011 Uridine-3'-phosphate (Uridylic Acid), C^Hj^OoNoP, colorless
prisms, m.p. 200° (dec), [a]„ +9.5 to 14.5° (in water).
HN
HOCH
O
(OHl^P O
OH
Yeast
The 5'-di- and triphosphates also have been isolated
from microorganisms.
Hellmut Bredereck and Gerd Richter, Ber. 7 IB 718 (1938).
W. E. Cohn and C. E. Carter, J. Am. Chem. Soc. 72 2606
(1950).
A. M. Michelson and A. R. Todd, /. Chem. Soc, 2476 (1949).
519
Pyrimidines
1012 C:vtidine-2'-phosphate (Cytidylic Acid) CuHi^OhN-,?, colorless
crystals, m.p. 238-240° (dec), [a]u +20.7° (c 1.0 In
water).
Yeast
Hubert S. Loring, Nydia G. Luthy, Henry W. Bortner and
Luis W. Levy, /. Am. Chern. Soc. 72 2811 (1950).
Hubert S. Loring and Nydia G. Luthy, ibid. 73 4215 (1951).
1013 Cytidine-3'-phosphate (Cytidylic Acid), C,,Hi40sN;{P, colorless
tablets, m.p. 230-234° (dec), [ali, +49°. (c 0.5 in water).
(OHIjP O OH
Yeast
The 5'-di- and triphosphates also have been isolated
from microorganisms.
Hubert S. Loring, Nydia G. Luthy, Henry W. Bortner and
Luis W. Levy, /. Am. Chem. Soc. 72 2811 (1950).
Hubert S. Loring and Nydia G. Luthy, ibid. 73 4215 (1951).
Pfizer Handbook of Microbial Metabolites
520
1014 Orotidine (Orotic Acid Riboside), CioHioOgNg, cyclohexylamine
salt, m.p. 183°.
O
HOCH2 ^o
COOH
OH OH
Neurospora crassa mutant
A. Michael Michelson, William Drell and Herschel K. Mitch-
eU, Proc. Nat. Acad. Sci. U. S. 37 396 (1951).
1015 Cytidine Diphosphate Glycerol, C12H21O12N3P2.
NH2
CH2— CH— CHo
I 1
OH OH
OH OH
Lactobacillus arabinosus
J. Baddiley and R. P. Mathias, /. Chem. Soc, 2723 (1954).
J. Baddiley, J. G. Buchanan, B. Cares, A. P. Mathias and
A. R. Sanderson, Biochem. J. 64 599 (1956).
1016 Cytidine-5'-diphosphatecholine ( CDP-Choline ) , C13H04O11N4P2,
amorphous white, hygroscopic powder.
CH3 CH3
O O ^^
\l II II An
N— CH2— CH2— O— P— O— P— O— CH2 O
/e II
CH3 O® OH
OH OH
521
Pyrimidines
Yeast
This compound is a biogenetic precursor of the lecithins
and cephahns.
Irving Lieberman, L. Berger and W. Theodore Gimenez,
Science 121 81 (1956).
Eugene P. Kennedy and Samuel B. Weiss, J. Biol. Cheni.
222 193 (1956).
1017 Cytidine Diphosphate Ribitol, Cj^Ho-PigNaPs.
O O N
T T /^N
CH2— CH— CH— CH— CH2— O— P— O— P— O— CHo O
OH OH OH OH
OH
O
H
OH OH
Lactobacillus arabinosus
J. Baddiley and A. P. Mathias, /. Chem. Soc, 2723 (1954).
J. Baddiley, J. G. Buchanan, B. Cares, A. P. Mathias and
A. R. Sanderson, Biochem. J. 64 599 (1956).
1018 Uridinediphosphateglucose (UDPG), C15H04O17N2P2.
OH
O
CH2OH
A — o.
K \l o o
koH yi II II
HO N K O— P— O— P-
-0— CHo
OH
OH OH
OH OH
Yeast, molds
A uridinediphosphateacetylglucosamine also has been
isolated from yeast.
R. Caputto, Luis F. Leloir, C. E. Cardini and A. C. Paladini,
J. Biol. Chem. 184 333 (1950).
E. Cabib, Luis F. Leloir and C. E. Cardini, ibid. 203 1055
(1953).
J. G. MofFatt and H. G. Khorana, /. Am. Chem. Soc. 80 3756
(1958). (Synthesis)
Pfizer Handbook of Microbial Metabolites
522
1019 Thymidine Diphosphate Rhamnose, C16H26O14N2P2.
OH
HO i— O.
/CH3 \ O
OH OH
O— P— O— P— O— CH2 /^^N
OH OH
CH3
Lactobacillus acidophilus
Reiji Okazaki, Biochem. and Biophys. Res. Comms. 1 34
(1959).
1020 Plicacetin (Amicetin B), C2r,H3-,07N5, colorless needles, m.p.
182-184° from H.O— CH3OH, [aW +181° (c 2.7 in
methanol).
CH3 CH3
OH
HOCHo
CH3
^7-
/-
NH2
Streptomyces plicatus
Theodore H. Haskell, Albert Ryder, Roger P. Frohardt, Sal-
vatore A. Fusari, Zbigniew L. Jakubowski and Quentin R.
Bartz, ;. Am. Chem. Soc. 80 743 (1958).
523
Pyrimidines
1021 Bamicetin, CosH^oO,,N,., white microcrystals, m.p. 240° (dec),
[a],,-"" +123° (c 0.5 in 0.1 N hydrochloric acid).
Partial Structure:
C13HJ4O5N
\/N
■r
N
NH-C-/ \
O
O CH3
NH— C— C— CH2OH
NH2
Streptomyces plicatus
Theodore H. Haskell, Albert Ryder, Roger P. Frohardt, Sal-
vatore A. Fusari, Zbigniew L. Jakubowsjci and Quentin R.
Bartz, ;. Am. Chem. Soc. 80 743 (1958).
1022 Amicetin (Sacromycin, Allomycin), C29H42O9N6, colorless nee-
dles, m.p. 165-169°, [a],.-' +116.5° "(c 0.5 in 0.1 N hy-
drochloric acid).
Amosamine
CH,
[ HOCH>
CH3
OH
CH3
CH3
0^\ /=N
N //
/
O
NH— C-
O CH3
II I
NH— C— C— CH2OH
NH,
a-Methyl-
D-serine
Cytosine
p-Aminobenzoic
Acid
Streptoviyces vinaceus-drappus, S. fasciculatus, S. sin-
denensis, S. plicatus
Edwin H. Flynn, J. W. Hinnan, E. L. Caron and D. O. Woolf,
Jr., ;. Am. Chem. Soc. 75 5867 (1953).
Pfizer Handbook of Microbial Metabolites 524
Calvin L. Stevens, Robert J. Gasser, Tapan K. Mukherjee
and Theodore H. HaskeU, ibid. 78 6212 (1956).
n. PURINES
The nature of nucleic acids and the participation of
purines in their structure were discussed in the preceding
section. The process of oxidative phosphorylation also
was mentioned although it is not yet entirely understood.
In this process inorganic phosphate ions disappear dur-
ing biological oxidation of substrates and become bound
in adenosine triphosphate (ATP), the universal storage
molecule for chemical energy wdthin cells. Many ex-
amples of ATP as an energy donor were seen in earlier
sections.
Adenosine polyphosphates have other functions, most
of them concerned with the activation and transfer of
various chemical moieties with formation of new chemi-
cal bonds. ATP, for example, can donate phosphate or
pyrophosphate groups to form new phosphate esters.
Two such known reactions are:
hexokinase
Glucose + ATP ;===^ Glucose-6-phosphate + ADP
M^
and phosphoribose
pyrophosphokinase
Ribose-5-phosphate -H ATP ^ ^ri Ribose-5-phosphate-l-
pyrophosphate + AMP
Adenosine-3'-phospho-5'-phosphosulfate has been estab-
Ushed as activated sulfate,^- - and it has been used in the
formation of sulfate esters of a number of phenols and
^ Robert S. Bandurski, Lloyd G. Wilson and Craig L. Squires,
/. Am. Chem. Soc. 78 6408 (1956).
2 P. W. Robbins and Fritz Lipmann, ibid. 78 2652, 6409 (1956).
525
Purines
NH2
1
o
r
HO— S-
i
o
0
T
0— P— 0— CH
OH
^
Adenosine-3'-phospho-
5'-phosphosulfate
1 1
0 OH
1
HO
— P— OH
i
0
alcohols in the presence of sulfokinases. The generality
of the sulfate transfer mechanism has been demonstrated
in yeast, neurospora and liver.
The recognition of S-adenosylmethionine as the active
complex in methyl group transfer from methionine (and
perhaps in its biosynthesis) was noted in the section on
amino acids.
In the section on aliphatic acids an ATP requirement
was noted in the formation of acyl coenzyme A. A num-
ber of acyl adenylates have been prepared or isolated
from natural sources.^' "*■ ^ These can be converted en-
zymically into acyl coenzyme As. The general structure
of these activated acids is:
R— C-
NH2
O
T
-0— P— O— CH;
I
OH
&^^
K^
OH OH
Acid Anhydrides of
Adenosine-5'-pliosphate
3 Paul Berg, ibid. 77 3163 (1955).
■* Preston T. Talbert and F. M. Huennekens, ibid. 78 4671 (1956).
•■^C. H. Lee Peng, Biochim. et Biophys. Acta 22 42 (1956).
Pfizer Handbook of Microbial Metabolites
526
In the same section the mediation of ATP in the forma-
tion of active carbon dioxide was seen:
NH2
ATP + CO2
O O
II T
HO— C— O— P— O— CH
OH
S.Xn'^
+ Pyrophosphate
OH OH
I Biotin phosphate
NH2
O
II
o 00
II T T
C— O— O— P— O— P— O— CH> .0
HN
1
CH-
N
I
-CH
OH OH
OH OH
CH. CH2— (CH,)4— COOH
\c/ i
Enzyme
Possible intermediate in
formation of activated
carbon dioxide
Synthetic adenosyl-5'-phosphoryl carbonate has been pre-
pared.*^
The role of adenine nucleotide as the terminal or ac-
tivating nucleotide of transfer RNA in protein synthesis
was mentioned in the amino acid section.
*^ B. K. Bachhawat, J. F. Woessner and M. J. Coon, Federation
Proc. 15 214 (1956).
527 Purines
Finally, the occurrence of the adenine nucleotide moiety
in various other coenzymes (coenzyme A, flavine-adenine
dinuclcotide, DPN, etc.) should not be forgotten. The
functions of these coenzymes are considered elsewhere.
Adenine polyphosphates, then, are so ubiquitous and so
metabolically important that they nearly all have been
encountered prior to this point in our discussions of mi-
crobial metabolism.
Guanosine polyphosphates, too, are widespread, and
they seem to be able to duplicate some of the less specific
functions of those of adenine. One reaction in which a
guanine polyphosphate is known to participate is : '
a-Ketoglutaric Acid + DPN© + CoA-SH -^
Succinyl-S-CoA + DPNH + H© + CO2
Succinyl-S-CoA + Guanosine Diphosphate + H3PO4 ;=^
Succinic Acid + CoA-SH + GTP
The enzyme catalyzing this reaction has been isolated
only from tissues of higher animals, and there is evidence
that in Escherichia colt at least the adenine nucleotide
seems to be involved.''
Guanosine and inosine nucleotides also participate in
the formation of phosphoenolpyruvate from oxaloace-
tate : "
Oxaloacetic Acid + GTP :;=± Phosphoenolpyruvic Acid + GDP + COn
but again this has been shown only in animal tissues.
The general function of GTP as an energy source in
the amination of inosinic acid during adenine biosynthe-
sis will be seen later.
Guanosine diphosphate mannose has been isolated
" D. R. Sanadl, David M. Gibson, Padmaslni Ayengar and Miriam
Jacob, ;. Biol. Chem. 218 505 (1956).
^ Roberts A. Smith, Irma F. Frank and I. C. Gunsalus, Federation
Proc. 16 251 (1957).
»M. F. Utter and K. Kurahashi, /. Biol. Chem. 207 821 (1954).
Pfizer Handbook of Microbial Metabolites
528
from yeast^° and a penicillium mold^^ as well as from
higher animals, and it probably occurs in plants. Guano-
OH
O O H2N
T T
I— O— P— O— P— O— CH2 ^o.
OH OH
OH OH
OH OH
Guanosine Diphosphate Mannose
sine diphosphate fucose has been isolated from Aerobacter
aerogenes,^'- and this organism has an enzyme which con-
verts GDP-mannose to GDP-fucose. This conversion re-
quires TPNH and must involve several steps to accom-
plish the requisite epimerizations and reduction of the
terminal carbon atom. The functions of these guanosine
derivatives are unknown, but yeast elaborates a mannan,
and fucose is a proven constituent of bacterial polysac-
charides (as well as blood group specific polysaccharides
in higher animals). This may then be a form in which
sugars are modified and transported for incorporation
into polysaccharides.
A substance of the vitamin B12 group isolated from
Nocardia rugosa has been identified as guanosine diphos-
phate factor B, i.e. a guanosine-5'-pyrophosphoric ester of
factor B in which ribose is linked to N-9 of guanine (par-
tial structure shown ).^^
10 E. Cabib and Luis F. Leloir, ibid. 206 779 (1954).
^^ A. Ballio, C. Casinovi and G. Serlupi-Crescenzi, Biochim. et
Biophys. Acta 20 414 (1956).
12 V. Ginsburg and H. N. Klrkman, J. Am. Chem. Soc. 80 3481,
4426 (1958).
'^^ R. Barchielli, G. Boretti, A. DlMarco, P. Julita, A. Migliacci,
A. Minghetti and C. Spalla, Biochem. J. 74 382 (1960).
529
Purines
CN
>f<
CN
° r "'"^
0<-P— O— P— O— CH .
I I
OH OH
OH
Guanosine Diphosphate
Factor B
(Factor B = Vitamin B12
minus the
dimethylbenzimidazole
nucleotide moiety)
OH OH
This substance has been suggested as an intermediate
near the end of the vitamin B12 synthesis just prior to
introduction of the dimethylbenzimidazole nucleotide.
There is evidence that labeled guanine is an isotopic
precursor of riboflavin in Eremothecium ashbyii. Ade-
nine also is a precursor of this vitamin. In each case
the Cs atom is lost. In the case of adenine, at least, the
pyrimidine ring is incorporated intact into riboflavin^*
although pyrimidines such as uracil and thymine are in-
effective precursors."
Inosine is an intermediate in the biosynthesis of ade-
nine and guanine, but beyond the phosphoenol pyruvate
formation and some of the less specific reactions of the
purine nucleotides (phosphate transfer, etc.) few func-
tions have been discovered.
The purine nucleotides have been reviewed.^" ^^' ^*- ^^- ^°- ^^
i-* Walter S. McNutt, Jr., /. Biol. Chem. 219 365 (1956).
15 John A. MacLaren, /. Bacteriol. 63 233 (1952).
1'' Paul D. Boyer, Henry Lardy and Karl Myrback, "The Enzymes"
Vol. II, Robert M. Bock, Adenine nucleotides and properties of pyro-
phosphate compounds. Academic Press, New York, 1960, pp. 3-27.
1" Ibid., Merton F. Utter, Guanosine and inosine nucleotides, pp.
75-87.
18 Jack L. Strominger, Physiol. Rev. 40 55-111 (1960).
"J. Baddiley and J. G. Buchanan, Quart. Rev. 12 152-172 (1958).
-° Standish C. Hartman and John M. Buchanan, Advances in En-
zymology 21 199-261 (1959). (Copyright 1959 by Interscience
Publishers, Inc., New York)
21 G. E. W. Wolstenholme and Cecilia M. O'Connor (Eds.), "CIBA
Foundation Symposium on the Chemistry and Biology of Purines,"
J. M. Buchanan, J. G. Flaks, L. C. Hartman, B. Levenberg, L. N.
Lukens and L. Warren, The enzymatic synthesis of inosinic acid
de novo. Little, Brown and Co., Boston, 1957, pp. 233-255.
Pfizer Handbook of Microbial Metabolites
530
The general scheme of purine biosynthesis is under-
stood now. It is outlined in the following equations :"
O3POCH2
OH OH
Ribose-5-
phosphate
ATP AMP O3POCH2 o
OH Mg^H)
OPocS
Glut- Glut-
amine amate
V ^
Mg<S>
OH OH
Ribose- 1 -pyrophos-
phate-5-phosphate ©
NH3
/
CH2
a
03POCH2
Glycine ADR
+ +©fi
NH. ATP HPO4 O3POCH2
c=o
I
NH
OH OH
1-Aminoribose-
5'-phosphate
OH OH
Glycinamide
Ribotide
H2O
CH2 CHO
N\Ni°-Anhydro-
- formyl THFA
■— ^THFA
.NK
© I
H2N=C
a
Glut- Glut- 0
note amii
k Mg(H>;
CH.
c=o
CHO
'O3POCH0 r. NH amate amine ""O3POCH2 ^ NH
OH OH ADP ATP
Formylglycin- HPO4© H;0
amidine Ribotide
OH OH
Formylglycin-
amide Ribotide
H2O ^1 ^^ ATP
HP04Q^^^-^ADP
" Reproduced from reference 20.
531
Purines
0
i
HC-
V
CH
©.
H,N'
OaPOCHj
OOC
XD3POCH,
\^.
CH
CO.
biotin
OH OH
Aminoimidazole
Ribotide
OH OH
5-Amino-4-imid-
azolecarboxylic
Acid Ribotide
O
II
,c.
HoN
^,
CH
© H.N'
O3POCH2
Fumarate
OH OH
5-Amino-4-imidazole-
carboxamide Ribotide
Aspartate--^ I ^ ATP + H2O
S..ADP + HPOr
COO®
I
CH2
I
CH— NH-
COO®
o
-c
:. H2N'
OaPOCH.
/
OH OH
5-Amino-4-imidazole-
N-succinocarboxamide
Ribotide
Sulfanilamide and other sulfa drugs inhibit the growth
of many bacteria by interfering with the incorporation
of p-aminobenzoic acid into the folic acid coenzymes
(p-aminosalicylic acid, etc., may do the same in mycobac-
teria), and E. coli cultures so inhibited accumulate isola-
ble quantities of 5-amino-4-imidazolecarboxamide ribo-
tide.-'
2^ Joseph S. Gots and Edith G. GoUub, Proc. Nat. Acad. Sci. U. S.
43 826 (1957).
Pfizer Handbook of Microbial Metabolites 532
Azaserine, a glutamine antagonist, inhibits purine syn-
thesis in some bacteria, and causes accumulation of for-
mylglycinamide ribotide in E. coli.-* Another antibiotic,
6-diazo-5-oxo-L-norleucine, also inhibits purine biosynthe-
sis at this stage. Purine-requiring mutants of E. coli and
A. aerogenes accumulate the following compounds or
derivatives : aminoimidazole,-'^ 5-aminoimidazolecarboxa-
mide,-'' 5-amino-4-imidazole-N-succinocarboxamide-^ and
xanthine.-' Yeast grown on a biotin-deficient medium
gives off aminoimidazole riboside and hypoxanthine.-^
Cell-free extracts of Neiirospora crassa are able to pro-
mote all the reactions shown in the biosynthetic scheme
above. All these facts as well as other evidence indicate
that this is the principal biosynthetic route to purines in
bacteria and fungi, and probably is quite general.
Inosinic acid is an intermediate in the biosynthetic
route to the other purines as shown in the formula se-
quence on page 533.
Extracts of Aerobacter aerogenes convert inosinic acid
to xanthylic acid, and there is other evidence that the
final stages of purine biosynthesis follow this route in
many bacteria and fungi as well as in animal cells.
Other references can be found in some of the reviews
of this subject.-"' ^^
There are indications that methylated purines may be
minor constituents of yeast and bacterial nucleic acids.
Traces of 6-methylaminopurine, 6-hydroxy-2-methylami-
nopurine and 1-methylguanine were detected in yeast
RNA.-^ Small amounts of 6-methylaminopurine, 6,6-di-
-^A. J. Tomisek, H. J. Kelley and H. E. Skipper, Abstr., 128th
Meeting, Am. Chem. Soc, 5C, Minneapolis, Sept., 1955.
25 Samuel H. Love and Joseph S. Gots, J. Biol. Chem. 212 647
(1955).
26 Joseph S. Gots, ibid. 228 57 (1957).
2^ Boris Magasanik, H. S. Moyed and Lois B. Gehring, ibid. 226
339 (1957).
2* D. P. Lones, C. Rainbow and J. D. Woodward, /. Gen. Microbiol.
19 146 (1958).
2^^ Max Adler, Bernard Weissmann and Alexander B. Gutman,
;. Biol. Chem. 230 717 (1958).
533
Purines
e ©
OOC— CH2— CH— coo
I
NH,
HN
©O3POCH2
Aspartate GDP
+ GTP +HP04^
OH OH
Inosinic Acid
MgO
•^3POCH2
DPN®
+ HjO ^
DPNH
+H©
:®
)>L^
OH OH ^^
Adenylosuccinic Fumarote
Acid
NH2
©O3POCH2
*/0
OH OH
Adenylic Acid
HN
O H
©O3POCH
OH OH
OH
Xanthylic
Acid
Glutamine, Glutamate,
ATP, H2O AMP, HP2O7©
NHj, ATP AMP, HP2O7S
N' ir %
H2N
©O3POCH2
OH OH
Guanylic
Acid
Pfizer Handbook of Microbial Metabolites
534
methylaminopurine and 2-methyladenine have been
found in bacterial RNA.^°
CH3
NH
H H
6-Methylamino- 6-Dimethylamino-
purine purine
OH
CH;,— NH H
2-Methylamino-6-
hydroxy purine
NH,
CH,— NH
^N^^N-
H2N H
1-Methylguanine
-N^^N^
CH3' H
2-Methyladenine
Kinetin is a substance isolated from yeast which stim-
ulates cell division in plant tissues. Work on kinetin and
related compounds has been reviewed. ^^
Several antibiotics contain the purine nucleus. Some
of these have excited interest as purine analogues for
tumor inhibition, but they are all toxic. Puromycin is
an inhibitor of protein synthesis. - The interference has
been shown to occur at the last stage — that is the ex-
change of the activated amino acid between transfer-
RNA and the growing protein chain.
3f'J. W. Littlefield and D. B. Dunn, Biochem. J. 68 8P (1958);
idem.. Nature 181 254 (1958).
2^ E. R. Squibb Lectures on Chemistry of Microbial Products, "Top-
ics in Microbial Chemistry," John Wiley and Sons, New York, 1958,
F. M. Strong, Kinetin and kinins, pp. 98-158.
"-Michael Yarmolinsky and Gabriel de la Haba, Chem. and Eng.
News April 25, 1960.
535
Purines
CH3 CH
HOCH
NH2
HOCH2
NH OH
OH OH
C— CH— CH,-
_// y
-OCH3
NH2
Puromycin
Adenine
Nucleoside
Substitution of other amino acids for the p-methoxy-
phenylalanine moiety gives analogues which still inhibit
protein synthesis, although the free nucleoside moiety
is a less effective inhibitor. The similarity in structure
suggests competition with adenine nucleoside.
Functions of coenzyme A have been discussed through-
out the appropriate sections. The biosyntheses of the
various moieties of the molecule also have been consid-
ered with the possible exception of ^-aminoethanethiol,
which is derived from cysteine.
The biosynthetic union of these moieties, originally
studied in animal tissues, follows the probable course:
CH3 OH
HOCH2— C CH— COOH
CH3
Pantoic Acid
+ HoN— CHo— CH2— COOH
^ATP
— >ADP
^-Alanine
Pfizer Handbook of Microbial Metabolites
536
Cysteine
i
CH3 OH O
I I II
HOCH2— C CH— C— NH— CHo— CH2— COOH
CH3
Pantothenic Acid
O
T
COOH
Pantothenylcysteine
CH3 OH O
HOCH2— C CH— C— NH
I I
CH3 CHz
I
CHz
I
HSCH2— CH2NHC=0
Pantetheine
ATP
ADP
CH3 OH O
HO— P— O— CH2— C CH— C-
I I
OH CHs
Pantothenic Acid
4'-Phosphate
r'^Cysteine
CH3 OH O
I I II
HO— P— O— CH2— C CH— C
I I
OH CH3
NH
I
CHz
CH2
COOH
o
T
NH
I
CH2
I
CH2
I
HSCHz- CH— NH— C=0
COOH
Pantethenylcysteine-
4'-Phosphate
O CH3 OH O ^ O
T I I II
HO— P— O— CH2— C CH— C— NH— CH2— CH2— C— NH— CH2— CH2SH
OH CH3
Pantetheine-4'-phosphate
11 ATP
537
Purines
11
o o
T T
CHo— O— P— O— P— O— CH2
OH OH
CH3 OH O
I I II
-C CH— C— NH
CH3 I
CH2
I
CH2
HSCH2— CH2— NH— C=0
3'-Dephosphocoenzyme A
i ATP
Coenzyme A
Most of these intermediates have been identified in mi-
croorganisms, e.g. Streptobacterium plantar urn. '-^^ Pan-
tothenic acid is required by some microorganisms, but
probably not by man, perhaps because of the excess pro-
duced by E. coli and other intestinal microbes.
A number of higher fungi and molds have been ex-
amined thoroughly for nucleotide content. Some of the
organisms which have been studied are: Penicillium
chrysogenum,^* Aspergillus oryzae/'' Polyporus squamo-
sus,^^ Amanita muscaria,^^ Lycoperdon pratense,^^
Hypholoma capnoides/'^ Armillaria mellea,^^ Pholiota
squarrosa,^'^ Lactarius vellereus,^''' Lactarius turpis,^'^ Toru-
lopsis utilis,^'' Micrococcus lysodeikticus,^^ Coprinus co-
matis,^^ and Polyporus sulfureus.*^
^3 Theodor Wieland, Walter Maul and Ernst Friedrich Moller,
Biochem. Z. 327 85 (1955).
^* A. Ballio, C. Casinovi and G. Serlupi-Crescenzi, Biochim. et
Biophys. Acta 20 414 (1956); Alessandro Ballio and Giovanni Serlupi-
Crescenzi, Nature 179 154 (1957).
^^ Kazuo Okunuki, Kozo Iwasa, Fumlo Imamoto and Tadoyoshi
Higashiyama, J. Biochem. (Tokyo) 45 795 (1958).
3«Rolf Bergkvlst, Acta Chem. Scand. 12 1549, 1554 (1958).
37 D. Gilbert and E. Yemm, Nature 182 1745 (1958).
38 J. V. Scaletti, Dissertation Abstr. 17 1191 (1957).
39 Paul Heinz List, Arch. Pharm. 291 502 (1958).
*°ldem., Planta Med. 6 424 (1958).
Pfizer Handbook of Microbial Metabolites 538
1023 Hypoxanthine, C5H4ON4.
H
Amanita muscaria. Boletus edulis, Agaricus nebularis,
Polyporiis sulfiireus
E. Buschmann, Pharm. Post 45 453 (1912). (Chem. Abstr.
6 2485)
E. Winterstein, C. Reuter and R. Korolev, 7. Chem. Soc.
104 I 433 (1913).
Nils Lofgren, Bjorn Liining and Harry Hedstrom, Acta
Chem. Scand. 8 670 (1954).
Paul Heinz List, Planta Med. 6 424 (1958).
1024 Xanthine, C5H4O0N4, colorless crystals, m.p. 220° (dec).
O
H H
Amanita muscaria
E. Buschmann, Pharm. Post 45 453 (1912). (Chem. Abstr.
6 2485 )
1025 Uric Acid, C-,H403N4, colorless crystals, m.p. >400° (dec).
O
OH
Aspergillus oryzae
Miazuko Sumi, Biochem. Z. 195 161 (1928).
1026 Adenine, C-.H-.N., (Trihydrate), colorless needles, m.p. 360-365°
(dec) (subl. from 220°) (Picrate), dec. 280°.
539 Purines
Coprinus comatis Gray, Boletus edulis, Polyporus sul-
fureus
Paul Heinz List, Arch. Pharrn. 291 502 (1958).
E. Winterstein and C. Reuter, Centr. Bakt. Parasitenk. II
Abt. 34 566 ( 1912). {Chem. Abstr. 6 3279)
Paul Heinz List, Planta Med. 6 424 (1958).
1027 Guanine, C3H5ON5, (Picrate) dec. from 190°.
HN
Coprimis comatis Gray, Boletus edulis
Paul Heinz List, Arch. Pharin. 291 502 (1958).
E. Winterstein, C. Reuter and R. Korolev, /. Chem. Soc. 104
I 433 (1913).
1028 Heteroxanthine, CgHeOoN^, colorless crystals, m.p. ~380°
(dec).
O ^^^
O H
Yeast
P. W. Wiardi and B. C. P. Jansen, Rec. trav. chim. 53 205
(1934).
1029 Toxoflavin, C6H6O2N4, yellow crystals, m.p. 171°.
CH3
N
An
O H
Pseudomonas cocovenenans
A. G. van Veen and W. K. Mertens, Proc. Acad. Sci. Amster-
dam 36 666 (1933). (Isolation) (Chem. Abstr. 27 5771)
A. G. van Veen and J. K. Baars, Rec. trav. chim. 57 248
(1938). (Structure)
Pfizer Handbook of Microbial Metabolites
540
1030
Kinetin ( 6-Furf urylaminopurine ) , C10H9ON5, colorless prisms,
m.p. 265° (sealed tube to prevent sublimation).
Yeast extracts
E. R. Squibb Lectures on Chemistry of Microbial Products,
"Topics in Microbial Chemistry," John Wiley and Sons, New
York, 1958, F. M. Strong, Kinetin and kinins, pp. 98-157.
1031 Nebularine (9-(/3-D-Ribofuranosyl) purine), C10H12O4N4, color-
less prisms, m.p. 181°, [alo^^ —48.6° (c 1 in water).
N
HOCH2
k:^
OH OH
Agaricus (Clitocybe) nebularis Batsch.
Lars Ehrenburg, Harry Hedstrom, Nils Lofgren and Bertil
Takman, Svensk Kem. Tidskr. 58 269 (1946).
Nils Lofgren, Bjorn Liining and Harry Hedstrom, Acta
Chem. Scand. 8 670 (1954).
David L Magrath and George Bosworth Brown, J. Am.
Chem. Soc. 79 3252 (1957). (Synthesis)
1032 Cordycepin, C10H13O3N5, colorless needles, m.p. 225°, [<xW°
—47° (in water).
HOCH2
541 Purines
Cordyceps militaris (Linn.) Link
K. G. Cunningham, S. A. Hutchinson, William Manson and
F. S. Spring, J. Chem. Soc, 2299 (1951).
H. R. Bentley, K. G. Cunningham and F. S. Spring, ibid.,
2301 (1951). (Structure)
1033 Adenosine, CioHi^O^N^, needles, m.p. 229°, [aW -60 to -63°
(in water).
HOCH2 ^
OH OH
Agaricus nehularis
Nils Lofgren, Bjorn Liining and Harry Hedstrom, Acta
Chem. Scand. 8 670 (1954).
1034 Guanosine, C10H13O5N5, colorless crystals, m.p. 237° (dec),
[alD'" -60° (in 0.1 N sodium hydroxide).
H:N
HOCH, Q
OH OH
Yeast
Hellmut Bredereck, Annelise Martini and Friedrich Richter,
Ber. 74B 694 (1941).
Pfizer Handbook of Microbial Metabolites
542
1035 Inosine-5'-phosphate (Inosinic Acid), C10H13O8N4P, a syrup.
OH
O
II
(OHliP— OCH2
OH OH
Yeast, Penicillium chrysogenum
The 5'-diphosphate also has been isolated.
E. Cabib, Luis F. Leloir and C. E. Cardini, /. Biol. Chem.
203 1055 (1953).
A. Ballio, C. Casinovi and G. Serlupi-Crescenzi, Biochim. et
Biophijs. Acta 20 414 (1956).
1036 Adenosine-2'-phosphate (Adenylic Acid a), C10H14O7N5P, color-
less crystals, m.p. 187° (dec).
NH"
HOCH2
^i
HO
O— P(OH)2
II
o
Yeast
D. M. Brown, G. D. Fasman, D. I. Magrath, A. R. Todd,
W. Cochran and M. M. Woolfson, Nature 172 1184 (1953).
C. E. Carter, J. Am. Chem. Soc. 72 1466 (1950).
Joseph X. Khym, David G. Doherty, Elliot Volkin and
Waldo E. Cohn, ibid. 75 1262 (1953).
D. M. Brown and A. R. Todd, /. Chem. Soc, 44 (1952).
543
Purines
1037 Adenosine-3'-phosphate (3-Adenylic Acid, Yeast Adenylic Acid),
C„,H,40;N-,P, colorless crystals, m.p. 191-195° (dec),
[a]i.-" —66° (c 2 in 5', sodium hydroxide).
NH2
Yeast, Penicillium chrysogenum
H. Steudel and E. Peiser, Z. physiol. Chem. 127 262 (1923).
D. A. Kita and W. H. Peterson, J. Biol. Chem. 203 861
(1953).
1038 Adenosine-5'-phosphate (Muscle Adenylic Acid), Ci(jHi407N5P,
colorless crystals, m.p. 178°, [aju"" —50° (in formamide).
NH..
OH
0=P— O— CH.
I
OH
OH OH
Yeasts, Lactobacillus arabinosiis, Penicillium chryso-
genum
The 5'-diphosphate (ADP) also has been isolated from
microorganisms.
E. Cabib, Luis F. Leloir and C. E. Cardini, ]. Biol. Chem.
203 1055 (1953).
J. Baddiley and A. C. Mathias, /. Chem. Sac, 2723 (1954).
A. Ballio, C. Casinovi and G. Serlupi-Crescenzi, Biochim. et
Biophys. Acta 20 414 (1956).
Pfizer Handbook of Microbial Metabolites
544
1039 Guanosine-3'-phosphate (Guanylic Acid), C10H14O8N5P, colorless
crystals, [ajo -7.5° to -13.5° (in water).
H.N
(OH)2P— O
O
OH
Yeast
The 5'-di- and triphosphates also have been isolated
from microorganisms.
Walter Jones and M. E. Perkins, /. Biol. Chem. 62 557
(1925).
1040 Adenosine-5'-triphosphate (ATP), CioHigOia N5P3.
OH OH OH
I I I
0=P— O— P— O— P— OCH >
I il II "
OH O O
OH OH
Yeasts, molds, bacteria, etc. (widely distributed)
Th. Wagner-Jauregg, Z. physiol. Chem. 238 129 (1936).
(Isolation)
G. A. LePage and W. W. Umbreit, J. Biol. Chem. 148 255
(1943).
D. A. Kita and W. H. Peterson, ibid. 203 861 (1953).
A. Endo, Ann. Report Takamine Lab. 11 45 (1959).
545
Purines
1041 Angustmvcin A, CjiH,304N.r,, colorless needles, m.p. (anhydr.)
169.5° (dec.), [<xW^ +48.3°.
Probable structure:
— C
II
C— OH
I
H— C— OH
I
H— C— OH
1
- C— H
I
CH3
Adenine
>L-2-Ketofucopyranose
Streptomyces hygroscopicus
Hsii Yiintsen and Hiroshi Yonehara, Bull. Agr. Chem. Soc.
(Japan) 21 261 (1957).
Hsii Yiintsen, Kazuhiko Ohkuma, Yoshio Ishil and Hiroshi
Yonehara, J. Antibiotics (Japan) 9A 195 (1956). (Isolation
and characterization)
Hsii Yiintsen, ibid. IIA 79 (1958). (Structure)
1042 Angustmycin C (Psicofuranine), C11H15O5N5, colorless crystals,
m.p. 202-204°, [aW^ -71.1° (c 1.8 in pyridine).
NH2
N \f
HOCHo
CH2OH
OH OH
Streptomyces hygroscopicus var. angustmyceticus
Hsu Yiintsen, /. Antibiotics (Japan) llA 244 (1958).
(Structure)
Pfizer Handbook of Microbial Metabolites
546
1043 Nucleocidin, CnH^eOgNfjS, colorless crystals, no definite m.p.,
[a],r*'' -33.3° (c 1.05 in 1 : 1 ethanol, 0.1 N hydrochloric
acid).
Partial structure:
NHo
I
CeHioOs
I
OSOoNH,
CeHioOs is an unusual
reducing sugar.
Streptomyces calvus
S. O. Thomas, V. L. Singleton, J. A. Lowery, R. W. Sharpe,
L. M. Pruess, J. N. Porter, J. H. Mowat and N. Bohonos, "An-
tibiotics Annual 1956-1957," Medical Encyclopedia Inc., New
York, p. 716. (Isolation)
C. W. Waller, J. B. Patrick, W. Fulmor and W. E. Meyer,
J. Am. Chem. Soc. 79 1011 (1957). (Structure)
1044 Adenylosuccinic Acid, Ci4HisOiiN.r5P, no properties listed.
HOOC— CH— CH.— COOH
NH
H2O3POCH.
OH OH
Penicillium. chrysogenum (mycelium)
About 16 known derivatives of adenine, guanine, cyti-
dine, uracil, etc., also were detected in this study.
Alessandro Ballio and Giovanni Serlupi-Crescenzi, Nature
179 154 (1957).
547
Purkies
1045 Diadenosinctetraphosphate, C2„H^.„0i.,Ni„P, [a]r,44o"" —39.2° (in
N sulfuric acid).
NH;
OH OH OH
I I I
0=P— O— P— O— P— O— CH
I II II
OH O O
-I '2
OH
-O— P— O— CH
OH
OH OH
Yeast
W. Kiessling and O. Meyerhof, Natunvissenschaften 26 13
(1938).
1046 Coenzyme A, C^iHaeOjcN-SPa, white amorphous powder.
NHo
CH2— O-
0 0 CH3 OH 0
-P— 0— P— 0— CH2-C CH— C— NH
OH C
>
\
P(OH);
i
0
OH OH CHj CH2
1
CH2
1
HSCHo— CH2— NH— C=0
Occurs widely in microorganisms and higher animals.
Yeast and certain streptomycetes were early sources.
F. M. Strong, "Squibb Lectures on the Chemistry of Mi-
crobial Products," Coenzyme A and related compounds, John
Wiley and Sons, Inc., New York, 1956, pp. 44-98. (This re-
view lists 117 earlier references.)
Pfizer Handbook of Microbial Metabolites
548
J. G. Moffatt and H. G. Khorana, /. Am. Chem. Soc. 81 1265
(1959). (Synthesis)
1047 Puromycin, C22H29O5N7, white crystals, m.p. 175.5-177°
(uncorr.), [a]D^^ —11° (c 1 in ethanol).
HOCH
0==C— CH— CH
OCH3
Streptomyces albo-niger
J. W. Porter, R. I. Hewitt, C. W. Hesseltine, G. Krupka, J. A.
Lowery, W. S. Wallace, N. Bohonos and J. H. Williams, Anti-
biotics and Chemotherapy 2 409 (1952).
Coy W. Waller, Peter W. Fryth, Brian L. Hutchings and
James H. Williams, /. Am. Chem. Soc. 75 2025 (1953).
( Structure )
B. R. Baker, Robert E. Schaub, Joseph P. Joseph and
James H. Williams, ibid. 77 12 (1955). (Synthesis)
0. PTERIDINES AND FLAVINES
Pteridines (pterins), originally discovered in insects,
occur widely, and several have been isolated from mi-
crobial sources. The most important of these from the
metabolic standpoint is folic acid. This substance, or
group of related substances, is a vitamin for most mam-
mals and plants and for some microorganisms unable to
produce it. Pure folic acid first was isolated from liver
and from yeast. The triglutamyl form was isolated from
a corynebacterium, and the heptaglutamyl derivative, first
isolated from yeast, since has been found in a variety of
microorganisms. The reason for the polypeptide chains is
not clear. These forms are as effective as folic acid in
549
Pteridines and Flavines
higher animals, but are not so active as folic acid for the
bacteria ordinarily used in bioassays.
The functions of folic acid as a B-vitamin have been in-
vestigated extensively and are now largely understood.
Some of these have been encountered earlier in our discus-
sions, but the role of folic acid derivatives in one-carbon
metabolism has not been considered as such.
In its coenzyme form folic acid is attached to a protein
apoenzyme, probably at the glutamic acid moiety, and the
pteridine ring is reduced. One of these pteroproteins has
been crystallized.^ The "active formate" form of the co-
enzyme has been shown to be N^'--formyltetrahydrofolic
acid,^- ^' ^ and the "active formaldehyde" form probably is
N'',N^'^-methylenetetrahydrofolic acid.^' ^- ''• *
HoN
/^N^-^N^
"Active Formaldehyde" N^ N^"-
Methylenetetrahydrofolic Acid
OH
\Xj
CHO
CH.— N ^^^— C— I
HoN
O COOH
I
NH— CH
1
CH2
I
CH2
COOH
"Active Formate"
N^^-Formyltetrahydrofoiic Acid
^ Jesse C. Rabinowitz and W. E. Pricer, Jr., Federation Proc. 17
293 (1958).
- H. M. Rauen and Lothar Jaenicke, Z. physiol. Chem. 293 46
(1953).
3 Lothar Jaenicke, Biochim. et Biophys. Acta 17 588 (1955).
4H. M. Rauen, Biochem. Z. 328 562 (1957).
5R. L. Blakley, Biochem. J. 58 448 (1954).
«Roy L. KisHuk, J. Biol. Chem. 227 805 (1957).
^ M. J. Osborn and F. M. Huennekens, Biochim.. et Biophys. Acta
26 646 (1957).
^ F. M. Huennekens and M. J. Osborn, Advances in Enzym.ology 21
370 (1959).
Pfizer Handbook of Microbial Metabolites 550
The two forms are interconvertible and this oxidation-
reduction equilibrium probably is mediated by an enzyme
with triphosphopyridine nucleotide (TPN) as the pros-
thetic group.
Formate added as a substrate is, then, activated in this
way. The N^"-formyl group also can be furnished by
glycine, either by way of glyoxylic acid'^ ^^ or by way of
S-aminolevulinic acid.^^ ^'' ^^ The equations are:
transam-
ination [O]
H2N— CH2— COOH , OHC— COOH *
Glycine Glyoxylic
Acid
COo -f Ni°-Formyltetrahydrofolic Acid
and
o 00
li NH3 II II
H,N— CH,— C— CH,— CH2— COOH . ^ ' H— C— C— CH,.— CHo— COOH
6-Aminolevulinic Acid a-Ketoglutoraldeiiyde
[O]
^ HOOC— CH>— CH2— COOH + N'o-Formyltetrahydrofolic Acid
Succinic Acid
Once formed "active formate" is the formylating agent
in certain metabolic reactions. The important formyla-
tions by this agent which have been discovered to date are
the two formylations already noted in the biosynthetic
route to the purines. Thus glycineamide ribotide is
formylated to furnish C-8 of the purine nucleus and, later,
5-amino-4-imidazolecarboxamide ribotide is formylated to
furnish C-2 of the purine nucleus.
^ Henry I. Nakada and Sidney Weinhouse, Arch. Biochem. and
Biophijs. 42 257 (1953).
1^' Sidney Weinhouse in W. D. McElroy and H. B. Glass (Editors),
"Amino Acid Metabolism," Johns Hopkins Press, Baltimore, 1955, pp.
637-57.
" David Shemin, ibid., p. 727.
^^ David Shemin, Tessa Abramsky and Charlotte S. Russell, /. Am.
Chem. Soc. 76 1204 (1954).
'"^ Irving Weliky and David Shemin, Federation Proc. 16 268
(1957).
551
Pteridines and Flavines
CH.NHj
\
NH
NH
/ \
CH, CHO
O C
\
NH
P— O— CH,
"Active Formate"
P— 0~CH,
OH OH
Glycineamide
Ribotide
and
OH OH
Formylglycineamide
Ribotide
O
II
c
HoN
-N
II
CH
H2N
P— O— CH,
"Active
Formate"
K®
H,N
OHC
P-O— CH,
-N
CH
HN
OH OH
5-Amino-4-imidazole-
carboxamide Ribotide
OH OH
5-Formamido-4-imidazole-
carboxamide Ribotide
As was seen in the biosynthesis of histidine the N-1 and
C-2 atoms of the purine nucleus are donated to this amino
acid during its formation so that
NH2
N— 1 I
N Y
C— 2
^^N^N
N N
1 T
c— 2
-CH-
NHo
-COOH
Adenine
Histidine
indirectly, at least, these atoms too are furnished by the
coenzyme.
Pfizer Handbook of Microbial Metabolites
552
The "active formaldehyde" form of the coenzyme is in-
termediate in the interconversion of glycine and serine:
"Active
Formaldehyde"
CH2— COOH ^
± HOCH2— CH— COOH
NH2
NH2
Glycine
The large literature on this subject has been reviewed.^
The "active formaldehyde" form may also be considered
to be a methyl group donor, although much remains to be
learned about the mechanisms of these donations. In the
biosynthesis of thymine from uracil, serine, formaldehyde
or formate are more effective precursors of the introduced
methyl group than is methionine, and this precursor effect
is inhibited by foUc acid antagonists.® Actually, the ac-
ceptor is probably not uracil, but deoxyuridine or deoxy-
uridylic acid:
OH
2'-Deoxyuridine
5'-phosphate
OH
2'-Deoxy-5-methyiol-
uridine-5'-phosphate
Thymidine-
5'-phosphate
The occurrence of 5-hydroxymethylcytosine in some spe-
cies has been cited as suggestive of formation of a hy-
droxymethyl intermediate in this way, at least in the
cytosine series."- ^^ On the other hand it has been re-
ported that in Lactobacillus leicJimamiii there is a vitamin
B12 requirement for the conversion of formic acid to the
thymine methyl group, and that the route does not involve
either methionine or a hydroxymethyl group. ^"^
" Seymour S. Cohen and Lawrence L. Weed, J. Biol. Chem. 209
789 (1954).
15 Maurice Green and Seymour S. Cohen, ibid. 225 387 (1957).
1*^ James S. Dinning, Barbara K. Allen, Ruth Young and Paul L.
Day, ibid. 233 674 (1958).
553
Pteridines and Flavines
The synthesis of the labile methyl group of methionine
has been shown to involve a one-carbon unit at the form-
aldehyde oxidation level, and the "active formaldehyde"
form of the coenzyme has been implicated.'"' '■ Here,
again, not everything is known. The following route has
been suggested : ''• ^^
€'
HOOC CH— CHo—CH.— S— CH,
NH2
OH OH
S-Adenosylhomocysteine
"Active
Formaldehyde"
Methionine
Homo-
cysteine
e
00c— CH— CH2— CH2— S— CH.
NH2
OH OH
S-Methylol-S-adenosylhomocysteine
TPNH + H®
G
OOC— CH— CH,— CHo— S— CHs
NH2
OH OH
S-Adenosylmethionine
1" David Elwyn, Arthur Weissbach and David B. Sprinson, J. Am.
Chem. Soc. 73 5509 (1951).
18 David B. Sprinson in W. D. McElroy and H. B. Glass (Editors),
"Amino Acid Metabolism," Johns Hopkins Press, Baltimore, 1955, p.
608.
I'' Audrey Stevens and W. Takami, Federation Proc. 17 316 (1958).
Pfizer Handbook of Microbial Metabolites 554
In an Escherichia coli mutant requiring either methi-
onine or vitamin B12 for growth methionine synthesis
from homocysteine and serine was stimulated by addition
of vitamin 612-""' '^ This suggests that again vitamin Bjo
may be involved in methyl group synthesis.
There is some evidence (from higher animals) that
there is a folic acid requirement for the introduction into
aminoethanol of some, if not all, of the methyl groups of
chohne.-" '-^^
Little is known about the biosynthesis of pteridines in
microorganisms. There are suggestions that both pteri-
dines and flavines are related to the purines in this respect.
•rr^
7 4I 5 CH
Pteridine
>N T ^6
0
COOH
2— NH— / V-C— NH-
-CH
CH2
1
1
CH2
Pteroyl-L-glutamic Acid
(Folic Acid)
COOH
Labeled molecule studies with butterflies indicate that
carbon atoms 4 and 5 of the pteridine ring in leucopterin
and xanthopterin are derived from glycine (4 from the
glycine carboxyl group and 5 from the a-carbon atom).-^
OH ■■ ^ O"
O I OH
N j ]
N
H2N H O H2N
Leucopterin Xanthopterin
The C-6 position seems to be furnished from carbon diox-
ide and the C-2 position from formate, reminiscent of the
purines. Carbon atoms 8 and 9 of the pteridine nucleus
20 c. W. Helliner and D. D. Woods, Biochem. J. 63 26 p (1956).
-1 R. L. Kisliuk and D. D. Woods, J. Gen. Microbiol. 18 xv (1957).
^- Jacob A. Stekol, Sidney Weiss and Ethyl I. Anderson, /. Am.
Chem. Soc. 77 5192 (1955).
23 R. Venkataraman and D. M. Greenberg, ibid. 80 2025 (1958).
2* F. Weygand and M. Waldschmidt, Angew. Chem. 67 328 (1955).
555
Pteridines and Flavines
(in leucopterin from butterflies) are furnished quite di-
rectly by glucose. Over 50 percent of the activity of
D-glucose-1-C" was found in these two positions, and
acetate was excluded as a direct precursor of this part of
the molecule.-^'
A sugar origin for this part of the pteridine ring is sug-
gested, too, by the natural occurrence of such substances
as erythropterin and biopterin, although, in these cases,
OH OH
OH _ OH
N ^
H.N
OH
C=C— CH>
CH— CH— CH3
N
^^
N^^N
HoN
OH OH OH
Erythropterin Biopterin
pentoses would be expected. Both erythropterin and
biopterin, incidentally, occur as glycosides. If a precursor
such as this were assumed, it would relate these sub-
stances closely with the riboflavin structure. There is
experimental support for the assumption of the pyrimi-
dine shown as a riboflavin precursor.^"
NH.
CH2
1
CH— CH— CH— CH2
1111
OH OH OH OH
O
CHj
CH3
CH2
I
CH— CH— CH— CH2
I I I I
OH OH OH OH
Assumed pteridine
precursor
Riboflavin
Many pteridine derivatives related to the pteridine
-' F. Weygand, H.-J. Schliep, H. Simon and G. Dahms, ibid. 71 522
(1959).
-^ Toyokazu Kishi, Mitsuko Asai, Toru Masuda and Satoru Kuwada,
Chem. and Pharm. Bull. (Japan) 7 515 (1959).
Pfizer Handbook of Microbial Metabolites 556
moiety of folic acid have been isolated from non-microbial
species. This subject has been reviewed.^' '^
Labeled xanthopterin was converted to 5-formyl-5,6-
7,8-tetrahydropteroic acid by Enterococcus stei. Strepto-
coccus fecalis, E. coli and Pichia membranaefaciensr'''
Folic acid was not formed even when p-aminobenzoic acid
was added to the medium. Cell extracts of these micro-
organisms produced folic acid principally.
The assembly of the three moieties of folic acid into the
complete molecule has been studied. Lactobacillus arabi-
nosus contains enzymes able to couple 2-amino-4-hydroxy-
pteridine-6-carboxaldehyde or the corresponding alcohol
with p-aminobenzoic acid.-^
OH OH
I .. .CHO I . /CH2OH
H2N H2N
2-Amino-4-hydroxy- 2-Amino-4-hydroxy-6-
pter'dine-6-carboxaldehyde hydroxy methylpteridine
These pteridines are even more effective precursors in
their reduced forms. Many other pteridines tested were
not used. ATP (and Mg*"^) was required. Its role is un-
known, although phosphorylation of the alcohol of the
pteridine hydroxymethyl group might be necessary to
activate it for coupHng.
p-Aminobenzoic acid was more effective than p-amino-
benzoylglutamic acid in this coupling reaction in E. coli,^^
although Mycobacterium avium was able to use the pep-
tide.^" Apparently adenylo-p-aminobenzoic acid was an
intermediate in the latter organism (ATP and Co A were
required ) .
The origin of p-aminobenzoic acid was considered in an
earlier section. It has been known for some time that the
anti-infective sulfonamide drugs function by interfering
27 J. J. PfifFner and O. D. Bird, Ann. Rev. Biochem. 25 416-^19
(1956).
27' F. Korte and Gotthard Synnatschke, Ann. 628 153 (1959).
28 T. Shiota, Arch. Biochem. and Biophys. 80 155 (1959).
2«Gene M. Brown, Federation Proc. 18 19 (1959).
^° H. Katunuma, Abstr. 32nd Congr. Japanese Biochem. Assoc,
Kyoto, July 1957.
557
Pteridines and Flayines
with the incorporation of p-aminobenzoic acid into fohc
acid. Enzyme studies (E. coli extracts) now seem to have
narrowed this to inhibition of the couphng of the pteridine
moiety with p-aminobenzoic acid," although in the Myco-
bacterium avium study inhibition of peptide formation by
prevention of adenylo-p-aminobenzoic acid formation was
suggested.
Investigation of the biosynthesis of riboflavin is facili-
tated by the existence of the two microorganisms, Eremo-
thecium ashbyii, a yeast, and Ashbya gossypii, a mold,
which are prodigious producers of this vitamin, evolving
large quantities into the culture medium.
Besides riboflavin several other substances have been
isolated from riboflavin fermentations. The structures of
these metabolites suggest that they may be biosynthetic
precursors of the vitamin.
CH3
\
c=o
I
CH-OH
CH3
HN
NH2
H NH.,
^V^
CH3
CHs
CH2— CH— CH— CH— CH2
OH OH OH OH
Acetoin 4,5-Diaminouracil 6,7-Dimethyl-8-(D- 1 '-ribityl)-lumazine
G-Compound (green fluorescence)
3HN
OH OH OH OH
6-Methyl-7-oxy-8-(D- 1 '-ribitylj-lumazine
V-Compound (violet fluorescence)
OH OH OH OH
Riboflavin
They are shown in the accompanying formulas.
Addition of purines to cultures of growing riboflavin
producers increases the yield of riboflavin.''- C"-8-Labeled
adenine contributes no radioactivity to the riboflavin mole-
■'*i Gene M. Brown, Physiol. Revs. 40 359 (1960).
32 John A. MacLaren, /. Bacteriol. 63 233 (1952).
Pfizer Handbook of Microbial Metabolites
558
cule,"'^ but C-4 of the purine nucleus is equivalent to C-4a
in riboflavin, and C-5 of purine to C-9a of riboflavin.^"*
The C-4 of riboflavin is furnished by carbon dioxide (cf.
C-6 in purines), and C-2 from formate (cf. C-2 in pu-
rines). These relationships are shown in generalized
diagram.
Sources of the Carbon Atoms in Purines, Pteridines and Flavines
co;
i
o
HCOOH
y
IN iT|
\
HCOOH HCOOH
Purine
HCOOH
The pyrimidine rings in all these systems seem to have
a common origin, and perhaps purines are precursors of
the other two classes of heterocycles.
Guanine-5-C^ * was converted to labeled riboflavin and to
labeled G-compound by Eremothecium ashbyii, Ashbya
gossypii, Candida fiareri, C. guilliermondii and C. parapsi-
lopsis.'^-' Pyrimidines and pteridines were not used di-
rectly, and, when labeled G-compound was added to grow-
ing cultures, it was not converted to riboflavin by E.
ashbyii nor was labeled 4,5-diaminouracil. V-Compound
was shown to be formed rather easily from G-compound
by air oxidation of a stored alkaline solution. While G-
compound was not used by growing whole cells, cell-free
extracts of E. ashbyii, Ashbya gossypii, Mycobacterium
smegmatis and M. avium were able to incorporate it into
the riboflavin molecule.-^'" ■"
33 Walter S. McNutt, 7. Biol. Chem. 210 511 (1954).
3*G. W. E. Plaut, ibid. 208 513 (1954).
"•"' Friedhelm Korte, Hans Ulrich Aldag, Gerhard Ludwig, Wilfried
Paulus and Klaus Storiko, Ann. 619 70 (1958).
3« Friedhelm Korte and Hans Ulrich Aldag, Ann. 628 144 (1959).
3" G. F. Maley and G. W. E. Plaut, /. Am. Chem. Soc. 81 2025
(1959).
559
Pteridines and Flavines
Adenine was found to be a more efficient precursor for
riboflavin than G-compound in C"-labeling studies,-^"^ and
guanine and xanthine have been found more efficient than
adenine. •'
Acetate'" and shikimic acid" have been shown to be im-
probable direct precursors of the A ring of riboflavin.
Acetoin has been isolated from riboflavin fermentations*-
and is a normal metabolite of these organisms and of
other yeasts. On the basis of chemical studies this sub-
stance (or near derivatives) was proposed as a precursor
of the A ring of riboflavin.''^ '* It has been confirmed that
acetoin is an efficient biological precursor of the vitamin"
although intermediates cannot be ruled out entirely.
At present, then, the following biosynthetic scheme
seems indicated:
Purine,
Purine nucleoside
or
Purine nucleotide
r^'
HO
NH
CH,
Pyruvic Acid
i
(CHOH)3
"Active Acetaldehyde
1
i
CH2OH
Acetoin
\y
--♦
2H2O
0
CH3
Acetoin
II
CH3
""^Y"^^
)\o]
H\f^
f^ Y^
-N--^-^
3H2O
„>M^
^N^
1 CH,
1 CH3
CHo
CH2
(CHOH),
(CHOH)3
CH2OH
CH2OH
3-^ R. Cresswell and H. Wood, Proc. Chem. Soc, 386 (1959).
3»E. G. Brown, T. W. Goodwin and S. Pendleton, Biochem. J. 68
40 (1955).
40 G. W. E. Plaut, ;. Biol. Chem. 211 111 (1954).
"T. W. Goodwin and D. H. Treble, Biochem. J. 70 14 p (1958).
42Toru Masuda, Pharm. Bull. (Japan) 5 136 (1957).
«A. J. Birch and C. J. Moye, /. Chem. Soc, 412 (1957); 2622
(1958).
Pfizer Handbook of Microbial Metabolites 560
The occurrence of V-compound could be explained as due
to a side-reaction in which pyruvate rather than acetoin
reacted with the pyrimidine, or it may merely be an oxida-
tion product of G-compound. The close relationship be-
tween pyruvate, active acetaldehyde and acetoin, which is
mediated by thiamine, has been discussed in an earlier
section.
The origin of the ribityl group remains obscure. It is
yet to be shown whether this moiety is derived from the
ribose of the purine nucleosides or whether it is formed in
some other way. Some work has been done on this facet
of the biosynthesis. ^'^ **• *^' ^'^
Riboflavin is phosphorylated by ATP to give riboflavin-
5'-phosphate, a coenzyme form. This, in turn, can react
again with ATP in the presence of the appropriate en-
zyme to form flavine-adenine dinucleotide, the other co-
Mg++
Riboflavin -f ATP -^ Riboflavin-5'-phosphate + ADP
Riboflavin-5'-phosphate -|- ATP :^ Flavine-adeninedinucleotide + Pyrophosphate
enzyme form. Flavine-adenine dinucleotide (FAD) is
produced commercially in Japan from E. ashbyii my-
celium.
The principal point of attachment of fiavinemononucle-
otide (FMN) to the apoenzyme seems to be the phosphate
group. There may be involvement of the 3-imino group
also. FAD is the most prevalent coenzyme form, although
FMN occurs in rather large proportions in some microor-
44 G. W. E. Plaut and Patricia L. Broberg, /. Biol. Chem. 219 131
(1956).
4=^ Edna B. Kearney and Sasha Englard, ibid. 193 821 (1951).
4^ Anthony W. Schrecker and Arthur Kornberg, ibid. 182 795
(1950).
561 Pteridines and Flavines
ganisms. Obligate anaerobes contain relatively large
quantities of flavoproteins. Surveys have been made of
the flavine content of microorganisms not used in com-
mercial production.'' '^ There is variation in the tight-
ness of binding of the coenzyme, and the modes of attach-
ment are not entirely understood.
One of the functions of the flavine enzymes has been
mentioned already, namely, the dehydrogenation of re-
duced DPN in the respiratory chain. Sites of DPNH for-
mation were seen earlier, particularly in the glycolysis
route and the citric acid cycle. The enzyme succinic de-
hydrogenase is a flavoprotein, and the FADH^ formed in
this reaction also is fed into the respiratory chain. Besides
the direct net synthesis of 2 moles of ATP during glycoly-
sis and of 1 mole of ATP in the citric acid cycle, the re-
maining energy released during glucose catabolism is
transferred in the form of hydrogen or electrons to en-
zymes with TPN, DPN or FAD as prosthetic groups.
These reduced enzymes are, in turn, oxidized by the
metal ion-porphyrin enzymes, which are oxidized by gase-
ous oxygen. When two hydrogen atoms are passed along
the entire respiratory chain, water is formed as well as 3
more molecules of ATP.
The exact number of particles in the chain is not en-
tirely clear, and there are variations with different or-
ganisms. In lactobacilli, for example, flavines seem to
replace heme proteins in electron transport. *^^ Also ob-
scure is the exact manner in which ATP is formed during
respiration and the precise way in which hydrogen is
transferred from one coenzyme to the next. There has
been interesting speculation in this area of biophysics.
The respiratory chain can be shown in a simplified form
as in the accompanying diagram. ^^
''"J. L. Peel, Biochem. J. 69 403 (1958).
*^ Chester DeLuca, Morton M. Weber and Nathan O. Kaplan,
/. Biol. Chem. 223 559 (1956).
^s" Cornelius F. Strittmatter, Federation Proc. 17 318 (1958).
■*» Albert L. Lehninger, Scientific American 202 102 (1960).
Pfizer Handbook of Microbial Metabolites
562
s
u
B
/"
^iSH
Jx <— dpnh4x
>'r>
+
H
The natures of the entities X, Y and Z are mysterious. If
they are assumed to possess nucleophiUc groups such as
R — S', R — COO" or H0PO4", then one scheme has been ad-
vanced to show how the requisite energy-rich bonds could
be formed in DPNH, FADH and Ferricytochrome ag.^"
The couphng methods and resonance systems involved are
shown in the diagram:
CHj
H Hilll
Rb-ADP
H H -K
/ +HX;=; r 'J; ^N; + oh©
^N
Rb-ADP
C H
N +2e -f- HjO
H % (3.
I ill! "
^0(2)
CHj 1 r ^>ri,„ CH:
ADP-Rb H
(1)
H X
HC— X
CjHs CH;
CH Fe(3) CH + HX
fatty CH
acid II
RCH
ADP-Rb ^)
+2e + H2O
CH—
-f-OHQ— a
Z
OH
R— C -t- HS— E ;^ R— C— SE -> R— C -f 2e -f- 2H©
\ I \
H H SE
5" Paul E. Glahn and Sigurd O. Nielsen, Nature 183 1578 (1959).
563
Pteridines and Flavincj
CYT
2
CYT
C"
H-f'-'U
&0*-'
zh^2nr:!Hz 2
CYT
+
H
Another hypothesis assumes close approach of DPNH
and riboflavin in parallel planes with interposition of in-
organic phosphate, held perhaps by hydrogen bonding,
e.g. to the amide moiety of nicotinamide.'^^ These geomet-
rical and chemical relationships can be represented as
follows :
ie "
"Barbro Grabe, Biochim. et Biophys. Acta 30 560 (1958).
Pfizer Handbook of Microbial Metabolites 564
When an electron is transferred from the N-atom of the
reduced pyridine ring to an unoccupied 7r-orbital of the
isoalloxazine ring of FAD, the N-atom assumes a positive
charge, which is neutrahzed by attraction of a proximate,
ionized phosphate hydroxyl oxygen. The increased elec-
tron density on the 0-atom at position 2 in the riboflavin
nucleus might cause formation of a bond to phosphorus
as shown in the activated complex above, the reaction
being :
DPNH + FAD + H2O3PO® + H® ^ DPN® + H2O3P— FADH + OH®
When this substance is oxidized by the subsequent carrier
(probably a cytochrome), two electrons, perhaps dislocal-
ized TT-electrons, are withdrawn from the FAD-complex
thus permitting dissociation of a proton and activation of
the phosphoryl group. In the presence of ADP, then, ATP
could be formed according to the equation:
FADH— PO3H2 + ADP + 2Fe€I5) ^ FAD + H© + ATP + 2Fe<£5
Other flavoprotein dehydrogenase substrates are: alde-
hydes, a-amino acids, a-hydroxy acids, purines, fatty acid-
coenzyme A esters and certain amines. Flavine enzymes
also participate in bacterial hydrogenase systems, in ni-
trate reduction and assimilation by fungi and higher
plants and in photosynthesis and bioluminescence. There
is currently much study of flavoprotein reactions, which
can often be followed by spectrophotometry and EPR tech-
niques.
Reviews of the flavine coenzymes and their biosynthesis
are available. ^^' ^^
1048 Xanthopterin, CgHjOoNg, yellow amorphous substance, isolated
as barium or sodium salts.
OH
I .OH
HoN
N Y 1
^2 Paul D. Boyer, Henry Lardy and Karl Myrback (Eds.), "The
Enzymes" Vol. II, 2nd ed., Helmut Beinert, Flavin coenzymes.
Academic Press, New York, 1960, pp. 340-416.
565 Pteridines and Flavines
Mycobacterium tuberculosis
Also occurs as a butterfly wing pigment.
Marguerite 0"L. Crowe and Amy Walker, Brit. J. Exptl.
Pathol. 35 18 (1954). (Isolation from this organism)
Robert Purrmann, Ann. 546 98 (1940), 548 284 (1941).
(Synthesis)
1049 Pterin-like Substance.
By paper chromatographic comparisons this purple
fluorescent substance was shown to be similar to or identi-
cal with 2-amino-4,7-dihydroxypteridine-6-acetic acid
(C,H,0,N,).
As-pergilli
Yasuyuki Kaneko, /. Agr. Chem. Soc. Japan 31 122 (1957).
1050 Erythropterin, C.,H;,0-,N-„ deep red crystals from 0.01 N hydro-
chloric acid.
OH
I /OH
H2N C=C— CH2OH
I I
OH OH
Mycobacterium tuberculosis var. hominis, M. lacticola
M. O'L. Crowe and A. Walker, Science 110 166 (1949).
Rudolf Tschesche and Frederic Vester, Chem. Ber. 86 454
(1953).
1051 Biopterin, C9H11O3N5, pale yellow crystals, m.p. 250-280°
(dec), [aln^" -50° (in 0.1 N hydrochloric acid).
OH
I XH— CH— CH3
N
/
H2N
-^Kl/-\l
OH OH
Yeast, Ochromonas malhamensis
E. L. Patterson, H. P. Broquist, Alberta M. Albrecht, M. H.
von Saltza and E. L. R. Stokstad, /. Am. Chem. Soc. 77 3167
(1955).
Pfizer Handbook of Microbial Metabolites
566
1052 V-Compound (8-Ribityl-6-methyl-7-oxylumazme, Compound A),
Ct.Hi607N4, colorless crystals, m.p. 263° (dec), [ocW
+4.5° (c 3.3 in water) +11.45° (in 0.1 N sodium hy-
droxide solution).
II M
XH3
OH
.CH3
CH2
I
(CHOH)3
1
CH2OH
T J I
I ^
CHo
I
(CHOH)3
I
CH2OH
Eremotheciuvt ashbyii
Toru Masuda, Toyokazu Kishi and Mitsuko Asai, Chem. and
Pharm. Bull (Japan) 6 291 (1958). (Structure)
Toru Masuda, Toyokazu Kishi, Mitsuko Asai and Satoru
Kuwada, ibid. 7 361, 366 (1959). (Synthesis)
Waher S. McNutt, /. Am. Chem. Soc. 82 217 (1960).
1053 G-Compound (8-Ribityl-6,7-dimethyllumazine), C13H18O6N4,
light yellow needles, m.p. 273° (dec), [ocW -164°.
HN I
XH3
CH3
CH2
I
(CHOH)3
I
CH2OH
Eremothecium ashbyii
1054 Z-3-Oxykynurenine, CHJH10O4N2
O
C— CHo— CH— COOH
NH2
O" NH,
567
Pteridines and Flavines
was isolated from the same culture. This metabolite re-
sembles 3-oxyanthranilic acid, known to be a biosynthetic
precursor of nicotinic acid.
Toru Masuda, Pharm. Bull. (Japan) 4 71 (1956). (Iso-
lation)
Idem., ibid. 5 28 (1957). (Structure)
Toru Masuda, Toyokazu Kishi, Mitsuko Asai and Satoru
Kuwada, Chem. and Pharm. Bull. (Japan) 7 361 (1959).
(Synthesis)
1055 Rhizopterin (N"'-Formylpteroic Acid) (Streptococcus lactis R
Factor) (SLR Factor), Ci5Hio04N„, light yellow crystals,
m.p. >300°.
OH
CH.— N— / \— COOH
CHO
H..N
Rhizopus nigricans
Edward L. Rickes, Louis Chalet and John C. Keresztesy,
J. Am. Chem. Soc. 69 2749 (1947).
Donald E. Wolf, R. Christian Anderson, Edward A. Kaczka,
Stanton A. Harris, Glen E. Arth, Philip L. Southwick, Ralph
Mozingo and Karl Folkers, ibid. 69 2753 (1947). (Synthesis)
1056 Riboflavin (Vitamin B^), Ci7H2i,OeN4, yellow-orange micro-
crystalline powder, m.p. ~280° (rapid heating), [a]ir^
-112° to -122° (50 mg. in 2 ml. of 0.1 N alcoholic
sodium hydroxide diluted to 10 ml. with water).
CHo
I
(CHOH)3
CH3
CH3
CHoOH
Ascomycetes such as EremotheciuTU ashbyii and Ashbya
gossypi produce high yields.
Leland A. Underkofler and Richard J. Hickey, "Industrial
Fermentations," Chemical Publishing Co., Inc., New York,
1954 Vol. II, Richard J. Hickey, Production of riboflavin by
fermentation, Chap. 5, pp. 157-190. (A review)
Pfizer Handbook of Microbial Metabolites
568
1057 Riboflavin-5'-phosphate, C17H21O9N4P, yellow microcrystals.
HN
,^^N^^N
CHo
H— C— OH
I
H— C— OH
I
H— C— OH
I
CH2
I
O
I
HO— P— OH
i
O
CH3
CH3
Yeast
Otto Warburg and Walter Christian, Biochem. Z. 254 438
(1932); 258 496 (1933); 263 228 (1933). (Isolation)
H. S. Forrest and A. R. Todd, J. Chem. Soc, 3295 (1950).
( Synthesis )
1058 Folic Acid (Pteroyl glutamic Acid Folacin, Vitamin B^.), C19H19-
OgN-, pale yellow-orange needles, which char above 250°.
HoN
OH
CH2— NH-
N Y 1'
(/ ^C— NH— CH— CH2— CH2— COOH
COOH
Yeasts and certain higher fungi
Yields of 19-80 ^g. per gram of dry cell weight are ob-
tained from brewers' yeast.
Leland A. Underkofler and Richard J. Hickey, "Industrial
Fermentations," Chemical Publishing Co., Inc., New York,
1954 Vol. Ill, J. M. Van Lanen, Production of vitamins other
than riboflavin. Chap. 6, pp. 191-216. (A review)
569 Pteridines and Flavines
1059 Citrovoriim Factor (Folinic Acid-SF, Leucovorin, N^-Formyltet-
rahydrofolic Acid) C^H.-fi^N- (Trihydrate) : Buff crys-
tals, m.p. 248-250° (dec), [a],,-" +16.76 (c 3.52 on
anhydrous basis in 5% sodium bicarbonate solution).
C— H O COOH
OH I ^^ II I
I ,CH..— NH— (/ \)— C— NH— CH
CH
I
H2N H CH2
1
COOH
Yeasts (probably widely distributed)
The corresponding compound with the formyl group
transferred to the amine group of the p-aminobenzoic acid
moiety (Nj,,) is also known.
C. H. Hill and M. L. Scott, J. Biol. Chem. 196 195 (1952).
(Isolation from brewers' yeast)
A. G. M. Sjostrom and L. E. Ericson, Acta Chem. Scand. 7
870 (1953). (Isolation from eight lichens)
Donna B. Cosulick, Barbara Roth, James M. Smith, Jr.,
Martin E. Hultquist and Robert P. Parker, /. Am. Chem,. Soc.
74 3252 ( 1 952 ) . ( Structure )
1060 Flavine-Adenine-Dinucleotide, CotH^sOi^NciPo, amorphous white
powder.
NH2
N
0 o
li II
CHo— O— P— O— P— O— CH,
1 I
OH OH
HC— OH OH OH
I
HC— OH
I
HC— OH
I
CHo
CH3 I o
CH,
Pfizer Handbook of Microbial Metabolites 570
Yeasts, molds, bacteria (widely distributed)
Otto Warburg and Walter Christian, Biochem. Z. 298 150
(1938). (Isolation)
S. M. H. Christie, G. W. Kenner and A. R. Todd, Nature 170
924 (1952).
Idem., J. Chem. Soc, 46 (1954). (Synthesis)
J. G. MofFatt and H. G. Khorana, /. Am. Chem. Soc. 80
3756 (1958). (Synthesis)
1061 Fermentation "Lactobacillus casei" Factor (Teropterin, Pteroyl-y-
glutamyl-y-glutamylglutamic Acid), C29H33O12N9.
CH2— NH— <f \— CO— NH— CH— COOH
{CH,)2
V '-"
H2N CO
NH
HOOC(CH2)2— CH— NH— CO— (CHo)^— CH— COOH
COOH
Corynebacterium sp.
Brian L. Hutchings, E. L. R. Stokstad, Nestor Bohonos, Na-
than Sloane and Y. Subbarow, Ann. N. Y. Acad. Sci. 48 265
(1946). (Isolation)
J. H. Boothe, J. H. Mowat, B. L. Hutchings, R. B. Angler,
C. W. Waller, E. L. R. Stokstad, J. Semb, A. L. Gazzola and
Y. Subbarow, /. Am. Chem. Soc. 70 1099 (1948).
J. H. Boothe, J. Semb, C. W. Waller, R. B. Angler, J. H.
Mowat, B. L. Hutchings, E. L. R. Stokstad and Y. Subbarow,
ibid. 71 2304 (1949). (Synthesis)
1062 Vitamin Bg Conjugate (Pteroylhexaglutamyl glutamic Acid),
C4oHoiOo4Ni3.
The structure is like that of the preceding formula, but
with four more glutamic acid units in the polypeptide side-
chain.
Bacteria, yeasts, molds (widely distributed among
microorganisms )
P. R. Burkholder, Ilda McVeigh and Katherine Wilson,
Arch. Biochem. 7 287 (1945).
J. J. Pfiffner, D. G. Calkins, E. S. Bloom and B. L. O'Dell,
J. Am. Chem. Soc 68 1392 (1946). (Structure)
571 Pteridines and Fla vines
1063 Ptcridine pigment.
A pigment which fluoresces under U.V. light is produced
by Microsporum species (some of which cause ringworm).
This pigment has been isolated and purified to some ex-
tent. The infrared spectrum indicates that it is a pteridine,
probably trisubstituted, and possibly 2-NHo (or — OH),
4— OH and 6— CH.OH substituted.
Microsporuw gijpseum, M. canis
Frederick T. Wolf, Ernest A. Jones and Helene A. Nathan,
Nature 182 475 (1958).
19.
Unclassified Metabolites
1064 Aburamycin (M5-18903), yellow crystals, m.p. 163-165° (169-
, 171°), [a]D'° +24.56° (c 1 in methanol) [aW -29° (c 0.5
in methanol).
Absorbs 2 moles of Ho. Acetylates (m.p. acetate = 205-
207°). A weakly acidic antibiotic, apparent molecular
weight 1295. Aburamycin and M5-18903 appear to be
optical antipodes of the same compound.
Streptomyces spp.
Haruo Nichimura, Toshiaki Kimura, Katsuya Tawara, Kunio
Sasaki, Kiyoshi Nakajima, Noboru Shimaoka, Saburo Okamoto,
Masafumi Shimohira and Jun Isono, J. Antibiotics (Japan)
lOA 205 (1957).
Richard M. Gale, Marvin M. Hoehn and Mack H. McCor-
mick, "Antibiotics Annual 1958-1959," Medical Encyclopedia,
Inc., New York, p. 489.
1065 Actinobolin, Cj;iH2o-2206N2, amorphous hygroscopic white pow-
der, [aW" (Sulfate) 4-54.5° (c 1 in water).
An amphoteric antibiotic. Forms an acetate: m.p.,
partial m. at 130°, resolidified 145°, dec. 263-266°, [a]^-^
+58° (c 1 in water). Positive ninhydrin, ferric chloride,
KMn04, Tehlings, iodoform tests. Absorbs no hydrogen.
Streptomyces sp.
Theodore H. Haskell and Quentin R. Bartz, "Antibiotics An-
nual 1958-1959," Medical Encyclopedia, Inc., New York, p.
505.
1066 Actinoleukin (C9Hi20HN2)n, colorless crystals, m.p. 191° (dec).
Analysis: C 55.53, H 6.05, N 14.05
55.68, 5.98, 14.01
Negative biuret, ninhydrin, Tollens, Fehling. Positive
FeClg.
5y3 Unclassified Metabolites
Streptomyces aureus
Masahiro Ueda, Yukio Tanigawa, Yoshiro Okami and Hamao
Umezavva. /. Antibiotics (Japan) 7A 125 (1954).
1067 Akitamycin, [a],r' +158° (c 0.5 in dimethylformamide), U.V.
291, 303.5, 319 m^t. Tetraene, C 57.26, H 7.68, N 1.64.
Streptomyces akitaensis
J. Antibiotics (Japan) 12B 293, 295, 297 (1959).
1068 Albidin, C-,H402 (proposed), red needles, not melting below
380°.
Unstable. Most stable below pH 3.
Penicilliurn albidum
P. J. Curtis and J. F. Grove, Nature 160 574 (1947).
P. J. Curtis, H. G. Hemming and C. H. Unwin, Brit. Mycol.
Soc. Trans. 34 332 (1951).
1069 Albofungin, bright yellow powder, dec. 190°, U.V. 240, 255, 305,
375 m,jL. Contains C, H, N, O.
Streptomyces albus var. fungus
A. S. Chochlov, Czech. Symposium on Antibiotics (Prague),
154 (1959).
1070 Albomycetin, C32H54O9N (proposed), colorless crystals, m.p.
166°.
A basic substance precipitated by ammonium reineck-
ate. Positive Fehlings, Tollens, cherry colored Elson-
Morgan. Negative FeCIa, Sakaguchi, Molisch, Millon.
May be a macrohde.
Streptomyces albus
Bunji Takahashi, J. Antibiotics (Japan) 7A 149 (1954).
1071 Alboverticillin (Hydrochloride), colorless, amorphous, [a]D^°
-33.5° (c 1.0 in water).
Negative U.V., Tollens, Molisch, Benedict, maltol, Elson-
Morgan, biuret, Millon, Sakaguchi, anthrone and FeClg.
Positive ninhydrin, Fehling.
Streptomyces sp.
Kenji Maeda, Sinichi Kondo, Kofumi Ohl, Hiroko Kondo,
E. Lin Wang, Yasusuke Osato and Hamao Umezawa, 7- Anti-
biotics (Japan) HA 30 (1958).
1072 Aliomycin, yellowish brown powder. Contains C, H, N, O, S.
Pentaene. U.V. 321, 330, 351 m^x.
Positive Fehling (on heating, weakly positive Molisch,
red purple in concentrated H2SO4).
Streptoinyces acidomyceticus
Pfizer Handbook o£ Microbial Metabolites 574
Seizi Igarasi, Koichi Ogata and Akira Miyake, J. Antibiotics
(Japan) 9B 101 (1956).
1073 Allomycin,* CogH4409, crystalline, m.p. 237-239° (dec.) [xW
-118.8 ± 0.5° (c 0.98 in 0.1 N hydrochloric acid).
Streptomyces sindenensis
Koichi Nakazawa, Shigehiro Fujii, Michitaka Inoue, Hiroshi
Hitomi, Ohira Miyake and Jyuzo Kaneko, /. Antibiotics (Ja-
pan) 7B 168 (1954).
Sueo Tatsuoka, Koichi Nakazawa, Michitaka Inoue and
Shigehiro Fujii, J. Pharm. Soc. Japan 75 1206 (1955).
1074 Alternarine, colorless needles, m.p. 230°.
Alternaria solani
Herman Darpoux, Albert Faivre-Amiot and Louis Roux,
Compt. rend. 2:J0 993 (1950).
1075 Althiomycin, Ci-Hi^NjS.O,., colorless crystals, m.p. 172-174°
(dec.) (browning" from 120-160°), [7.W +20.3 (c 1.33
in methyl cellosolve).
Unstable at pH <5.0 or >7.0.
A streptomycete
Hiroshi Yamaguchi, Yuya Nakayama, Keiichi Takeda,
Kosaku Tawara, Kenji Maeda, Tomio Takeuchi and Hamao
Umezawa, /. Antibiotics (Japan) lOA 195 (1957).
1076 Anisomycin (PA-106, PA-107), Ci4Hi,,04N, white needles, m.p.
140°, [a]D'' -45° ± 3° (c 1.0 in chloroform).
Streptomyces griseolus, other Streptomyces spp.
Ben A. Sobin and Fred W. Tanner, Jr., J. Am. Chem. Soc. 76
4053 (1954).
Fred W. Tanner, Jr., B. A. Sobin and J. F. Gardocki, "Anti-
biotics Annual 1954-1955" Medical Encyclopedia, Inc., New
York, p. 809.
1077 Antibiotic A 246,t C4]H,;6.-„0]4, crystalline, m.p. 235° (dec),
[aW -160° (c 0.2 in methanol).
Reacts with HIO4.
Streptomyces sp.
M. L. Dhar, V. Thaller and M. C. Whiting, Proc. Chem. Soc,
148 (1958).
1078 Antibiotic B-456, m.p. 176° (dec), UW' -22.9°.
C 57.52, H 6.67, N 11.12
Positive biuret, Millon. Negative Molisch, Benedict,
Fehling.
* See amicetin.
t Identical with lagosin, entry 229.
575 Unclassified Metabolites
Valine, leucine, proline, aspartic, glutamic, D-tyrosine
and ornithine produced after hydrolysis.
Bacillus suhtilis
Yuzuru Tanaka, J. Antibiotics (Japan) 9B 1 (1956).
1079 Antibiotic C-159.
U.V. 260-280, 345 m^x in aqueous solution.
C 58.7, H 7.4, N 9.9, O 24.0
Inhibits growth of organisms containing glycine, ala-
nine, threonine, aspartic acid.
Streptojiiyces caiius
Bristol Laboratories, British Patent 814,794 (1959).
1080 Antibiotic D-13, dense crystals, m.p. 243°.
C 56.91, H 6.97, O 22.61, N 13.51.
Streptomyces vinaceus-drappiis
Upjohn Co., British Patent 708,686 (1954).
1081 Antibiotic E-212, colorless needles, m.p. 233-234°.
U.V. 235, 273 m/x in 0.1 N hydrochloric acid. C 49.14,
H 4.34, N 23.77, O 22.55
Negative ninhydrin, biuret, Fehling, FeClj, Molisch,
Millon and Ehrlich.
Streptomyces sp. like S. albus
Ko Kikuchi, J. Antibiotics (Japan) 8A 145 (1955).
1082 Antibiotic LA-7017, greenish yellow powder, m.p. 154-157°
(dec), [aj,r' —155° (c 0.4 in ethanol).
Contains only C, H, O (C 56.99, H 7.18). Contains
two acidic groups, Equiv. Wt. = 1180. Decolorized
KMn04. Negative Fehling's test.
Streptomyces sp. 7017
P. Sensi, A. M. Greco and H. Pagani, Antibiotics and Chemo-
therapij 8 241 (1958).
1083 Antibiotic M-4209, C4„-4i;Hfi-.7,0,,;N, white crystals m.p. 210-
214° (dec), [a],r' -54 ± 2° (c 1 in methanol), U.V. 240,
330 ruii.
Methoxyl, acetyl and iso-valeryl groups present.
Streptomyces hygroscopicus
James D. Dutcher, John Vandeputte, Sidney Fox and L. J.
Heuser, Antibiotics and Chemotherapy 3 910 (1953).
1084 Antibiotic WC 3628, C4.H7..iO,fiN, white crystals, m.p. 220-222°
(Kofler), [a]D"-57±3° (c 0.5 in ethanol).
Pfizer Handbook of Microbial Metabolites 576
Streptomyces sp. WC 3628
McCormick, Canadian Patent 513,324 (1955).
1085 Antibiotic T, trichothecin-like, crystalline prisms, m.p. 126°,
[ale'" +135° (c 1 in chloroform).
A basidiomycete.
E. T. Glaz, Eszter Scheiber, J. Gyimesi, I. Horwath, Katalin
Steczek, A. Szentirmai and G. Bohus, Nature 184 908 (1959).
1086 Antibiotic X-206, C4fjHgoOi3, colorless crystals, m.p. 126-128°,
[a]D-" +15.0° (c 2.0 in methanol).
Streptomyces sp.
Julius Berger, A. I. Rachlin, W. E. Scott, L. H. Sternbach
and M. W. Goldberg, J. Am. Chem. Soc. 72 5295 (1951).
1087 Antibiotic X-464, C25H40O7, white crystals, m.p. 172-174°
(dec), [aW +65.9° (c 2.0 in methanol).
Streptomyces sp.
Julius Berger, A. I. Rachlin, W. E. Scott, L. H. Sternbach
and M. W. Goldberg, J. Am. Chem. Soc. 73 5295 (1951).
1088 Antibiotic X-537A, C34H-,o08, colorless crystals, m.p. 100-109°,
[alD'** -7.2° (c 1.0 in alcohol), U.V. 317, 249 m^ in iso-
propyl alcohol.
Positive FeClg test.
Streptomyces sp.
Julius Berger, A. I. Rachlin, W. E. Scott, L. H. Sternbach
and M. W. Goldberg, /. Am. Chem. Soc. 73 5295 (1951).
1089 Antibiotic X-1008, CaoHgsOyNgS, cube-like crystals, m.p. 209-
216° (dec), [o^W -282° (c 1 in chloroform).
Resembles echinomycin
Streptomyces sp.
J. Berger, E. R. LaSala, W. E. Scott, B. R. Meltsner, L. H.
Sternbach, S. Kaiser, S. Teitel, E. Mack and M. W. Goldberg,
Experientia 13 434 (1957).
1090 Antibiotic from B. cepae, colorless crystals, m.p. 185° (dec.)
C 40.8, H 5.3.
Bacillus cepae
Isolated from rotting onion.
M. Fiuczek, Med. Doswiadczalna i Mikrobiol. 2 175 (1950).
(Biol. Abstr. 26 3975).
1091 Antibiotic from B. pumilis, CgHgNoOaS, white crystals, m.p.
252°.
Negative ninhydrin.
577
Unclassified Metabolites
Bacillus pumilis
A. T. Fuller, Nature 175 722 (1955).
1092 Antibiotic from Monosporium honorden, CiyHibOy, colorless
crystals, m.p. 193.5°, [a],r" +203° (in chloroform).
Two phenolic hydroxyl groups, one active hydrogen on
an aromatic ring, one double link in a side-chain and a
free carboxyl group present.
Molecular structure may be closely related to the struc-
ture proposed for mycophenolic acid.
Monosporium honorden
P. Delmotte and J. Delmotte-Plaquee, Nature 171 344
(1953).
1093 Antibiotic from Penicillium spinulosum, fine white needles,
m.p. 183-185°.
Penicillium spinulosum
Shegejii Kondo and Bunji Takahashi, /. Penicillin (Japan),
1 147 (1947).
1094 Antibiotic from S. abikoensis, yellow powder. Heptaene. U.V.
242, 358, 400 m/x in ethanol. Actinoleukin in mycelium.
Streptomyces abikoensis
Masahiro Ueda and Hamao Umezawa, J. Antibiotics (Ja-
pan) 9A 86 (1956).
1095 Antibiotic from S. /ungicirfict/s. U.V. 290, 303, 317 m^^. Similar
to fungicidin or rimocidin.
Positive Fehling, Molisch, Negative Millon, Sakaguchi,
Schiff, ToUens, FeCl.v Blue with FeClg-K ferricyanate;
decolorizes KMn04.
Streptomyces fungicidicus
Hamao Umesawa, Yoshio Okami and Ryozo Utahara, Japa-
nese Patent 5744 (1956).
1096 Antibiotic from S. griseus. Heptaene. U.V. 359-362, 378-
382, 401-405 m/x.
Streptomyces griseus
Richard A. Pledger and Hubert Lechevalier, "Antibiotics
Annual 1955-1956," Medical Encyclopedia, Inc., New York,
p. 249.
1097 Antibiotic 26/1, yellow crystalline. Heptaene. U.V. 359, 380,
404 m^ in ethanol.
Alcohol solution turns violet with H2SO4; decolorizes
KMn04. Negative biuret and ninhydrin.
Pfizer Handbook of Microbial Metabolites 578
Actinomyces globisporus
V. A. Tsyganov, P. N. Golyakov, A. M. Bezborodov, V. P.
Namestnikova, G. V. Khopko, S. N. Solov'ev, M. A. Malyshkina
and L. O. Bol'shakova, Antibiotiki 4 21 (1959).
1098 Antibiotic 446, white crystalline powder, m.p. 81-87°, [a]u^^
-82° (c 0.5 in ethanol). U.V. 230-231, 280 m^i.
C 60.47, H 7.99, N 2.02
Negative Fehling.
Nocardia mesenterica
Masahiro Ueda and Hamao Umezawa, J. Antibiotics (Ja-
pan) 8A 164 (1955).
1099 Antibiotic 720-A,* C2SH40O9N0, white needles, m.p. 139.5-140°,
[a]i/' +73.5° (c 1.0 in acetone) U.V. 227, 346 m^.
Positive FeClg; negative Molisch, ninhydrin, biuret,
Ehrlich and 2:4 DNPH.
Streptomyces n. sp.
Yoshio Sakagami, Setsuo Takeuchi, Hiroshi Yonehara,
Heiichi Sakai and Matao Takashima, /. Antibiotics (Japan)
9A 1 (1956).
1100 Antibiotic 587/13, Hydrochloride
C 39.5, H 6.97, N 15.7, CI 16.75
Streptomyces lavendulae
D. M. Trakhtenberg, V. M. Baikina, E. 1. Rodionovskaya,
1. M. Prosnyakova, O. A. Kalinovskii, Yu V. Zakharova and
A. A. Khokhlov, Antibiotiki (U.S.S.R.) 4 9 (1959).
1101 Antibiotic 1037, crystalline needles, m.p. 283-289°, [^W^ -51°.
C 49.33-49.47, H 4.56-4.90, N 23.75-24.14, no halo-
gen or sulfur
Streptomyces sp.
Hiroshi Yamamoto, Shlgehlro Fujli, Koichi Nakazawa,
Akira Miyake, Hiromu Hitomi and Masahiko Imanishl, Ann.
Repts. Takeda Research Lab. 16 26 (1957).
1102 Antibiotic 6270,t CooHs-NeSO^.^, crystalUne.
Streptomyces fiavochromo genes
M. G. Brazhnikova, Czech. Symposium on Antibiotics
(Prague), 140 (1959).
1103 Antibiotic 6706,1 C26-27H32O8N4, colorless needles, m.p. 214-
216°, U.V. 304" ni;,.""
Gives negative FeCLj, Fehling, Tollens, ninhydrin and
Millon tests.
* See entry 269 (antimycin Ai).
t Cf. entry 1089.
X See pyridomycin, entry 752.
579 Unclassified Metabolites
Streptomyces sp.
Masahiko Kuraya, Bunji Takahashi, Yorio Hinuma, Takaaki
Yashima, Kenzo Watanabe, Masa Kuroya and Susumu Ha-
mada, /. Antibiotics (Japan) 7A 58 (1954).
1104 Antifungal Substance, colorless needles, m.p. 283-289°, [a]i,''
-51°.
A water-soluble compound similar to toyokamycin and
monilin. Analysis: C 49.33-49.47, H 4.56-4.90, N
23.75-24.14.
Streptomyces sp.
Hiroshi Yamamoto, Shigehiro Fujii, Koichi Nakazawa, Akira
Miyake, Hiromu Hitomi and Masahiko Imanishi, Takeda
Kenkyusho Nempo 16 26 (1957).
1105 Antifungal substance produced by Streptomyces strain No. 1037.
Crystalline needles, m.p. 283-289°, [alo'-' -51°. C
49.33-49.47 H 4.56-4.90 N 23.75-24.14, no halogen or
sulfur.
It seems to belong to the same group of substances as
toyokamycin and monilin.
Hiroshi Yamamoto, Shigehiro Fujii, Koichi Nakazawa, Akira
Miyake, Hiromu Hitomi and Masahiko Imanishi, Ann. Rept.
Takeda Research Lab. 16 26 (1957).
1106 Argomycin, ConH^gO^N, m.p. 164°, [(x]ir' +8.2° (in ethanol).
May be a macrolide.
Streptomyces griseolus
Toji Hata, Yoshimoto Sano, Hideo Tatsuta, Ryozo Sugawara,
Akihiro Matsumae and Kokichi Kanamori, J. Antibiotics (Ja-
pan) 8A 9 (1955).
1107 Aspelein, C29H20O10, dark red plates, no m.p.
This pigment contained two hydroxyl groups (diacetate,
yellow crystals, m.p. 276-285°) and an alkoxyl group.
Spectra described.
Aspergillus elegans
P. E. Gregoire, Bull. soc. chim. biol. 33 1681 (1951).
Aterrimins — complex containing aterrimins A and B, exhibiting
characteristics of a lactone; contain C, H and O and have
no definite m.p.
1108 Aterrimin A, [a],.-" +245° in ethanol. U.V. 277, 287, 310-325
m^ in absolute alcohol C. 65.5 H 7.8 O 26.7 (by differ-
ence).
Pfizer Handbook of Microbial Metabolites 580
1109 Aterrimin B, [aU-° +342° in ethanol. U.V. same as A. C 69.7
H 8.05 O 22.25 (by difference).
Bacillus subtilis var. aterrimus
Gordon Alderton and Neva S. Snell, U. S. Patent 2,850,427
(1958).
1110 Aureolic Acid, Mg salt: (C56.6oH96-io4029-3i)2Mg, yellow crystals,
[aln +68° (c 1 in methanol).
A weak acid, green FeClg test, negative FehUngs,
an throne.
Streptomyces sp.
Walton E. Grundy, Alma W. Goldstein, Charles J. Rickher,
Marjorie E. Hanes, Halleck B. Warren, Jr. and John C. Sylves-
ter, Antibiotics and Chemotherapy 3 1215 (1953).
im Azalomycin B, C14H24O5, white needles, 185-187° (dec.) [ajc^'
-48° (c 1.0 in methanol). U.V. 252.5 m,x.
Streptomyces hygroscopicus
Manoru Aral, /. Antibiotics (Japan) ISA 51 (1960).
1112 Azalomycin F, C30H50O10N2, white needles, m.p. 125-127° (dec.)
[ccW +46° (c 1.0 in methanol).
U.V. resembles that of musarin and hygrostatin. I.R.
differs.
Positive ninhydrin, negative FeCls, MoHsch, anthrone
and Millon.
Streptomyces hygroscopicus
H. D. Tresner and E. J. Backus, Appl. Microbiol. 4 243
(1956).
S. A. Waksman and A. T. Henrici, Bergey's "Manual of
Determinative Bacteriology," 1957, pp. 796-797.
Mamoru Arai, /. Antibiotics (Japan) ISA 51 (1960).
1113 Baccatine A, C26H48O6N0 (proposed). Colorless crystals, m.p.
135°. Mol. Wt. -^480.
May be a depsipeptide (peptolide).
Gibberella baccata.
Jean Guerillot-Vinet, A. Guerillot-Vinet, Lucien Guyot, Jac-
ques Montegut and Louis Roux, Compt. rend. 230 1424 (1950).
M. M. Shemyakin, Angew. Chem. 72 342 (1960).
1114 Bacilipin A, sheaves of needles, m.p. 76-78°.
C 42.6, H 6.3, N 2.5, Ba 24.6.
Negative Mohsch, 2,4-DNPH, AgNOg.
Positive Br2.
581 Unclassified Metabojites
M15 Bacilipin B, crystals, m.p. 105°.
C 52.45, H 6.75, N 2.09, Ba 21.6
Gave same tests as Bacilipin A.
Both A and B gave positive ninhydrin after hydrolysis.
Bacillus subtilis
G. G. F. Newton, Brit. J. Exptl. Biol. -iO 306 (1949).
1116 Bacilysin, white powder containing C, H, O and N.
Gives a positive ninhydrin; negative biuret and MoUsch
tests.
Produced by the soil bacillus NTCC 7197.
E. P. Abraham and H. W. Florey, "Antibiotics," Vol. I
Antibiotics from bacteria in the genus bacillus, Oxford Uni-
versity Press, London, 1949 Chap. 10, pp. 457-458.
1117 Biformyne 1 (Biformin), C9H20O0, white crystalHne solid, m.p.
40-43°, U.V. 276, 278, 291 m^x in alkaH.
Polyporus biformis
Marjorie Anchel and Marvin P. Cohen, /. Biol. Chem. 208
319 (1954).
1118 Blasticidin A, C4r,..,2, H^.^o N4.7, light yellow powder, m.p. 197-
201°. U.V. 216 m^. Soluble in HoO.
1119 Blasticidin B, colorless liquid, b.p. 36° (0.001 mm.). Insoluble
in H.O.
1120 Blasticidin C, red-brown powder. Insoluble in HoO.
Streptomyces griseochromogenes
Kazuo Fukunaga, Tomomasa Misato, Itaru Iskii and Masaru
Asakawa, Bull. Agr. Chem. Soc. (Japan) 19 181 (1955).
1121 Blasticidin-S, Ci4H2o05N6, white needles, m.p. 235° (dec),
[ale" +108.4° (c 1.0 in water).
A basic antibiotic (forms a picrate).
Negative FeCl.j, Fehling, Tollens, Millon, Ehrlich,
Sakaguchi, MoUsch, biuret, ninhydrin, aldehyde and
ammoniacal AgNOg tests. Blasticidin-S is a member of a
complex with at least three other components, blasticidins
A, B and C.
Streptomyces griseochromogenes
Setsuo Takeuchi, Kosei Hirayama, Kazaburo Ueda, Heiichi
Sakai and Hiroshi Yonehara, /. Antibiotics (Japan) llA 1
(1958).
Pfizer Handbook of Microbial Metabolites 582
1122 Borrelidin, C2sH4:{0(jN, m.p. 145°, [a],r' -28° (in ethanol).
An acidic compound.
Streptomyces rochei
J. Berger, L. M. Jampolsky and M. W. Goldberg, Arch.
Biochem. 22 476 (1949).
1123 Caerulomycin, Ci2Hi,02N;^, colorless needles, m.p. 175°.
Red FeCl^ test. Contains one methoxyl group.
Streptomyces caeruleus
A. Funk and P. V. Divekar, Can. J. Microbiol. 5 317 (1959).
1124 Camphomycin, white needles, m.p. -^ 149°. Positive Nessler and
Tollens.
Streptomyces rutgersensis var. castelarense
Augusto P. Cercos, Rev. argentian agron. 20 53 (1953).
1125 Candidulin, C,,H,,-,0..jN, white needles, m.p. 88°, [a]ir' +15°
±2° (c 1 in chloroform).
A neutral, non-aromatic substance. Negative ninhydrin,
2,4-DNPH, FeCl-i.
Aspergillus Candidas
P. G. Stansly and N. H. Ananenko, Arch. Biochem. 23 256
(1949).
1126 Canescin, Cir,Hi,0-, white needles, m.p. 201-202° (dec).
Purple color with FeClj in ethanol.
Penicillium canescens
Yield 30-110 mg. per liter.
P. W. Brian, H. G. Hemming, J. S. Moffatt and C. H. Unwin,
Trans. Brit. Mtjcol. Soc. 36 243 (1953).
1127 Cardinophyllin (Carzinophilin), potassium salt: colorless
needles, m.p. 220° (dec).
Contains C, H, O, N. Positive xanthoprotein, negative
ninhydrin, diphenylamine. Negative resorcinol, Millon,
Liebermahn.
Streptomyces sahachiroi
Toju Hata, Fumiwaka Koga, Yoshimoto Sano, Koklchi
Kanamori, Akihiro Matsumae, Ryozo Sugawara, Tadashi Hoshi
and Tatsuo Shima, /. Antibiotics (Japan) 7A 107 (1954).
Fujiki Hata and Takamoto Sano, Japanese Patent 7590
(1956).
1128 Carzinophilin A, colorless needles, m.p. 217-222° (dec), [cz]i."^
+57.8° (in chloroform).
Positive ninhydrin, 2,4-DNPH, bromine uptake, an-
583 Unclassified Metabolites
throne, Baeyer, xanthoproteic. Unstable in aqueous solu-
tion.
Strcptomijces sahachiroi n. sp.
Hideo Kamada, Shigetoshi Wakaki, Yasuo Fujimoto, Keitaro
Tomioka, Satoshi Ueyama, Hakudai Marumo and Keizo Uzu,
;. Aiitibiotics (Japan) 8A 187 (1955).
1129 Cerevioccidin, C:.._.H:^n04Nr„ colorless needles, m.p. 249° (dec).
Negative biuret, ninhydrin, Fehling, Sakaguchi, Tollens,
glucosamine. Positive Janovsky.
Streptoviyces sp. resembling S. cacaoi
Satoru Yamashita, Teruzo Sawazaki, Makoto Kawasaki,
Goto Nakamura, Kentaro Anzai, Kiyoshi Isono, Yoshiko
Serizawa, Yoshiko Sekiyama and Saburo Suzuki, /. Antibiotics
(Japan) 8A 42 (1955).
Chlamydosporin, complex of two closely related antibiotics pro-
duced by the fungus Fiisarium MLF 1230 found in insects
and their larvae.
1130 Chlamydosporin A, light brown amorphous substance insoluble
in water.
1131 Chlamydosporin B, colorless, crystalline, soluble in water.
Both contain 4.3% N but no sulfur.
Albert Faivre-Amiot, Hermon Darpoux and Louis Roux,
Compt. rend. 235 912, 982 (1952).
1132 Chromomycin A.j (main component of complex), C.22.-2Aiir2.:MOii,
yellow powder, m.p. 183° (dec), [a],.'-'" -26° (c 1 in
ethanol.
May be related to the actinomycins.
Streptomyces griseus No. 7
Yoshitomo Aramaki, Junmei Watanabe, Ichiro Ishikawa,
Akira Miyake, Homu Ito, Koichi Nakazawa, Koichi Ogata,
Motoo Shibata, Masaji Igarashi and Kazuo Tanabe, Ann. Repts.
Takeda Research Lah. 14 60 (1955).
Tatsuoka et al, Gann. 49 Suppl. 23 (1958).
S. Wakaki et al.. Antibiotics and Chemotherapy 8 228
(1958).
Motoo Shibata, Kazuo Tanabe, Yoshio Hamada, Koiti
Nakazawa, Akira Miyake, Hiroshi Hitoma, Masuo Miyamoto
and Komei Mizuno, /. Antibiotics (Japan) 13B 1 (1960).
1133 Chrysergonic Acid, C.^H;,, •j^O,.,, fine yellow needles, m.p. 268—
270° from chloroform (250-257° from acetic acid), UW"
-3° -^ +34° (in pyridine).
Claviceps purpurea
Pfizer Handbook of Microbial Metabolites 584
A. Stoll, J. Renz and A. Brack, Helv. Chim. Acta 35 2022
(1952).
1134 Chrysomycin, C22H00O7 (proposed), greenish yellow crystals,
m.p. 255-260° (dec), [o(W^ +16° (c 1 in acetic acid).
Neutral, photosensitive compound. Takes up 4H2 with
loss of color.
Streptomyces sp.
Frieda Strelitz, Helen Flon and Igor V. Asheshov, J. Bacteriol.
69 280 (1955).
1135 Clitocybin, colorless crystals, m.p. 77°.
Clitocybe Candida
A. Charles Hollande, Compt. rend. 221 361 (1945); 228 1758
(1949).
1136 Coelicolorin, purpUsh red powder, 142-146°.
Streptomyces coelicolor
Yuichi Hatsuta, /. Antibiotics (Japan) 2 276 (1949).
1137 Collinomycin, orange prisms, m.p. 280°.
Streptomyces collinus (mycelium)
Hans Brockmann and Karl-Heinz Renneberg, Naturwissen-
schaften 40 166 (1953).
1138 Compound CuHooOgNo.
A basic red pigment, yellow in alkaline, red in acid
solutions. Positive Bayer, diazo tests.
Inocybe patoullardii Bres.
Helmut Miiller, Dissertation, Wiirzburg, 1959.
1139 Cosynthetic Factor-1 C14.15H17O7N3, crystalline. An acidic com-
pound, Mol. Wt. 340-360.
Thought to be a cefaclor in the biosynthesis of tetra-
cyclines.
Streptomyces aureofaciens strain W-5, S. albo-niger, S.
griseus, S. albas, S. platensis, S. hygroscopicus, S. rimosus
Jerry Robert Daniel McCormick, Nancy Hazlett Arnold,
Ursula Hirsch, Philip Andrew Miller and Newell Oscar
Sjolander, Union of South Africa Patent Application 59-2174
(1959).
1140 Croceomycin, C.oRx&Of.,, m.p. 325° (subl. 240° at 1-2 mm.),
UW^ -32 ±4°.
Forms a triacetate. Diazomethane adds two methyl
groups.
Streptomyces arabicus
585 Unclassified Metabolites
Motoo Shibata, Koichi Nakazawa, Akira Miyake, Michitaka
Inoue and Akira Akabori, Takeda Kenkyusho Nempo 16 32
(1957). (Chem. Ahstr. 52 10279e)
1141 Cyanomycin, C15H10N0O0 (proposed), dark blue needles, m.p.
128° (dec.)-
A basic antibiotic pigment with pH-indicating prop-
erties, apparently distinct from other known pigments.
Aureothricin occurs in the same culture.
Streptomyces strain No. 4738
Masanao Funaki, Fumiyasu Tsuchiya, Kiyoharu Maeda and
Takeshi Kamiya, /. Antibiotics (Japan) llA 143 (1958).
1142 Datemycin, C-,><Hlo-O^JN4, colorless powder, m.p. 197° (dec),
[a]i/^ -43.7° (c 1 in water).
U.V. maximum at 247 m/x. Negative ninhydrin
6N HCl
— — > positive ninhydrin. Negative Hopkins-
Cole, xanthoprotein, Sakaguchi, Millon, Elson-Morgan,
Molisch, Fehling, silver mirror tests.
"M-14" strains
Masahiko Kuroya and Yasuo Koyama, Japanese Patent 6648
(1959).
1143 Desertomycin, C33H(;,,.yoOi4N, snow white crystals, m.p. 189°.
Positive ninhydrin, C-methyl. Acetylates, hydrogenates,
decolorizes bromine or permanganate.
A crystalline antifungal agent, flavofungin, has been
isolated from the same culture.
Streptomyces flavofungini
J. Ori and I. Behesi, Nature 181 908 (1958).
J. tJri, R. Bognar and B. Varga, ibid. 182 401 (1958).
1144 Diaporthin, C13HJ4O3, white crystals, m.p. 91.5-92.5° [ajn^^ +58°
(c 1 in chloroform).
Endothia parasitica
A. Neelameghan, Hindustan Antibiotics 2 13 (1959).
1145 Diplococcin, antibacterial substance elaborated by certain milk
streptococci. In the same category as the sulfur-free
polypeptides, gramicidin and tyrocidine. Unlike these
polypeptides diplococcin contains arginine residues, shows
no tendency to crystallize and is obviously of greater mo-
lecular complexity.
C 50.5, H 7.3, N 13.1, no sulfur.
Pfizer Handbook of Microbial Metabolites 586
Streptomyces lactis
A. E. Oxford, Biochem. 7. 38 178 (1944).
Idem., ibid. 39 xiii (1945).
1146 Distamycin A, pure white powder, basic, forms salts.
Positive biuret test.
CIBA, Australian Patent 28,469 (1957).
1147 D-Substance, white needles, m.p. 124-125°.
Highly toxic.
Streptomyces flavus 0-2
Isao Takahashi, /. Antibiotics (Japan) 6A 117 (1953).
1148 Elaiophylin (C^HioOo),,, no N, S, X, white crystals, m.p. 178-
183° (dec.) [air'' -49° (in chloroform).
Streptomyces melanosporus (sine melanosporofaciens)
F. M. Arcamone, C. Bertazzoh, M. Ghione and T. Scotti,
Giorn. microbiol. 7 207 (1959).
1149 Endosubtilysin, yellow powder, soluble in alcohol and chloro-
form. Forms a water-soluble sodium salt. Appears to
be an organic acid.
Bacillus subtilis
Louis de Saint-Rat and Henry R. Olivier, Compt. rend. 222
297 (1946).
1150 Enteromycin, m.p. 167-168°, U.V. 282 m,x.
C 38.2, H 4.62, N 4.3.
Streptococcus albireticuli
Teisuke Osato, Masahiro Ueda, Setsuko Fukuyama, Koki
Yagishita, Yoshiro Okami and Hamao Umezawa, /. Antibiotics
(Japan) 8A 105 (1955).
1151 Ergochrysin, CosHosOjo, yellow-golden leaflets, m.p. 266° from
chloroform (242-244° from alcohol-pyridine).
Claviceps purpurea
C. Jacoby, Arch. exp. Pathol. Pharmakol. 39 85 (1897).
Werner Bergmann, Ber. 65 1486, 1489 (1932).
1152 Ergoflavin, C3oH2fjO,4, yellow needles, m.p. 350° (dec.) from
methanol or dioxane, [a]i,-' +37.5° (c 1.236 in acetone).
Structural features determined :
4 phenolic hydroxyls
2 alcoholic hydroxyls
2 carbonyls
2 y-lactones
Claviceps purpurea
587 Unclassified Metabolites
The yield is 1-2% of the weight of the dry sclerotia.
G. Eglinton, F. E. King, G. Lloyd, J. W. Loder, J. R. Marshall,
Alexander Robertson and W. B. Whalley, /. Chem. Soc, 1833
(1958).
The relationship of ergofiavin to the other yellow pig-
ments, secalonic acid, ergochrysin, chrysergonic acid,
sclererythrin, scleroxanthin, sclerocristallin and ergoxan-
thin (some of them identical) is discussed in the above
paper as well as in an earlier paper by:
Albert Freeborn, Pharm. J. 88 568 (1912).
A. Stoll, J. Renz and A. Brack, Helv. Chim. Acta. 35 2022
(1952).
1153 Estin, C„iHi40,.CL, m.p. 223°.
Contains two methoxyl groups. A second and similar
compound, Nordin, is produced with it. A 143 mg. sam-
ple of the mixture was obtained from 1480 ml. of culture
solution.
Penicillium paxilli var. echinulatum
Eitaro Komatsu, Japanese Patent 4799 (1953).
1154 Eumycetin, fine white needles, m.p. 148-150°.
Positive FeCl.-,, negative biuret, ninhydrin, Molisch,
Fehling.
Streptomyces sp. similar to S. purpurochromogenes
Edwin A. Johnson and Kenneth L. Burdon, J. Bacteriol. 51
591 (1946).
1155 Eumycin, amorphous precipitate, heat-stable in acid, unstable
in alkaline solutions above pH 8.0.
Bacillus subtilis
Edwin A. Johnson and Kenneth L. Burdon, J. Bacteriol. 51
591 (1946).
1156 Exfoliatin, CotH^oOisCI, colorless needles, m.p. 172°.
Positive FeClg, Molisch, Negative Fehling.
Streptomyces exfoliatus
Hamao Umezawa, Kiyoshi Oikawa and Motoko Suzuki, /.
Antibiotics (Japan) 5 466 (1952).
1157 Fairodin, crystalline, m.p. 237-239° (dec.) [a]v'^ -102° (c 1
in water).
C 59.6, H 6.7, N 14.3.
Bacillus brevis
Pfizer Handbook of Microbial Metabolites 588
S. Oya, Japanese Patent Application SHO 32-3997 (1957).
1158 Fermicidin, C14H01O4N, colorless needles, m.p. 96°, [aW^ +52.3°
±1.5° (c 0.65 in water).
Streptomyces sp. similar to S. griseolus
Seizi Igarasi and Shozo Wada, /. Antibiotics (Japan) 7B
221 (1954).
1159 Fermizin, C14H21O4N, needles, m.p. 96-98°.
An antifungal agent.
Streptomyces griseus
About 10 g. were obtained from 100 1. of fermentation
broth. Apparently identical with fermicidin.
Koichi Ogata, Masaji Igarashi and Shozo Wada, Japanese
Patent Application 6150 (1958).
1160 Fervenulin, C7H7O2N5, yellow crystals, m.p. 178-179° (dec).
Mol. Wt. 193. Acid-stable, base-labile. U.V. peaks at
275, 239 rrifi.
Streptomyces fervens
T. E. Eble, E. C. Olson, C. M. Large and J. W. Shell, 7th
Annual Symposium on Antibiotics, Washington, D. C, 1959.
1161 Flavensomycin, pale yellow crystals, m.p. 152°.
A water soluble compound containing nitrogen but not
sulfur or halogen. Some carbohydrates tests were posi-
tive. U.V. maximum at 251 m^u.
Streptomyces tanaschiensis type
R. Craveri and G. Giolitti, Nature 179 1307 (1957).
1162 Flavucidin, C34H55NO9, colorless needles, m.p. 144-145°, [ixW°
94°, U.V. 275 nifx.
Positive Molisch. Negative ninhidrin.
Streptomyces sp. No. 14420
Motoo Shibata, Koichi Nakazawa, Akira Miyake, Michitaka
Inoue, Jiro Terumichi and Hiroshi Kawashima, Ann. Rept.
Takeda Research Lab. 17 16 (1958).
1163 Folimycin, m.p. 163-164° (dec.) agricultural antifungal anti-
biotic.
Streptomyces nayagawaensis n. sp.
Hiroichi Yamamoto, Koiti Nakazawa, Satoshi Horii and
Akira Miyake, J. Agr. Chem. Soc. Japan 34 268 (1960).
1164 Fomecin A, CgHgOg, m.p.: dec. >160°.
Weakly acidic, thermostable, alkali labile.
Fomes (Polyporus) juniperinus
589 Unclassified Metabolites
Marjorie Anchel, Annette Hervey and William J. Robbins,
Proc. Nat. Acad. Sci. U. S. 38 655 (1952).
1165 Fuscomycin, m.p. 180° (dec.)-
Streptomyces fuscus
Fujiki Hata and Keigen Sano, Japanese Patent 5046 (1953).
1166 Glutinosin, C4sH,ioOio (proposed), colorless plates, gradual dec.
to 300°, [aW" ^+54° (c 0.2 in benzene).
Metarrhizium gliitinosum
P. W. Brian and J. C. McGowan, Nature 157 334 (1946).
1167 Grisaminc, C^sH^sOioN^ or Co„H;5,)07N4 (proposed), colorless
needles, m.p. 167-170°.
Negative Fehling, FeCIs, Sakaguchi, ninhydrin, biuret.
Streptomyces sp. similar to S. griseoflavus
Teruzo Sawazaki, Goto Nakamura, Makato Kawasaki, Satoru
Yamashita, Kiyoshi Isono, Kentaro Anzai, Yoshiko Serizawa,
Yoshiko Sekiyama and Saburo Suzuki, /. Antibiotics (Japan)
8A39 (1955).
1168 Griseoflavin, colorless needles, m.p. 210-215° (dec).
Not precipitated by peptide reagents. Negative carbo-
hydrate and amino sugar tests, FeClg.
Streptomyces griseoflavus
Yoshio Waga, /. Antibiotics (Japan) 6A 66 (1953).
1169 Griseoviridin, C22H29O7N3S (proposed), colorless crystals, m.p.
(polymorphic') 158-166°, 194-200°, 230°, 240° (dec),
[oiW -237° (c 0.5 in methanol).
Neutral compound. Negative FeClg, Sakaguchi, posi-
tive Bayer. Gives cystine on acid hydrolysis. Further
structural features are suggested in the last reference
below.
StreptoTTiyces griseus, S. griseoviridus n. sp.
Quentin R. Bartz, Jean Standiford, James D. Mold, Doris W.
Johannessen, Albert Ryder, Andrew Maretzki and Theodore H.
HaskeU, "Antibiotics Annual 1954-1955," Medical Encyclope-
pedia, Inc., New York, p. 777.
John Ehrlich, George L. Coffey, Myron W. Fisher, Margaret
M. Galbraith, Mildred Penner Knudsen, Raymond W. Sarber,
A. S. Schlingman, Robert M. Smith and Jean K. Weston, ibid.,
p. 790 (1954-1955).
Lucia E. Anderson, John Ehrlich, Sung Huang Sun and
Paul R. Burkholder, Antibiotics and Chemotherapy 6 100
(1956).
Pfizer Handbook of Microbial Metabolites 590
D. E. Ames, R. E. Bowman, J. F. Cavalla and D. D. Evans,
J. Chem. Soc, 4260 (1955).
D. E. Ames and R. E. Bowman, ibid., 4264 (1955).
1170 Helenine.
An unstable, little characterized antiviral agent. A
ribonucleoprotein.
Penicillium funiculosum
Richard E. Shope, J. Exp. Med. 97 601, 639 (1953).
U. J. Lewis, Edward L. Rickes, Laurella McClelland and
Norman G. Brick, J. Am. Chem. Soc. 81 4115 (1959).
1171 Heliomycin, needles, chars >300°, complex U.V., Mol. Wt. 235.
Positive FeClg and Millon.
May be a polypeptide.
Actinomyces flavochromo genes var. heliomycini
M. G. Brazhnikova, T. A. Uspenskaya, L. B. Sokolova, T. P.
Preobrazhenskaya, G. F. Gauze, R. S. Ukholina, V. A. Shorin,
O. K. Rossolimo and T. P. Vertogradova, Antibiotiki 3 29
(1958).
1172 Hirsutic Acid C, Ci-,H.o04 (proposed), colorless crystals, m.p.
179.5°, [cz]d'" +li.9° (in absolute ethanol).
A group of acidic materials. Hirsutic acid C has been
best characterized. It is a monobasic acid, only slightly
soluble in H^-O, soluble in most organic solvents. Neg-
ative 2,4-DNPH, FeCl;^, Fehling. White precipitate with
Br water.
Stereum hirsutum
N. G. Heatley, M. A. Jennings and H. W. Florey, Brit. J.
Exp. Path. 28 35 (1947).
1173 Hygroscopin A, C13H.4O3N., oil, b.p. 64° (0.003 mm.), ni.^^
1.4830, [a],," 84.7° (in methanol).
1174 Hygroscopin B, Ci.-.Ho.O^N,, oil, b.p. 70° (0.008 mm.), n„^^
1.4935, [a],/' -38.8° (in ethanol).
Streptoniyces hygroscopicus
Koichi Nakazawa, Kinzo Oki, Isao Tadokoro, Mikio Honjo,
Hiroshi Hitomi and Jisaburo Ueyanagi, J. Agr. Chem. Soc.
Japan 28 296 (1954).
Sueo Tatsuoka, Akira Miyake, Mikio Honjo, Hiroshi Hitomi,
Jisaburo Ueyanagi. Masuo Miyamoto, Koiti Nakazawa and
Kinzo Oki, J. Antibiotics (Japan) 7B 329 (1954).
591 Unclassified Metabolites
1175 Hygrostatin, light yellow powder, m.p. 129-131° (dec), [a]ii""
+43° (c 1.21 in methanol).
Contains nitrogen, but no sulfur or halogen. U.V. at
240 m^.
Streptomyces Jiygrostaticus
Kenzo Furushiro, Kiyotake Shimizu, Heiichi Sakai, Masayuki
Minoyata and Toshio Fujisawa, lyaku, Shigen Kankyusho
Nevipo 24-39 (1958). (Chem. Abstr. 54 10048b)
1176 Ilhidin M, Cj,H^.o07, prismatic rods in ethanol, m.p. 216° (cor.)-
[a],,-" -126° in ethanol. Mol. Wt. 386. U.V. 247, 330 m^
in 95 ^f ethanol.
Contains two acidic groups and an a,/8-unsaturated
carbonyl group.
Yield 0.08 g. per liter.
1177 Illudin S, Ci.-,R.o04, crystalline, m.p. 124-125°. Mol. Wt. 264.
U.V. 235, 328 m^ in 95 ^c ethanol.
Yield 0.33 g. per liter.
Clitocybe illudens
Marjorie Anchel, Annette Hervey and William J. Robbins,
Proc. Nat. Acad. Sci. U. S. 36 300 (1950); 38 927 (1952).
A third, antibiotically inactive substance, Ci,|Hi(.04 or
CinHo^Oe, crystals, m.p. 72-74°, [aln'" -107° (in absolute
ethanol) occurred in the same culture.
1178 Imoticidin, m.p. 245° (darkening from 210°).
An antibiotic isolate, C 64.71, H 9.50, N 0.0, H.O 7.63.
Mol. Wt. 532-553.
Streptomyces albus
Tadao Inouye, Yasuhiro Okamoto and Yosikazu Nishikado,
Ber. Ohara Inst. Landjuirtsch. Biol., Okayama Univ. 11 95
(1959). (In English)
1179 Indigoidine, deep blue pigment, no melting point.
Low solubility in most solvents. Soluble in dilute hy-
drochloric acid. Analysis of partially purified compound:
C 47.74, H 3.82, N 17.95. Formed a red crystalline ace-
tate, m.p. >300° (dec), but more soluble: C 49.63,
H 3.98, N 16.05, acetyl 16.9. A red benzoate was also
prepared.
Corynebacterium insidiosiim (McCulloch) Jensen,
Pseudomonas indigofera, Erwinia chrysanthemi, Arthro-
bacter sp.
Pfizer Handbook of Microbial Metabolites 592
B. Elazari-Volcani, Arch. Mikrobiol. 10 343 (1939).
D. A. Kuhn and M. P. Starr, Bacteriol. Proc. 58 (1956).
Mortimer P. Starr, Arch. Mikrobiol. 30 325 (1958).
1180 Isorhodomycin A,* CooHogOgN or CsiHgiOgN, hydrochloride: deep
red prisms, m.p. 220°, [aleoeo-Teoo'" +268° ±30° (c 1 in
methanol).
Occurs wdth rhodomycin A.
Either compound on mild hydrolysis yields a water-
soluble, N-containing moiety and a water-insoluble chro-
mophore.
Streptomyces purpurascens
Hans Brockmann and Peter Patt, Chem. Ber. 88 1455
(1955).
1181 Itaconitin, yellow needles, m.p. 169°.
Negative Beilstein, fuchsin, xanthogen. Legal, Ehrlich,
Liebermann, FeClg tests. Decolorized bromine and
KMn04. Formed an acetate, semicarbazone and 2,4-
DNPH. Hydrogenated to hexahydroitaconitin.
Aspergillus itaconicus
Kono Kinoshita and Shoichi Nakajima, Hoshi Yakka
Daigaku Kiyo 7 17 (1958).
1 1 82 Laterosporin
Appeared to be a peptide. Isolated as a hydrochloride.
Soluble in water. Tendency to precipitate out of solution
in NaCl solution or in 0.2 m phosphate buffer.
Bacillus laterosporus
Ella M. Barnes, "Antibiotics," Vol. II Antibiotics from
bacteria in the genus bacillus, Oxford University Press, Lon-
don, 1949, Chap. 10 appendix, pp. 1540-1541.
1183 Latumcidin (Sulfate), C11H13O2N -112804, white needles, m.p.
140°, [ocId"' +148.9° (c 0.1 in 0.1 N sodium hydroxide).
A basic, unstable, antifungal agent. Positive diazo,
Baeyer, bromine. Negative FeCl^, Fehling, Tollens, Ehr-
lich, Sakaguchi, ninhydrin, biuret, Molisch.
Somewhat resembles eulicin, and abikoviromycin.
Streptomyces reticuli var. latumcidus
Yoshio Sakagami, Ichiro Yamaguchi, Hiroshi Yonehara,
Zoichiro Okimoto, Sadazi Yamanouchi, Kazuo Takiguchi and
Heiichi Sakai, /. Antibiotics (Japan) llA 6 (1958).
* Identical with entry 597.
593
Unclassified Metabolites
1184 Lenamycin, C4H^0;^No or C4H40._.No (proposed), colorless crys-
tals, m.p. 202-207° (dec.) optically inactive.
Apparently an a,/?-unsaturated amide. Negative nin-
hydrin, biuret, anthrone, FeCl^, Sakaguchi, Elson-Morgan,
nitro and oxime tests.
A streptomycete
The yield was 72 mg. from 5 1. of broth. Occurs to-
gether wdth fra ns-cinnamic acid amide and ethoxyethene-
1 ,2-dicarboamide.
Yasuharu Sekizawa, /. Biochem. (Japan) 45 159 (1958).
1185 Lenzitin, colorless needles, m.p. 166°.
Contains C, H, O only. Positive FeClg, KMn04.
Lenzites sepiaria (Wulf)
M. Litvinov and E. Moiseeva, Priroda 1 60 (1951).
1186 Litmocidin, m.p. 144-146° (dec).
An acid-base indicator. Decolorized by bisulfite or zinc
dust, color restored by air oxidation.
Proactinomyces cyaneus var. antibioticiis
G. F. Cause, /. Bacteriol. 51 649 (1946).
M. G. Brazhnikova, ibid. 51 655 (1946). (Isolation)
1187 Longisporin, CgeHsgOio, crystals, m.p. 99-101°, [ajo -f2.62°.
Alkaline hydrolysis yields a hydroxy acid C^oHi60(OH)
(COOH). It was suggested that the antibiotic is a cychc
ester of three such acid units.
Actinomyces longispori
G. P. Menshikov and M. M. Rubinshtein, Zhur. Obshchei
Khim. 26 2035 (1956).
1188 Lustericin, C4oHti40i:i, white crystals, m.p. 130° [aJD-*" 0°, mol.
wt. 130.
Streptomyces sp.
Motoo Shibata, Koichi Nakazawa, Michitaka Inoue, Jiro
Terumichi and Akira Miyake, Ann. Rept. Takeda Research Lab.
17 19 (1958).
1189 Lycopersin, C^.^HisOg, bright red needles, darkens from 250°,
dec. 305°.
Fusarinm lycopersici, F. vasinfectum
G. Kreitman and F. F. Nord, Arch. Biochem. 21 457 (1949).
Gerald Kreitman, Oldrlch K. Sebek and F. F. Nord, ibid. 28
77 (1950).
Pfizer Handbook of Microbial Metabolites 594
1190 Malucidin, complex yeast protein, soluble in water, not coagula-
ble, not dialyzable. Contains organic phosphorus to
which its activity can be related.
The protein is combined with RNA, while the latter by
itself has very little, if any, antibacterial property.
Brewers' and bakers' yeasts
I. A. Parfentjev, Federation Proc. 16 428 (1957).
1191 Marasmic Acid, C10H00O4 (proposed) colorless needles, m.p.
174° (sealed tube), [x]r>^^ 176° (c 1.4 in acetone).
A monobasic acid with reducing properties. Negative
FeCl^, Br^ in CCI4. Forms a 2,4-dinitrophenylhydrazone.
Marasmius conigenus
Frederick Kavanagh, Annette Hervey and William J. Rob-
bins, Proc. Nat. Acad. Sci. U. S. 35 343 (1949).
1192 Marcomycin, Ci-Ha^OyN:,, white crystals, m.p. 160-180° (dec).
Streptomyces hygroscopicus
German Patent 1,027,846 (1958).
1193 Megacidin, C24H38OJ0 (proposed), colorless crystals, m.p. 162-
164°, [ain -51° (c 0.958 in ethanol).
A neutral compound with an easily saponifiable ester
or lactone group.
Also isolated from the same fermentation were: L-leu-
1194 cyl-L-proline anhydride, m.p. 158-165°, [aln —128° (c
1195 0.968 in ethanol) and L-leucyl-L-leucine anhydride.
Streptomyces sp.
L. Ettlinger, E. Gaumann, R. Hiitter, W. Keller-Schierlein,
F. Kradolfer, L. Neipp, V. Prelog, P. Reusser and H. Zahner,
Monatsh. Chem. 88 989 (1957).
1196 Melanosporin, C56-63H105-117O20-22N3, yellowish white amorphous
solid, m.p. 132-134°, [aW° +30° (c. 1.57 in methanol).
Strong" acid hydrolysis yields three ninhydrin-positive
compounds. Negative FeClg. Positive ninhydrin.
Streptomyces melanosporus {sine m,elanosporofaciens)
n. sp.
F. M. Arcamone, C. Bertazzoli, M. Ghione and T. Scotti,
Giorn. microbial. 7 207 (1959).
1197 Mesenterin, colorless needles, m.p. 122-126°.
A basic compound, analysis: C 65.82, H 7.10, N 8.66.
Positive Molisch, negative ninhydrin, biuret, Fehling,
Feci,.
595
Unclassified Metabolites
Occurs with azomycin and antibiotic 446.
Nocardia mesenterica
Masahiro Ueda and Hamao Umezawa, /. Antibiotics (Ja-
pan) 8A 164 (1955).
1198 Metabolite, C24H-0O2, colorless crystals, m.p. 82°.
Negative Liebermann-Burchard, KMnO,, tetranitro-
methane tests.
Amanita phalloides
Heinrich Wieland and Gustav Coutelle, Ann. 548 270 ( 1941 ).
1199 Metabolite of Coprinns comatis, Ci2Hi,.0N<>S, m.p. 157°.
A basic compound, containing a phenolic hydroxyl
group. Positive Millon, Pauly diazo tests. Raney nickel
desulfurization gave a compound, m.p. 250° (dec).
Copriniis comatis Gray
Paul Heinz List, Arch. Pharm. 291 502 (1958).
1200 Metabolite from Curvularia lunata, Ci4His,05, colorless needles,
m.p. 195°.
Insoluble in aqueous sodium carbonate, soluble in aque-
ous sodium hydroxide. Brown color with alcoholic ferric
chloride.
Curvularia lunata
Also isolated from the same culture were mannitol and
a trace of crystalline material, m.p. 176-178° (dec).
T. Krishna Murty and S. Sankara Subramanian, Indian J.
Pharm. 20 72 (1958).
1201 Metamycin, white crystals, m.p. 173° (dec.) [ajr^^^ +36.6 (c
d.ll in methanol) U.V. 237, 305-307 m^ in 0.1 N sodium
hydroxide.
C 43.95, H 4.06, N 14.45, S 13.57.
Positive Fehhng, Tollens, Bro, decolorization of per-
manganate, 2,4-DNPA tests. Negative FeClg and Saka-
guchi tests.
Streptomyces matensis
P. Sensi, R. Ballotta and G. G. Gallo, Antibiotics and Chemo-
therapy 9 76 (1959).
1202 Microcin A, neutral, reddish violet in color, separated at pH 7.0.
1203 Microcin B, acidic, yellowish red, slightly soluble in water sepa-
rated at pH 2.0.
Both give negative Molisch and FeClg; vary from mi-
cromonosporin in activity, have much resistance to U.V.
Pfizer Handbook of Microbial Metabolites 596
Micromonospora sp.
Tomotsune Taira and Shigehiro Fujii, J. Antibiotics (Japan)
5 187 (1952).
1204 Mikamycin A, C31H39O9N3, yellowish white crystals, m.p. 147-
152° (dec), [aln'" -152° (c 0.5 in methanol).
Apparently identical with the principal active com-
ponent of the streptogramin and antibiotic No. 899 com-
plexes.
A neutral antibiotic. Negative ninhydrin, biuret, glu-
cosamine, maltol and Millon. Green-black FeCla. Brown
precipitate with the Tollens reagent. Positive Benedict.
Forms a 2,4-DNPH.
Streptomyces mitakaensis
Mamoru Aral, Keiko Karasawa, Shoshiro Nakamura, Hiroshi
Yonehara and Hamao Umezawa, J. Antibiotics (Japan) 11 A
14 (1958).
Mamoru Aral, Koichi Okabe, Hiroshi Yonehara and Hamao
Umezawa, ibid. IIA 21 (1958).
Koichi Okabe, ibid. 12A 86 (1959).
1205 Mikamycin B, C45H5sOiiNg (proposed), white platelets, m.p.
160°, dec. 262°, [aW -61.3° (c 1.0 in methanol).
Similar to PA-114 B in physical and chemical proper-
ties but differs from staphylomycin S. It is thought to be
different from both.
Gives a positive FeClj. Negative Ehrlich, biuret,
Fehling, Tollens, nearly negative ninhydrin.
Streptomyces mitakaensis
Kiyoshi Watanabe, Hiroshi Yonehara, Nobuo Tanaka and
Hamao Umezawa, J. Antibiotics (Japan) 12A 112 (1959).
Koyoshi Watanabe, ibid. 13A 57 (1960).
Mitomycins.
1206 A complex from which several compounds were iso-
1207 lated: colorless fractions W-1 (m.p. 148°), W-2 (m.p.
1208 138°) and W-3 (m.p. 187°). Pigmented fractions A (red
1209 crystals) m.p. 167°, B (violet crystals), C (bluish violet
1210 crystals), Y (yellow crystals) m.p. 180-240° (dec.) and
1211 R (red-brown amorphous powder). Pigmented fractions
1212 are antibiotic.
1213
1214 Mitomycin C, C54H61OJ9N13 (tentative), deep bluish violet crys-
tals, m.p.: no melting or dec. noted below 360°.
597 Unclassified Metabolites
:• Positive FeCl;,, Fehling, biuret, Ehrlich, decolorization
of permanganate. Negative Benedict, Tollens, ninhydrin,
Milton, Raymond. Mol. Wt. ~1120.
The mitomycins may be related to the actinomycins.
Streptomyces caespitosus
S. Wakaki, H. Marumo, K. Tomioka, G. Shimizu, E. Kato,
H. Kamada, S. Kudo and Y. Fugimoto, Antibiotics and Chemo-
therapy 8 228 (1958).
Toju Hata, Yoshimoto Sano, Ryozo Sugawara, Akihiro
Matsumae, Kokichi Kamamori, Tatsuo Shima and Tadashi
Hoshi, ;. Antibiotics (Japan) 9A 141 (1956).
1215 INIoldin, gives positive Molisch and FeCls but negative biuret,
ninhydrin, Tollens, Fehling and Sakaguchi tests.
Streptomyces sp. res. S. phalochroviogenus
Kenji Maeda, Yoshiro Okami, Osamu Taya and Hamao
Umezawa, J. Antibiotics (Japan) 5 465 (1952).
1216 Monilin, Ci^HooOgNfi, colorless needles, m.p. 235-238° (dec).
An antifungal compound. Positive ninhydrin.
Streptomyces sakaiensis
Shigehiro Fujii, Hiromu Hitomi, Masahiko Imanishi and
Koichi Kakazawa, Ann. Rept. Tdkeda Research Lab. 14 8
(1955).
1217 Musarin (C35H6oOi4N2)n (proposed), Mol. Wt. ^5000, yellow
powder, m.p. 170° (dec), UW" +35.1° ±1.6° (c 1.21 in
methanol).
An acidic substance.
Streptomyces sp.
H. R. V. Arnstein, A. H. Cook and Margaret S. Lacey, J. Gen.
Microbiol. 2 111 (1948).
1218 Mutomycin, C7H11.12O2, white crystalline powder, m.p. 141.5-
142°.
Actinomyces atroolivaceus var. mutom.ycini
G. F. Gauze, T. S. Maksimova, O. L. Popova, M. G. Brazh-
nikova, T. A. Uspenskaya and O. K. Rossolimo, Antibiotiki
U.S.S.R. 4 20 (273 in EngUsh) (1959).
1219 Mycelin, m.p. 263° (dec).
Water insoluble, contains no nitrogen or sulfur. Neg-
ative Molisch. Flavomycin is produced by the same or-
ganism. Mycelin has antifungal properties.
Streptom.yces roseofiavus
Kazuyoshi Also, Tadashi Aral, Kazuhiro Washlda and Tei
Tanaami, J. Antibiotics (Japan) 5 217 (1952).
Pfizer Handbook of Microbial Metabolites 598
1220 Mycelin-IMO, yellow crystalline, m.p. 214-222° (dec), [a]n^^
+70 ±2 (c 1 in 1,4-dioxane) U.V. 243, 294, 335, 355, 373
m/j,. Mol. Wt. 335, C 71.29, H 5.96, N 11.31.
Streptomyces diastatochromogenes
Koichi Ogata, Masaji Igarashi, Akira Miyake and Hiroichi
Yamamoto, Japanese Patent 5898 (1957).
1221 Mycorhodin, bright red needles, m.p. 200-202° (dec.) U.V.
420, 471, 250m;x in ethanol. C 58.7 H 5.2 N 2.1.
Mol. Wt. 698, 635.
Acid-base indicator.
Streptomyces sp.
M. Misiek, A. Gourevitch, B. Heinemann, M. J. Cron, D. F.
Whitehead, H. Schmitz, I. R. Hooper and J. Leln, Antibiotics
and Chemotherapy 9 280 (1959).
1222 Mycospocidin (C20H32O9N2),,, colorless crystals, dec. 233°,
[a]D-" +56° "(c i in pyridine).
Negative ninhydrin, biuret, Tollens, Fehling, ferric
chloride tests. Positive diazo reaction.
Acid hydrolysis yielded two ninhydrin-positive sub-
stances, one perhaps being glycine.
Streptomyces bobiliae
Shoshiro Nakamura, Mamoru Aral, Keiko Karasawa and
Hiroshi Yonehara, J. Antibiotics (Japan) lOA 248 (1957).
1223 Mycothricin, colorless crystals, complex consists of strong or-
ganic bases.
Negative ninhhydrin, biuret, Fehling, Tollens, Molisch,
Millon, maltol and Sakaguchi.
Streptomyces lavendulae
G. Rangaswami, Hindustan Antibiotics Bull. 2 46 (1959).
1224 Mycoticin, CigHsoO-, (proposed), yellow crystals.
Contains a hydroxyl group, has reducing properties,
fluoresces under U.V.
Streptomyces ruber
Ruth C. Burke, Jacob H. Swartz, S. S. Chapman and Wei-
Yuan Huang, J. Invest. Dermatol. 23 163 (1954).
1225 Nigericin, C3i,H,;,,0i,, colorless needles, m.p. 246-254°.
A monobasic acid.
Streptomyces sp. resembling S. violaceaniger
Roger L. Harned, Phil Harter Hidy, Cyril J. Corum and Ken-
neth L. Jones, Antibiotics and Chemotherapy 1 594 (1951).
599 Unclassified Metabolites
1226 Nocardianin, C6r,.67H»6.i04Oi5Ni8, red prisms, m.p. 228-235°
(dec), [a]i."" -223° (c 0.3 in methanol).
Negative biuret, ninhydrin.
Nocardia sp.
I. R. Bick, Gregory J. Jann and Donald J. Cram, Antibiotics
and Chemotherapy 2 255 (1952).
1227 Nocardorubin, crimson powder, darkens from 180° (dec.).
Nocardia narasinoerisis
J. Antibiotics (Japan) 8B 253 (1955).
1228 Nonactin, C;,oH^^O,,, colorless crystals, m.p. 147°, optically in-
active.
Slight U.V. at 264 m^ (log e = 1.5 in ethanol). Inert
to chemicals and microbes.
Streptomyces spp. which produce cycloheximide.
R. Corbaz, L. Ettlinger, E. Gaumann, W. Keller-Schierlein,
F. Kradolfer, L. Neipp, V. Prelog and H. Zahner, Helv. Chini.
Acta 38 1445 (1955).
1229 Nordin, CigHieO^sCL, m.p. 134-136°.
Occurs with estin (q.v.).
Penicilliuin paxilli var. echinulatum
Eitaro Komatsu, Japanese Patent 4799 (1953).
1230 Nudic Acid A, C,4H2i,0;^ (proposed), colorless crystals, m.p.
123.5°.
No reducing properties. Takes up bromine.
Tricholoma nudum
H. W. Florey, E. Chain, N. G. Heatley, M. A. Jennings, A. G.
Sanders, E. P. Abraham and M. E. Florey, "Antibiotics," Oxford
University Press, London, 1949, p. 358.
1231 Nybomycin, C1SH14O4N0, colorless crystals, which darken at 330°
without melting.
Negative ninhydrin, biuret, FeClg; sugar tests, Ehrlich,
KM,.04, Bro.
Streptomyces sp.
Frieda Strelitz, Helen Flon and Igor N. Asheshov, Prac. Nat.
Acad. Sci. U. S. 41 620 (1955).
T. E. Eble, G. A. Boyack, C. M. Large and W. H. De Vries,
Antibiotics and Chemotherapy 8 627 (1958).
1232 Oligomycin A, C24H4yO(., colorless crystals, m.p. 140° (dec),
150° (dec.) (polymorphic), [alo"^ —54.5° (c 4.40 in diox-
ane).
Pfizer Handbook of Microbial Metabolites 600
Mol. Wt. = 424. Absorbs 2 moles H2. Four active H.
Five C — CH3 groups. Forms a diacetate.
1233 Oligomycin B, C22H36O6, colorless crystals, m.p. 160°, 169°
(polymorphic), [aW^^ —49.5° (c 1.03 in methanol).
Mol. Wt. = 396. Four active H. Five C— CH3 groups.
Forms a diacetate.
1234 Oligomycin C, CorH^.-Oc colorless crystals, m.p. 198-200°, [aW^
-80.7° (c 3.70 in dioxane).
Contains six C — CH3 groups.
Streptomyces sp. (may be S. diastatochromo genes)
Robert M. Smith, William H. Peterson and Elizabeth McCoy,
Antibiotics and Chemotherapy 4 962 (1954).
Satoru Masamune, J. M. Sehgal, E. E. van Tamelen, F. M.
Strong and W. H. Peterson, /. Am. Chem. Sac. 80 6092 (1958).
1235 Ophiobalin, C28H30O4, white prisms, m.p. 181-182°.
Ophiobalus miyabeanus
A. Neelameghan, Hindustan Antibiotics 2 13 (1959).
1236 Oregonensin, C20H32OS (proposed), colorless needles, m.p. 82°.
A neutral substance. Positive 2,4-DNPH.
Ganoderma oregonense
H. W. Florey, E. Chain, N. G. Heatley, M. A. Jennings, A. G.
Sanders, E. P. Abraham and M. E. Florey, "Antibiotics," Oxford
University Press, London, 1949, p. 362.
1237 Oryzacidin (Oryzasizine), CgHigOsN, colorless, hygroscopic nee-
dles, m.p. 162° (dec), [ajn -138°.
y3-Nitropropionic acid also occurs free in the culture
broth.
Aspergillus oryzae
Chujiro Shimoda, /. Agr. Chem. Soc. Japan 25 254 (1951).
Seiji Nakamura and Chuji Shimoda, ibid. 28 909 (1954).
1238 PA-128, C37.46H6i.75O13.1cN, Ught yellow rectangular plates, m.p.
143° [aln'' -2.0° (c 1 in methanol).
Negative FeClg, no colors in aqueous base nor concen-
trated H2SO4. Positive 2,4-DNPH, decolorizes Brs water
and permanganate. Takes up >6 mM of hydrogen per
gram of antibiotic.
Unclassified Streptomycete
Koppaka V. Rao and John E. Lynch, Antibiotics and Chemo-
therapy 8 437 (1958).
6oi Unclassified Metabolites
i239 PA-132, CicHissoOr,, free acid is a colorless amorphous powder,
[a].,-' —161° (c 1.0 in methanol). Handled as the ben-
zylamine salt: white crystals, m.p. 128-131°, [a]i)~^ —130°
(c 1.0 in methanol).
A lactonic acid containing two C-methyl groups. De-
colorizes bromine or permanganate. Negative FeCla,
Fehhng, 2,4-DNPH, Tollens, AgNOg and NaOI.
Streptomyces sp.
B. Kenneth Koe, Ben A. Sobin and Walter D. Celmer, "Anti-
biotics Annual 1956-1957," Medical Encyclopedia, Inc., New
York, p. 672.
1240 Phagolessin A 58, light yellow hygroscopic powder.
Negative FeClg, biuret, Millon and ninhydrin test.
Streptomyces sp.
Igor N. Asheshov, Freda Strelitz and Elizabeth A. Hall, Anti-
biotics and Chemotherapy 2 366 (1952).
1241 Phalamycin, CaeH^iOi^N^S (proposed), colorless crystals, no
sharp m.p.
Positive FeClg, Bro absorption. Has primary or second-
ary alcohol groups.
Streptomyces noursei variant
Rachel Brown, N. Y. State Dept. Health, Ann. Kept. Div.
Labs and Research 18 (1956). (Chem. Abstr. 51 16672e)
1242 Phalofacin gives positive FeCls but negative biuret, Millon, nin-
hydrin, MoHsch, Tollens and Sakaguchi tests.
Streptomyces sp. res. S. aureus
Kenji Maeda, Yoshiro Okami, Osamu Taya and Hamao
Umezawa, /. Antibiotics (Japan) 5 465 (1952).
1243 Phleomycin, C53H93O32N17, white to pale green amorphous pow-
der, isolated as a blue monocopper complex. U.V. 244,
295-300 lUfi.
Gives positive ninhydrin and diazo tests. Negative
Fehling, Tollens, Sakaguchi and Molisch.
Streptomyces verticillis
Tomohisa Takita, Kenji Maeda and Hamao Umezawa, J.
Antibiotics (Japan) 12A 111 (1959).
Tomohisa Takita, ibid. 12 285 (1959).
1244 Phytonivein, C29H46O2, colorless needles, m.p. 138°.
Fusarium bulbigenum
The watermelon wilt toxin.
Pfizer Handbook of Microbial Metabolites 602
Isamu Hirose and Seiyo Aoe, Ann. Phytopathol. Soc. Japan
19 162 (1955). (Chem.' Abstr. 50 14058g)
Isamu Hirose and S. Nishimura, Nippon Nogii-kagaku
Kaishi 30 528 (1956).
1245 Piricularin, C17H14N2O3 or C18H14N0O3, colorless crystals, m.p.
73.5°, [a]D'« -19°.
Absorbs 4 moles of hydrogen over platinum catalyst,
contains two phenolic or enolic hydroxyls, no methoxyl.
Reacts with 3 moles of 2,4-dinitrophenylhydrazine. Has
1 N-methyl, no NH or NHo. A max. in HoO = 240 m/x.
Ejom/"^^ 2824. A toxin of rice blast disease.
Piricularia oryzae
Kinjiro Tamari and Jun Kaji, Nippon Nogei-kagaku Kaishi
31 387 (1957).
1246 neomycin, C,4Hj20s, rectangular plates from ethanol, m.p.
235°, U.V. 270, 330, 340 m^^ in 0.13 m phosphate buffer.
Streptomyces pleofaciens
Roy A. Machlowitz, Jesse Charney, Alfred A. Tytell and
W. P. Fisher, "Antibiotics Annual 1954-1955," Medical Ency-
clopedia, Inc., New York, p. 806.
1247 Pleuromutilin (Drosophilin B), C22H340r,, colorless crystals,
m.p. 170°, [aW +20° (c 3.0 in absolute ethanol).
Forms a diacetate, non-phenolic, probably has a lactone
ring, forms a hydrazone.
Pleurotus mutilus
Marjorie Anchel, /. Biol. Chem. 199 133 (1952).
1248 Pleurotin, C20H22O5, yellow-amber needles, m.p. 220-215°
(dec), [a]v~^' —20° (c 0.59 in chloroform).
A neutral, photosensitive compound. Negative FeCls,
oxidized KI.
Pleurotus griseus
William J. Robbins, Frederick Kavanaugh and Annette
Hervey, Proc. Nat. Acad. Sci. U. S. 33 171 (1947).
1249 Pluramycin A, orange needle crystals, dec. from 177°, U.V. 208,
245 (265-270) m^^ in ethanol.
C 66.63, H 6.30, N 3.66
Negative FeCl^, Fehling, ToUens and 2,4-DNPH.
1250 Pluramycin B, reddish brown powder, possible neutral sub-
stance. The pluramycins may be related to the actino-
mycins.
6o3 Unclassified Metabalites
Tomio Takeuchi, Kazuo Nitta and Hamao Umezawa, J. Anti-
biotics (Japan) 9 A 22 (1956).
Kenji Maeda. Tomio Takeuchi, Kazuo Nitta, Koki Yagishita,
Ryozo Utahara, Teisuke Osato, Masahiro Ueda, Shinichi Kondo,
Yoshiro Okami and Hamao Umezawa, ibid. 9A 75 (1956).
1251 Poin, crystals, m.p. 142-143°.
C 59.70, H 7.77, O 32.53
Fusarium sporotrichiella var. poae
O. K. filpidina, Antibiotiki U.S.S.R. 4 46 (273 in English)
(1959).
1252 Primycin, C,.,H.5-0;N, white microcrystals, m.p. 166-168° (dec).
No reducing properties. Can be acetylated. Strong
Sakaguchi test.
An unclassified actinomycete
T. Valyi-Nagy, J. Ori and I. Szilagy, Nature 174 1105 (1954).
1253 Psalliotin, crystalline, water soluble, inactivated by bright light.
Psalliota xanthoderma
Nancy Atkinson, Nature 174 598 (1954).
Idem., Australian Patent 20,272,156 (1957).
1254 Pulvilloric Acid, buff colored needles, turning bright yellow in
air.
An acidic, antifungal antibiotic, containing only C, H,
O. Blue FeCli, negative Tollens. Yield 600 mg. per liter.
PenicilliuTn pulvillorum Turfitt
P. W. Brian, P. J. Curtis, H. G. Hemming and G. L. F. Norris,
Brit. Mycol. Soc. Trans. 40 369 (1957).
1255 Pumilin, lemon-yellow crystals, m.p. >360°.
Negative FeCl-,, copper-red in 5 N hydrochloric acid.
Bacillus pumilis
0.7 g. was obtained from 500 gal. of broth.
D. S. Bhate, Nature 175 816 (1955).
1256 Racemomycin A
1257 Racemomycin B,* C60H128O32N20, white powder, m.p. (Hydro-
chloride) 175° (dec), [o^W -45° (c 0.5 in water).
Positive Molisch, Elson-Morgan and biuret. Negative
Sakaguchi, maltol, FeCl^, 2,4 DNPH and Fehhng. Yields
^-lysine and roseonine on hydrolysis.
1258 Racemomycin C, isolated in a small amount as a salt (m.p.
210°).
* See entry 790.
Pfizer Handbook of Microbial Metabolites 604
Streptomyces racemochromogenes n. sp.
Hyozo Taniyama and Shoji Takemura, J. Pharm. Soc. Japan
77 1210, 1217 (1957); 78 742 (1958).
1259 Ractinomycin A, C33H3nOi4N3, orange needles, m.p. browns
-157°, blackens at 205°.
Negative ninhydrin, biuret, Sakaguchi, Millon. Posi-
tive Tollens, Molisch, FeClg. Decolorizes KMn04. De-
colorized by HoOo. Alkali-unstable. Turns purple above
pH 6.5. Contains no amino acids.
1260 Ractinomycin B, reddish orange needles, m.p. 172-175° (dec).
Negative FeClg.
The ractinomycins are said to resemble the actinomy-
cins in some respects.
Streptomyces sp. similar to S. phaeochromogenes
Ryozo Utahara, Hideo Oyagi, Koki Yagishita, Yoshiro Okami
and Hamao Umezawa, J. Antibiotics (Japan) 8A 132 (1955).
Ryozo Utahara, ibid. lOA 115 (1957).
S. Wakiki et al., Antibiotics and Chemotherapy 8 228
(1958).
1261 Raisnomycin, dark yellow basic material, insoluble in water.
The hydrochloride and disulfate are slightly soluble. The
impure material does not have an end absorption in U.V.
Streptomyces kentuckensis
Fred S. Barr and Paul E. Carman, Antibiotics and Chemo-
therapy 6 286 (1956).
1262 Rammacin, C26H43O8, crystalline, m.p. 235°, Mol. Wt. 499.
Negative Brs; positive benzenoid.
Streptomyces sp.
K. Ahmad and M. F. Islam, Nature 176 646 (1955).
1263 Ramycin (Mol. Wt. 478, contains only carbon, hydrogen and
oxygen), 'colorless plates, m.p. 158° (dec), optically in-
active.
Structural features:
A non-phenolic hydroxy acid with one or more carbon-
carbon double bonds.
Mucor ramannianus
P. J. van Dijck and P. deSomer, J. Gen. Microbiol. 18 377
(1958).
1264 Raromycin, m.p. 211-213° C 57.97, H 8.46, N 0.44, O 33.13 by
difference.
6o5 Unclassified Metabolites
'.' Streptomyces sp.
Nabuo Tanaka, Hisaji Yamazaki, Koichi Okabe and Hamao
Umezawa, /. Ajitibiotics (Japan) lOA 189 (1957).
1265 Roseomycin, crystalline helianthate, m.p. 211-216° (dec.) and
reineckate m.p. 114° (dec).
Positive Molisch, Tollens, indole, glucosamine and
Fehling.
Negative maltol, biuret, ninhydrin and Sakaguchi.
Streptomyces roseochromogenes
Nakao Ishida, J. Antibiotics (Japan) 3 845 (1950).
1266 Rhizobacidin, crystalline, m.p. 215-220° (dec). Contains C,
H, O and N but not S. Positive biuret, xanthoproteic,
ninhydrin and Sakaguchi. Negative Ehrlich, Molisch and
FeCla.
Bacillus subtilis
Carlos Casas-CampiUo, Ciencia (Mexico) 11 21 (1951).
1267 Rhodocidin, red powder, U.V. shows a broad peak at 500-530
mix. Soluble in water and organic solvents.
Streptomyces phoenix
Jesse Charney, Roy A. Machlowitz, W. S. Roberts and W. P.
Fisher, Antibiotics and Chemotherapy 3 788 (1953).
Ristocetins (Spontins, Ristins).
Two closely related amphoteric antibiotics containing
amino and phenolic groups and sugars. Each contains
four reducing sugars: glucose, mannose, rhamnose and
D-arabinose.
Negative biuret, Sakaguchi, maltol. Positive phospho-
molybdic acid test for phenols, ninhydrin (after acid hy-
drolysis), anthrone. Mol. Wt. 2500-5000. Contain C, H,
O, N, S.
1268 Ristocetin A (Sulfate): [alo'^ -120-133° (in water).
1269 Ristocetin B (Sulfate): [ajn" -144-149° (in water).
Nocardia lurida
Julian E. Philip, Jay R. Schenck and Martha P. Hargle,
"Antibiotics Annual 1956—1957," Medical Encyclopedia, Inc.,
New York, p. 699.
1270 Rotaventin, white crystals, m.p. 170-175° (dec).
Streptom.yces reticuli
Nobukiko Komatsu and Momoe Soeda, Japan. J. Exp. Med.
21 279 (1951).
Pfizer Handbook of Microbial Metabolites 606
1271 Rubromycin, thin square rods, m.p. 215° (dec.) U.V. 518-520,
546, 584 m^.
C 60.30, H 4.26, O 33.91
Contains no N (differing from rhodomycin). Differs
from rhodomycetin in that the latter is found in the cul-
ture solution; the present compound is in the mycelium.
Streptomyces collinus n. sp.
Hans Brockman and Karl Heinz Renneberg, Naturwissen-
schaften 40 59 (1953).
1272 Ruticin, orange needle-hke crystals, U.V. 227, 262, 364 m^x.
Streptomyces res. S. rutgersensis
W. P. Fisher, Jesse Charney, Ray A. Machlowitz, James E.
Blair and Alfred A. Tytell, "Antibiotics Annual 1953-1954,"
Medical Encyclopedia, Inc., New York, p. 174.
1273 Sarcidin, m.p. 274-275° (dec).
C 41.89, H 5.02, N 21.82 and a qualitative sulfur test.
Tamio Takeuchi, Kazuo Nitta and Hamao Umezawa, /. Anti-
biotics (Japan) 6A 31 (1953).
1274 Secalonic Acid, C31H30.32O14, lemon-yellow needles, m.p. 244-
250° from chloroform, [a],,-" -81° (acetone), -66° (chlo-
roform), -198°->-59° (pyridine).
Claviceps purpurea
F. Kraft, Arch. Pharm. 244 336 (1906).
A. Stoll, J. Renz and A. Brack, Helv. Chim. Acta 35 2022
(1952).
1275 Seligocidin, crystalline powder, U.V. 304 m^j, in ethanol.
Positive Sakaguchi and ninhydrin; negative biuret.
Streptomyces res. S. roseochromogenes
Shoshiro Nakamura, Kenji Maeda, Yoshiro Okami and
Hamao Umezawa, J. Antibiotics (Japan) 7A 57 (1954).
1276 Sirenin, CoiHsgO^N.
Mol. V^t. : found 386, calculated 414. Contains a lac-
tone ring, a carbonyl group and a — C=C — or — C=N —
bond. The absence of hydroxyl and carboxyl groups and
of aromatic rings was ascertained.
Allomyces species
Sirenin is a sex hormone of this water-mold.
Leonard Machlis, Nature 181 1790 (1958).
6o7 Unclassified Metabolites
1277 Sporidesmin (probably) Ci9H:;iO,iN;<SXlCCl4, colorless crystals
(carbon tetrachloride solvate) sintering from 109°-^
resins 125° semi-solid -^ meniscus at 130-134°, [a]i.-"
-19° (c 2.2 in methanol).
Other formulae without chlorine are not excluded,
since the solvent-free compound has not been isolated.
The compound is a toxin in animals.
Sporidesmiiim bakeri Syd.
R. L. M. Synge and E. P. White, Chem. and Ind., 1546
(1959).
1278 Streptocardin, Crystalline, U.V. 365 (242) (252) m^^ in phos-
phate buffer (pH 6) forms water-soluble alkali salts.
Streptomyces sp., Nocardia sp.
W. P. Fisher, Roy A. Machlowitz, Alfred A. Tytell and Jesse
Charney, "Antibiotics Annual 1953-1954," Medical Encyclope-
dia, Inc., New York, p. 177.
1279 Streptolydigin, C;i.H4e09No (or C3,-H.-^oOioNo), m.p. 144-150°
(dec), [alo"' —93° (c 1.6 in chloroform).
An enolic acid. Positive FeCls, iodoform. Negative
biuret, ninhydrin, Fehling, Molisch. Reacts with Bto in
CCI4.
Streptomyces lydicus
T. E. Eble, C. M. Large, W. H. DeVries, G. F. Crum and
J. W. Shell, "Antibiotics Annual 1955-1956," Medical Encyclo-
pedia, Inc., New York, p. 893.
Streptovaricin (Dalacin). A complex consisting of at least five
active closely related components. These were separated
by countercurrent distribution into Streptovaricins :
1280 A, C34H4-.490i;^N, yellow crystals, m.p. 182-184°, [2W +454°
(CHCI3).
1281 B, C34H4749O13N, yellow crystals, m.p. 195-200°, [aW* -fl68°
(CHCI3).
1282 C, C34H4-.4c,0,3N, yellow crystals, m.p. 168-171°, [ajir" +317°
(CHCI3).
1283 D, yellow crystals, m.p. 115-118°, hW^ +102° (CHCI3).
1284 E, yellow crystals, m.p. 102-105°, [aW +6.13° (CHCI3).
Pfizer Handbook of Microbial Metabolites 608
Streptoinyces spectabilis
Paul Siminoff, Robert M. Smith, Walter T. Sokolski and
G. M. Savage, Am. Rev. Tuherc. Pulmonary Diseases 75 576
(1957).
George B. Whitfield, Edward C. Olson, Ross R. Herr, John A.
Fox, Malcolm E. Bergy and Gerald A. Boyack, ibid. 75 584
(1957).
Upjohn Co., British Patent 811,757 (1959).
1285 Streptozotacin, C14H17O12N5, m.p. 115-125° (dec).
Probably still a mixture. Base-unstable neutral
substance. Seems to contain the partial structure
0
R — Cf /N=0. Alkaline treatment liberates diazo-
^CH3
methane.
Streptomyces achromogenes
R. R. Herr, T. E. Eble, M. E. Bergy and H. K. Jahnke, 7th
Annual Symposium on Antibiotics, Washington, D. C, 1959.
1286 Substance 1404, yellow crystalline, Hexaene. M.p. 210-220°
(dec), [aln'' +67.5 ±2.0° (c 1 in dioxane).
Contains N 10.47, no sulfur, no halogen.
Streptomyces diastatochromogenes (Mycelium)
Masaji Igarashi, Koichi Ogata and Akira Miyake, J. Anti-
biotics (Japan) 8B 113 (1955).
1287 Sulfactin, C3sH.-r,07NiiS4 or C27H4oO,-,NsS3 (proposed), hygro-
scopic white needles, m.p. 245-275° (dec).
Positive Fehling. Reduces KMn04. Negative biuret,
FeCl3, Molisch, Sakaguchi.
Streptomyces roseus
Renate Junowicz-Kocholaty, Walter Kocholaty and Albert
Kelner, J. Biol. Chem. 168 765 (1947).
1288 Sulfocidin, yellow-brown crystals, m.p. 166-178°, [a]D^^ —58.5°
(c 0.51 in chloroform).
Neutral antibiotic, analysis C 64.88, H 8.38, N 4.25, S
1.80. Negative nitroprusside and azide iodine, ninhydrin,
FeCl3, Sakaguchi, maltol, biuret, Fehling, 2,4-DNPH. De-
colorizes permanganate.
Streptomyces sp.
Morris Zief, Robert Woodside and George E. Ham, "Anti-
biotics Annual 1957-1958," Medical Encyclopedia, Inc., New
York, p. 886.
6o9 Unclassified Metabolites
1289 Taitomycin, yellow-brown powder, U.V. at 330, 420 m^x.
C 53.57, H 4.87, N 9.50 ash 2.8.
Positive Fehling and ninhydrin (acid hydrolysate).
Streptoynyces afgJianensis
Mitsuo Shimo, Tatsuji Shiga, Takashi Tomosugi and Ikuzo
Kamoi, /. Antibiotics (Japan) 12A 1 (1959).
Takashi Tomosugi, Ikuzo Kamoi, Tatsuji Shiga and Mitsuo
Shimo, ibid. 12A 7 (1959).
1290 Tardin, CnHir.Oa (proposed), pale yellow oil, [a]v^° —11.4° (in
alcohol).
Positive FeCl... Negative 2,4-DNPH. Hydrolyzes to an
acidic and a neutral fraction.
PeniciUium tardum
N. Borodin, F. J. Philpot and H. W. Florey, Brit. J. Exp.
Path. 28 31 (1947).
1291 Terrecin, light yellow prisms, m.p. 219°.
Analysis: C 51.89, H 3.51, N 3.8, CI 19.1. Alkali
soluble. Positive FeCl^.
Aspergillus terrens
Kazuo Iwata and Itiro Yosioka, /. Antibiotics (Japan) 3 192
(1950).
1292 Thiactin, acid and alkali metal salts (previously identified as
bryamycin). M.p. 220-234°, [a]n'' -68.5 -69.5° (c 1
in chloroform).
Streptomyces hawaiiensis
Bernard Heinemann, Irving R. Hooper and Martin J. Cron,
British Patent 790,521 (1958).
1293 Thioaurin (Orosomycin, Antibiotic HA-9), CyHeOoN^So or
Ci4H,.j04N4S4 (proposed), yellow crystals, m.p. 178-180°,
optically inactive.
Strong U.V. at 232, 370 m^. Negative FeClg.
Streptomyces sp. resembling S. lipmanii
William A. Bolhofer, Roy A. Machlowitz and Jesse Charney,
Antibiotics and Chemotherapy 3 382 (1953).
William Eisenman, P. Paul Minieri, Anthony Abbey, John
Charlebois. Mary Moncrieff-Yates and Neil E. Rigler, ibid. 3
385 (1953).
1294 Thiomycin, golden yellow needles, m.p. 176-178° (dec).
Resembles thioaurin somewhat. May be identical.
Analysis: C 49.61, H 5.50, N 8.88, S 16.26. Negative
FeCl,, ninhydrin, Fehling.
Pfizer Handbook of Microbial Metabolites 6io
Streptomyces sp. resembling S. phaeochromogenes var.
chloromyceticus
Yorio Hinuma, Susumu Hamada, Takaaki Yashima and
Kyoko Ishikara, /. Antibiotics (Japan) 8A 118 (1955).
1295 Totomycin, C2iH;.90iiN, amorphous.
Streptomyces crystallinus
Jacques Loewe Research Foundation, Inc., British Patent
758,276 (1956).
1296 Toyocamycin, C12H14O4N-,, colorless needles, prisms (mono-
hydrate), m.p. 243°.
Analysis: Negative FeClg, Fehling, Mohsch, Millon,
Sakaguchi, EhrUch. Mol. Wt. 286, 266.
Streptomyces toyocaensis
Kg Kikuchi, J. Antibiotics (Japan) 8A 145 (1955).
Haruo Nishimura, Ken Katagiri, Kozaburo Sato, Mikao
Mayama and Noburo Shimaoka, ibid. 9A 60 (1956).
1297 Tubercidin, C11H14O4N4, crystals, m.p. 247° (dec).
Forms a picrate, reineckate, helianthate, and penta-
chlorophenolate. A basic substance stable to acid and
alkali.
A streptomycete
Kentaro Anzai, Goto Nakamura and Saburo Suzuki, /. Anti-
biotics (Japan) lOA 201 (1957).
1298 Unclassified Compound, Ci^HioO.No, m.p. 220° (dec).
Contains two enolic groups. U.V. bands at 243 and
374 m/x. Photosensitive.
Penicillium puherulum (mycelium)
A. H. Campbell, M. E. Foss, E. L. Hirst and J. K. N. Jones,
Nature 155 141 (1945).
1299 Unnamed antibiotic, CnHiyO^N, hygroscopic light yellow crys-
tals, m.p. 195° (dec).
U.V. absorption at 365, 410 m^u,.
Proteus immunitatis anticarcinomatosa n. sp. (on a
special blood plasma-bouillon medium)
Atsuo Ushiyama and Takaaki Miyasaka, Japanese Patent
Application 3998 (1957).
1300 Vancomycin (Hydrochloride), amphoteric white solid, Mol. Wt.
3200-3500 ±200 (titr.).
Streptomyces orientalis n. sp.
6ii Unclassified Metabolites
M. H. McCormick, W. M. Stark, G. E. Pittenger, R. C. Pit-
tenger and J. M. McGuire, "Antibiotics Annual 1955-1956,"
Medical Encyclopedia, Inc., New York, p. 606.
H. Nishimura, Ann. Kept. Shionogi Res. Lab. 1 479 (1957).
1301 Variotin, Ci.sH^jyOiN, colorless oil, [a],r' -5.68° (c 1.0 in meth-
anol).
A neutral oil with an ester-like odor. C 67.35, H 8.58,
N 4.16, contains no halogen, sulfur or phosphorus. Posi-
tive diazo, nitroalkyl and hydroxamic acid reactions; nega-
tive ferric chloride, Millon, Ehrlich, Sakaguchi, Molisch,
biuret, xanthoprotein and ninhydrin tests.
Paecilomyces variotis Bainier var. antibioticus
Hiroshi Yonehara, Setsuo Takeuchi, Hakao Umezawa and
Yusuke Sumiki, /. Antibiotics (Japan) 12A 109, 195 (1959).
1302 Vengicide, C04H09O9N10, white, amorphous, m.p. 241.5-243°,
[a]i>-" —51.6° (in 0.1 N hydrochloric acid solution).
Mol. Wt. -600. U.V. Amax. 233.5 and 273.5 m^x in 0.05
N hydrochloric acid. C 47.05, H 4.85, O 24.85, N 23.85.
Streptomyces vendargensis
Oxytetracycline is produced also in this fermentation.
N. V. Koninklijke Nederlandsche Gist — en Spiritus — fabriek,
British Patent 764,198 (1956). (Chem. Abstr. 51 10009a)
A. P. Struyck, Canadian Patent 514,164 (1955).
1303 Vertimycin C, crystalline, m.p. 152-155°. C 62.4, H 6.84, O
21.9, N 8.0.
Streptomyces verticillatus
Canadian Patent 575,235 (1959).
1304 Violacetin, fine yellow needles, m.p. (hydrochloride) >210°.
Basic compound. Positive ninhydrin, diazo tests. Pre-
cipitated from aqueous solution by picric acid, phospho-
tungstic acid, forms reineckate. Analysis: C 38.26, H
6.74, N 24.71, CI 9.33. Negative biuret, Fehling, ninhy-
drin, glucosamine, maltol, Sakaguchi, Millon, xanthopro-
tein.
Streptomyces sp. resembling S. purpurochromogenes
Kazuyoshi Aiso, Tadashi Aral, Ichiro Shidara, Hiroo Kurihara
and Yoshiro Morita, /. Antibiotics (Japan) 8A 33 (1955).
1305 Violarin, C22-24H.i:j .S4OS-9, dark violet color or amorphous red
powder, dec. 130°, somewhat similar to litmocidin, rubidin
and rhodomycetin.
Pfizer Handbook of Microbial Metabolites 612
Streptomyces violaceus
N. A. Krasilnikov, G. K. Skryabin and O. I. Artamonova,
Antibiotiki (U.S.S.R.) 3 (1958).
Idem., J. Antibiotics (Japan) 13A 1 (1960).
D. M. Trakhtenberg, L. V. Cerenkova and A. S. Chochlov,
Symposium on Antibiotics, Prague (1959).
Viridins, CigHjgOe (isomers).
1306 a-Viridin, fine colorless needles, m.p. 208-217° (dec), [a]D^°
-213.4° (in chloroform).
1307 yS-Viridin, Fine colorless needles, m.p. 140° (dec), [ajn^" -50.7°
(in chloroform).
Both compounds show: negative Schiff, FeCly, iodo-
form. Red- violet color with phloroglucinol-hydrochloric
acid. Positive ketone derivative tests, Fehling, Tollens.
Tricho derma viride
P. W. Brian and J. C. McGowan, Nature 156 144 (1945).
P. W. Brian, P. J. Curtis, H. G. Hemming and J. C. McGowan,
Ann. Appl. Biol. 33 190 (1946).
E. B. Vischer, S. R. Rowland and H. Raudnitz, Nature 165
528 (1950).
1308 Virtosin, C27H40O9N2, colorless needles, m.p. 142.5-143°, [aW^
+80° ± 0.5° (c 1 in acetone).
Positive Fehling and Sakaguchi reactions; negative
ninhydrin and maltol tests.
Streptomyces olivochromogenes
Akira Miyake, Shozo Wada, Motoo Shibata, Koichi Naka-
sawa, Jujo Kaneko and Yasuharu Mamiya (to Takeda Pharma-
ceutical Industries Ltd.), Japanese Patent Appl. 6149 (1957).
1309 Wortmannin, colorless needles, m.p. 240° (yellowing in sun-
light).
A neutral antifungal antibiotic, containing only C, H, O.
Yields were about 100 mg. per liter.
Penicillium wortmanni Klocker
P. W. Brian, P. J. Curtis, H. G. Hemming and G. L. F. Nor-
ris, Brit. Mycol. Soc. Trans. 40 365 (1957).
1310 Xanthicin, C].3H]-,0-,N, yellowish silky crystals, m.p. 211-213°
(dec), [cxW +319° (c 0.25 in acetone).
U.V. maxima at 270 m^ (CH3OH). 260 m^, 325 nifx
(0.1 MKOH). Positive aldehyde, indole, FeClg tests.
Negative amino, nitro, Fehling's, phosphomolybdic acid
tests. Alkaline KMn04 oxidation gives succinic acid.
6i3 Unclassified Metabolites
Streptomyces xanthochromo genes
Yasuji Sekizawa and Keiko Miwa, Nippon Noget-kagaku
Kaisld 30 471 (1956).
1311 Xanthomycin-like Antibiotic, C29n420-N,)S4Cr (Reineckate), yel-
low-orange glass, U.V. 264.5, 335 m^^ in water, pH 2.
Positive Benedict, bromine, silver nitrate, potassium
iodide, sodium hydrosulfite and periodic acid.
Streptomyces sp.
James D. Mold and Quentin R. Bartz, /. Avi. Chem. Soc. 72
1847 (1950).
1312 Xanthomycins (Protomycins), C23H09.31O7N3, free base: deep
orange-red amorphous solid. Dihydrochloride : bright
orange-yellow plates, [a]ir^ -fll5° (c 0.4 in water).
Reineckate: long, orange needles, m.p. 165-170° (dec).
Contains components A and B. Acid hydrolysis yields
ethanolamine, methylamine and ammonia. Red-purple
color with alkali. Positive Bro uptake, Benedict, silver
nitrate, sodium hydrosulfite, ketone derivatives. Negative
ninhydrin, Molisch, Sakaguchi, FeCls.
Streptomyces sp.
C. B. Thorne and W. H. Peterson, /. Biol. Chem. 176 413
(1948).
K. V. Rao and W. H. Peterson, /. Am. Chem. Soc. 76 1335
(1954).
1313 Xanthothricin, yellow needles, m.p. 165° (s. 161-162°).
Analysis: C 43.64, H 3.82, N 35.21, O 17.34.
Streptomyces sp. similar to S. albus
Roy A. Machlowitz, W. P. Fisher, Betsey S. McKay, Al-
fred A. Tytell and Jesse Charney, Antibiotics and Chemo-
therapy 4 259 (1954).
BIBLIOGRAPHY, REVIEWS AND
GENERAL REFERENCES
A book closely related to this one in intent and format is
Walter Karrer's "Konstitution und Vorkommen dcr organischen
Pflanzenstoffe (exclusive Alkaloide)." This lists over 2600
compounds with simple physical properties and thorough refer-
encing. The emphasis is on metabolites of higher plants, al-
though many fungal products are listed.
Another related book is "Type Reactions in Fermentation
Chemistry," by Lowell L. Wallen, Frank H. Stodola and Rich-
ard W. Jackson. Here the emphasis is on non-sugar substrates,
and classification is by type of reaction (oxidation, reduction,
etc.) accomplished. Many microbial transformations of ster-
oids are included, for example. Structural formulas, names of
microorganisms and references are listed.
The revised edition of W. W. Umbreit's "Metabolic Maps"
should be mentioned. This is essentially a list of equations,
outlining various metabolic pathways, with no discussion and
little referencing, but including catabolic routes and those in
higher organisms.
"Naturally Occurring Quinones," by R. Thomson, is similar
in method to our handbook, but is confined to the single class
of compounds with more thorough discussion of each entry.
"The Comparative Biochemistry of the Carotenoids" by T. W.
Goodwin is somewhat similar in its restriction to a single class
of chemicals. Both books are broader in scope as far as pro-
ducing organism is concerned, and are not limited to micro-
organism products.
"The Chemistry of Microorganisms," by Arthur Bracken, is
descriptive in style, showing some of the degradations and
syntheses leading to establishment of chemical structures and
offering essays on related topics. There is, perhaps, some
emphasis on substances isolated and characterized by the
Raistrick group.
We have not designated antibiotics as such nor have we
attempted to separate the commercial from the non-commercial
or to give the trade names or the biological properties. Data
on biological properties are difficult to evaluate and, on the
newer antibiotics, may conflict. Trade names tend to change
due, for example, to improvements in dosage forms.
Pfizer Handbook of Microbial Metabolites 6i6
Many antibiotic spectra as well as physical properties and
references are given in the "Handbook of Toxicology, Vol. II,
Antibiotics" edited by W. S. Spector.
The "Physicians' Desk Reference" is an annual publication
listing antibiotics and other medicines by brand name, by man-
ufacturer and by type of medicine. There is also a therapeutic
indications index, Usting medicines available for the treatment
of a given condition, and an index Usting professional informa-
tion (composition, dosage, etc.) on each product.
The "Antibiotics Annual" series also is a useful reference
work on antibiotics.
Various other monographs, reviews and general references
are in the hst below.
1 "Konstitution und Vorkommen der orpanischen PflanzenstofFe (ex-
clusive Alkaloide)," Walter Karrer, Birkhauser Verlag, Basel, 1958,
1207 pp. An index similar in intent to this book, but with its scope
the entire plant kingdom. Thoroughly referenced.
2 "Type Reactions in Fermentation Chemistry," L. Wallen, F. Stodola
and R. Jackson, Agricultural Research Service, United States De-
partment of Agriculture (ARS-71-13), Peoria, 1959. A compilation
of the types of chemical conversions by microorganisms which have
been reported in the literature with emphasis on non-sugar sub-
strates.
3 "Metabolic Maps," W. W. Umbreit, Burgess Publishing Co., Minneap-
olis, 1960.
4 "The Chemistry of Microorganisms," Arthur Bracken, Pitman and
Sons, London, 1955, 343 pp.
5 "Antibiotics and Mold Metabolites," a symposium at the March 26,
1956 meeting of the English Chemical Society. Reprinted as Special
Publication No. 5.
6 "Chemical Compounds Formed from Sugars by Molds," B. Gould,
Scientific Report Series No. 7 of the Sugar Research Foundation,
New York, 1947.
7 "The Microbes Contribution to Biology," Albert J. Kluyver and C. van
Niel, Harvard University Press, Cambridge, 1956, 182 pp.
8 "Industrial Fermentations," Leland A. Underkofler and Richard J.
Hickey, Chemical Publishing Co., Inc., New York, 1954, Vol. I, 565
pp.. Vol. II, 578 pp.
9 Industrial and Engineering Chemistry Annual Unit Process Review
of Fermentation, Samuel C. Beesch and G. M. Shull, Ind. and Eng.
Chem. 48 1585 (1956). These reviews list, among other things,
new antibiotics and new microbiological transformations of steroids.
10 Industrial and Engineering Chemistry Annual Unit Processes Review
of Fermentation, Samuel C. Beesch and G. M. Shull, Ind. and Eng.
Chem. 49 1491 (1957).
6 1 7 General References
n Industrial and Enqiveering Chemistry Avnnal Unit Process Review
of Ferjuentation, Samuel C. Beesch and Fred W. Tanner, Jr., Ind.
and Eng. Chein. 50 1341-1354 (1958).
12 Biochemistrii of microorganisms, C. B. van Niel, Ann. Rev. Biochem.
12 551-586 (1943). A review with 371 references.
13 "Handbook of Toxicology, Vol. II, Antibiotics," W. S. Spector (Ed.),
W. B. Saunders and Co., Philadelphia, 1957. This is a compilation
of data on physical and biological properties of 340 antibiotics or
substances which have been tested as antibiotics. Most of these are
microorganism metabolites. Thoroughly referenced. This compila-
tion was prepared under the direction of the Committee on the
Handbook of Biological Data, Division of Biology and Agriculture,
the National Academy of Sciences, The National Research Council.
14 Chemistry and biochemistry of antibiotics, E. B. Chain, Ann. Rev.
Biochem. 27 167-212 (1958). A review with 297 references.
15 Structural chemistry of actinomycetes antibiotics, Eueene van Tame-
len, Fortschr. Chem. org. Naturstoffe 16 90-138 (1958). A review
with 113 references.
16 Biochemistry of antibiotics, S. B. Binkley, Ann. Rev. Biochem. 24
597-626 (1955). A literature survey complete to October 1954
with 284 references.
17 Biochemistry of antibiotics, B. Duggar and V. Singleton, Ann. Rev.
Biochem. 22 459-496 (1953). A review of the literature to Novem-
ber 1952 with 288 references.
18 "Biochemistry of Some Polypeptide and Steroid Antibiotics," CIBA
Lectures in Microbial Biochemistry, E. Abraham, John Wiley and
Sons, Inc., New York, 1957.
19 "Topics in Microbial Chemistry," Antimycin, Coenzyme A, Kinetin
and Kinins, E. R. Squibb Lectures on Chemistry of Microbial Prod-
ucts, F. M. Strong, John Wiley and Sons, Inc., New York, 1957.
20 Antibiotics produced by fungi, P. Brian, Botan. Rev. 17 357—431
(1951). A review with 276 references.
21 Antibiotics produced by actinomycetes, R. Benedict, Botan. Rev. 19
229-320 (1953). A review with 251 references.
22 "The Phvsicians' Desk Reference (to Pharmaceutical Specialties and
Biologicals)," 14th Ed., Medical Economics, Inc., Oradell, N. J., 1960.
23 "Lectures in Antibiotics," G. F. Cause, Medgiz, Moscow, 1959, 356
pp. (In Russian)
24 "Antibiotics," Milos Herold, Czechoslovakian Academy of Science,
Prague, 1957, 363 pp. (In Czechoslovakian)
25 "New Antibiotic Binan (Usnic Acid)," Symposium on usnic acid
and its use as an antibiotic. (In Russian) Academy of Science.
U.S.S.R., 1957, 224 pp.
Pfizer Handbook of Microbial Metabolites 6i8
26 "Streptomycin and Dihydrostreptomycin," Louis Weinstein and
N. Joel Ehrenkranz, Antibiotic Monographs No. 10, Medical Ency-
clopedia Inc., New York, 1958, 111 pp.
27 "Streptomycin, Nature and Practical Applications," Selman A. Waks-
man (Ed.), The Williams and Wilkins Co., Baltimore, 1949, 612 pp.
28 "Polymyxin, Neomycin, Bacitracin," Ernest Jawetz, Antibiotic Mono-
graphs No. 5, Medical Encyclopedia Inc., New York, 1956, 85 pp.
29 "Antibiotics Derived from Bacillus Polymyxa," (a symposium) Roy
Waldo Miner (Ed.), Annals of the New York Academy of Sciences,
51, 853-1000 (1949).
30 "Terramycin, Review of the Literature," Chas. Pfizer and Co., Inc.,
1953, 76 pp.
31 "Terramycin, Oxytetracycline," Merle M. Musselman, Medical Ency-
clopedia Inc., New York, 1956, 141 pp.
32 "Terramycin" (a symposium) Roy Waldo Miner (Ed.), Annals of
the New York Academy of Sciences, 53, 223-459 (1950).
33 "Tetracycline," Harry F. Dowling, Antibiotics Monographs No. 3,
Medical Encyclopedia Inc., New York, 1955, 57 pp.
34 "A Review of the Clinical Uses of Aureomycin," Lederle Laboratories
Div., American Cyanamid Co., 1951, 241 pp.
35 "Aureomycin, Chlortetracycline," Mark H. Lepper, Medical Encyclo-
pedia Inc., New York, 1956, 149 pp.
36 "Chloromycetin, Chloramphenicol," Theodore E. Woodward and
Charles L. Wisseman, Jr., Antibiotics Monographs No. 8, Medical En-
cyclopedia Inc., New York, 1958, 152 pp.
37 "Erythromycin," Wallace E. Herrell, Antibiotics Monographs No. 1,
Medical Encyclopedia Inc., New York, 1955, 56 pp.
38 "Penicillin," Harold L. Hirsh and Lawrence E. Putnam, Antibiotics
Monographs No. 9, Medical Encyclopedia Inc., New York, 1958,
144 pp.
39 "Antibiotics, A Survey of Penicillin, Streptomycin, and Other Anti-
microbial Substances from Fungi, Actinomyces, Bacteria, and
Plants," H. W. Florey, E. Chain, N. G. Heatley, M. A. Jennings, A. G.
Sanders, E. P. Abraham and M. E Florey, Oxford University Press,
London, 1949, Vol. I, 628 pp.. Vol. II, 1662 pp.
40 "Neomycin, Its Nature and Practical Application," Selman A. Waks-
man (Ed.), The Wilhams and Wilkins Co., Baltimore, 1958, 396 pp.
41 "The Fifth Year of Aureomycin," Lederle Laboratories Div., Ameri-
can Cyanamid Co., 1952, 374 pp.
42 "Antibiotics," Robertson Pratt and Jean Dufrenoy, J. P. Lippincott
Co., Philadelphia, 2nd. ed., 1953, 369 pp.
Gig General References
43 "Antibiotics and Antibiotic Therapy," Allen E. Hussar and Howard L.
HoUey, Macmillan Co., New York, 1954, 463 pp.
44 "Chemistry of Proteins," Shiro Akabori (Ed.), Chap. 9, Antibiotic
Polypeptides, Kyoritsu Shuppan, Tokyo, 1957. (In Japanese)
45 "Physiology of Fungi," Vincent W. Cochrane, John Wiley and Sons,
Inc., New York, 1958, 524 pp. Particularly pertinent is Chapter 2
(pp. 35-55), Tlie Composition of Fungus Cells.
46 "Chemical Activities of Fungi," Jackson W. Foster, Academic Press,
New York, 1949, 648 pp.
47 Chemistry of the Fungi, C. Stickings and H. Raistrick, Ann. Rev.
Biochem. 25 225-256 (1956). A review with 182 references.
48 Chemistry of the Fungi, J. Birkinshaw, Ann. Rev. Biochem. 22 371-
399 (1953). A review with 152 references.
49 Biochemistry of Fungi, Edward L. Tatum, Ann. Rev. Biochem. 13
667-704 (1944). A review with 333 references.
50 Biochemistry of the Lower Fungi, Harold Raistrick, Ann. Rev.
Biochem. 9 571-592 (1940). A review with 95 references.
51 Oxygen Heterocyclic Fungal Metabolites, W. Whalley, Prog, in Org.
Chem. 4 72-113 (1958).
52 "Essays in Biochemistry," Samuel Graff (Ed.), Some metabolic prod-
ucts of basidiomycetes, M. Anchel, John Wiley and Sons, Inc., New
York, 1957, pp. 1-13. A review with 40 references.
53 "Organic Acid Production by some Wood-Rotting Basidiomycetes,"
G. Walter, Univ. Microfilms Publ. No. 10,417, 99 pp. Dissertation
Abstracts 15 321 (1955).
54 "Chemistry of Lichen Substances," Y. Asahina and S. Shibata, Japan
Society for the Promotion of Science, Tokyo, 1954, 240 pp.
55 Chemistry of Lichens, Carl Axel Wachtmeister, Svensk Kent. Tidskr.
70 117-133 (1958). A review in English with 74 references.
56 Chemical Constitution and Antibiotic Action of Lichen Substances,
Josef Klosa, Pharmazie 8 435^42 (1953). A review with 59 refer-
ences.
57 Algal Chemistry, B. Wickberg, Svensk Kem. Tidskr. 71 87-106
(1959). A review in English with 73 references.
58 "The Chemistry and Chemotherapy of Tuberculosis," E. Long, The
Williams and Wilkins Co., Baltimore, 3rd ed., 1958.
59 The Chemistry of the Lipids of the Tubercle Bacillus and Certain
Other Microorganisms, R. J. Anderson, Fortschr. Chem. org. Natur-
stoffe 3 145-302 (1939).
60 Chemistry of Bacterial Lipids, J. Asselineau and E. Lederer, Fortschr.
Chem. org. Naturstoffe 10 170-256 (1953). A review with 362 ref-
erences; E. Lederer, Angew. Chem. 72 372 (1960). (A review)
Pfizer Handbook of Microbial Metabolites 620
61 "Bacterial Fermentations," H. Barker, John Wiley and Sons, Inc.,
New York, 1956, 90 pp.
62 "Bacterial Anatomy," Sixth Symposium of the Society for General
Microbiology, E. Spooner and B. Stocker (Eds.), Cambridge Univer-
sity Press, Cambridge, 1956, 360 pp.
63 The (phenazine) bacterial pigments, in "Phenazines," George A.
Swan and Desmond G. I. Felton, Interscience Publishers, New York,
1957, pp. 174-209.
64 Structure and Synthesis of Naturally Occurring Polypeptides, F. Rob-
inson, /. Pharm. and Pharmacol. 8 297-308 (1956). A review with
89 references.
65 "Biochemistry of the Amino Acids," Alton Meister, Academic Press,
New York, 1957.
66 Paper Chromatographic Investigation of the Amino Acid Content of
a Variety of Bacterial Hydrolysates, I. Kandler and C. Zehender,
Arch, filr Mikrobiol. 24 41-48 (1956). (Semiquantitative)
67 Bacterial and fungal products containing amino sugars, P. W. Kent
and M. W. Whitehouse, in "Biochemistry of the Amino Sugars," But-
terworths, London, 1955, pp. 133-161.
68 Branched Chain Sugars of Natural Occurrence, F. Shafizadeh, Ad-
vances in Carbohydrate Chemistry 11 263-283 (1956).
69 Bacterial Dextrans, M. Stacey and C. Ricketts, Fortschr. Chem. org.
Naturstoffe 8 28-43 (1951).
70 Die natUrlich vorkommenden Polyacetylen-Verbindungen, F. Bohl-
mann, Angew. Chem. 67 389 (1955).
71 Natural Alkynes, J. Beer, Wiadomosci Chem. 9 460^81 (1955). A
review with 74 references.
72 Acetylenverbindungen im Pfianzenreich, F. Bohlmann and H. Mann-
hardt, Fortschr. Chem. org. Naturstoffe 14 45-53 (1957).
73 Occurrence of Acetylenic Compounds in Nature, P. Wailes, Revs.
Pure and Appl. Chem. (Australia) 6 61-98 (1956). A review with
tabulation of ultraviolet absorption data and 89 references.
74 Acetylenic Compounds as Natural Products, J. Bu'Lock, Quart. Rev.
10 371-394. A review with 102 references.
75 Carotenoids, T. W. Goodwin, Ann. Rev. Biochem. 24 497-522 (1955).
76 Carotenoids in fungi, bacteria and algae, in "The Comparative Bio-
chemistry of the Carotenoids," T. W. Goodwin, The Chemical Pub-
lishing Co., New York, 1954, pp. 99-155.
77 Some Biochemical Aspects of Fungal Carotenoids, F. Haxo, Fortschr.
Chem. org. Naturstoffe 12 169-197 (1955). A review with 116 ref-
erences.
621 General RefercHces
78 The Biosynthesis and Function of the Carotenoid Pigments, T. W.
Goodwin, Advances in Enzymology 21 295-361 (1959).
79 "Naturally Occurring Quinones," R. Thomson, Butterworths, Lon-
don, 1958. Literature covered through 1956.
80 Occurrence and Biochemical Behavior of Quinones, O. Hofmann-
Ostenhof, Fortschr. Chem. org. Naturstoffe 6 159-224 (1950).
81 Anthraquinone Pigments Produced by Molds, Shoji Shibata, Kagaku
(Science) 26 391-396 (1956). A review with 41 references.
82 Tetracyclic Triterpenes, E. Jones and C. Halsall, Fortschr. Chem.
org. Naturstoffe 12 68-96 (1955).
83 Chlorine Containing Metabolic Products, I. Yoshida, Kagaku no
Ryoiki (J. Japan. Chem.) 5 406-409, 419 (1951). A review with 19
references.
84 Vitamins in Microorganisms, J. Van Lanen and F. W. Tanner, Jr.,
Vitamins and Hormones 6 163-224 (1948). A review with 361 ref-
erences.
85 "Special Publication No. 12 of the English Chemical Society," 1958,
especially The Biosynthesis of Aromatic Compounds from C, and C,
Uiiits, A. J. Birch and Herchel Smith, pp. 1-13, and Biosynthesis of
Aromatic Ring Systems from C^ and C, fragments, Gosta Ehrensvard,
pp. 17-31.
86 "The Structural Relations of Natural Products," R. Robinson, Oxford
University Press, London, 1955, 150 pp.
87 Biosynthetic Relations of Phenolic and Enolic Compounds, A. J.
Birch, Fortschr. Chem. org. Naturstoffe 14 186-216 (1957).
88 "Perspectives in Organic Chemistry," Alexander Todd (Ed.), Inter-
science Publishers, New York, 1956, especially Biosynthetic Theories
in Organic Chemistry, A. J. Birch, pp. 134—155, and Microorganisms
in Organic Chemistry, Karl Folkers, pp. 392-430.
89 A Region of Biosynthesis, H. Raistrick, Proc. Roy. Soc. A 199 141-
168 (1949). A review of fungal metabolites with 157 references.
90 Microbiological Conversions of Steroids, Drurey H. Peterson, Record
Chem. Prog. 17 211-240 (1956).
91 Transformations of Steroids by Molds, Gilbert Shull, Trans. N. Y.
Acad. Sci. 19 147-72 (1956). A review with 63 references.
92 Microbiological Alterations of Steroids, P. Enthoven, Chem. Weekblad
52 166-172 (1956). A review with 40 references.
93 Microbiological Conversions of Steroids for Technical Purposes,
E. Vischer and A. Wettstein, Angew. Chem. 69 456-463 (1957). A
review with 70 references.
94 Enzymic Transformations of Steroids by Microorganisms, E. Vischer
and A. Wettstein, Adv. Enzymol. 20 237-282 (1958). A review.
Pfizer Handbook of Microbial Metabolites 622
95 "Chemical Transformations by Microorganisms," F. Stodola, John
Wiley and Sons, Inc., New York, 1958, 134 pp.
96 The oxidation of aromatic rings by microorganisms in metabolism,
F. Happold in Biochemical Symposium No. 5, "Biological Oxidation
of Aromatic Rings," R. T. Williams (Ed.), 1950. A review with 46
references.
97 The use of biochemical oxidations and reductions for preparative
purposes, F. Fisher, "Newer Methods of Preparative Organic Chem-
istry," Interscience Publishers, Inc., New York, 1948, pp. 159-196.
98 Allgemeine Methoden zur Ausfiihrung biochemischer Reaktionen,
B. Helferich, H. Stetter and J. Krebs, "Methoden der organishen
Chemie," Georg Thieme Verlag, Stuttgart, 1955, Band IV, pp. 822-
902.
APPENDIX A
The Chemical Composition of the Tissues
and Large Molecules of Bacteria and Fungi
The composition of the cell wall, the capsule and the proto-
plast membrane in bacteria and of the mycelial wall in molds
is generally more specific to the organism than that of the
lower molecular weight metabolites. For that reason these
substances are more interesting in taxonomy and immuno-
chemistry. The toxins, pyrogens and lipoproteins are also in-
teresting from these standpoints.
The advent of paper chromatography has so facilitated the
identification of amino acids, sugars and other fragments of
the hydrolysis of the higher molecular weight components of
microorganisms that the literature on this topic has blossomed
during recent years.
Some of the results have been unexpected. For example,
the actinomycetes, which resemble the molds superficially,
have been found closer chemically to the bacteria.
This appendix is a list of references on the subject. While
the paper titles may not always so indicate, they are all con-
cerned in some way with the composition or structure of the
tissues and macromolecules of bacteria and fungi.
Pastenrella septica (P. multocida). I. The occurrence of type-
specific polysaccharides containing aldoheptose sugars.
A. P. MacLennan and C. J. M. Rondle, Nature 180 1045 (1957).
Specific polysaccharide of Pasteurella pestis.
D. A. L. Davies, Biochem. J. 63 105 (1956).
Natural occurrence of a new aldoheptose sugar.
D. A. L. Davies, Nature 180 1129 (1957).
Elemental and amino acid composition of purified plague toxin.
D. F. Bent, H. Rosen, S. M. Levenson, R. B. Lindberg and Samuel J.
Ajl, Proc. Soc. Exptl. Biol. Med. 95 178 (1957).
Role of a,e-diaminopimelic acid in the cellular integrity of Escher-
ichia coli.
Lionel E. Rhuland, J. Bacterial. 73 778 (1957).
A colicin from Escherichia coli SG710.
Rainer Niiske, Gottfried Hosel, Harry Venner and Helmut Zinner,
Biochem. Z. 329 346 (1957).
Pfizer Handbook of Microbial Metabolites 624
An agent from Escherichia coli causing hemorrhage and regression
of an experimental mouse tumor. IV. Some nitrogenous components
of the phospholipid moiety.
Miyoshi Ikawa, J. B. Koepfli, S. G. Mudd and Carl Niemann, }. Am.
Chem. Soc. 75 3439 (1953).
Colominic acid, a polymer of N-acetylneuraminic acid.
Guy T. Barry, J. Exp. Med. 107 507 (1958).
Capsular polysaccharides of Escherichia coli types K28A and
K34A.
BiU B. Wiley and Henry W. Scherp, Can. J. Microbiol. 4 505 (1958).
The chemical and serological relationships of certain polysac-
charides containing sialic acid.
Guy T. Barry, Tien-Hu Tsai and Francis P. Chen, Nature 185 597
(1960).
Structure of the capsular polysaccharide of Aerobacter aerogenes
(NCTC 418).
S. A. Barker, A. B. Foster, I. R. Siddiqui and M. Stacey, /. Chem. Soc,
2358 (1958).
The extracellular polysaccharide of Aerobacter aerogenes A3 (Sj).
J. F. Wilkinson, W. F. Dudman and G. O. Aspinall, Biochem. J. 59
446 (1955).
Chromatographic analysis of hydrolysates of Salmonella typhosa.
F. Savoia, Boll. soc. ital. biol. sper. 32 226 (1956).
Chemical composition of Salmonella antigen II. Chemical com-
position of antigen O of Salmonella kirkei and Salmonella hvitting-
foss.
G. Bo, A. Defranceschi and G. C. Nava, Giom. microbiol. I 247
(1955).
Contributions to the study of the antityphi-paratyphi vaccines II.
A comparative chemical study of the somatic antigens of Salmonella
typhi (S. typhosa) extracts.
E. Soru, C. Barber, S. Toma, V. Gritaenco and B. Bogokowski, Acad,
rep. populare Romine, Studii cercetari chim. 4 243 (1956).
The biological action of highly purified pyrogens (lipopolysac-
charides) from Salmonella ahortivoequina.
E. Eichenberger, M. Schmidhauser-Kopp, H. Hurni, M. Fricsay and
O. Westphal, Schweiz. med. Wochschr. 85 1190, 1213 (1955).
The hexose constituents of some shigella polysaccharide hydroly-
zates.
D. A. R. Simmons, J. Gen. Microbiol. 17 650 (1957).
Epidemiology of Shigella sonnei. I. Biochemical characteristics.
Szymona Szturm-Rubensten and Danielle Piechaud, Ann. inst. Pas-
teur 92 335 (1957).
The chemical constitution of brucella.
E. M. Gubarev, E. K. Alimova and G. D. Bolgova, Biokhimiya 21 647
(1956).
The specific polysaccharides of some gram-negative bacteria.
D. A. Davies, Biochem. J. 59 696 (1955).
625 Appendix A.
The chemistry and biochemistry of typhoid antigens.
A. De Barbicri. Atti Congr. intern, standard Immunomicrobiol.
(Rome) 2 257 (1956).
Toxic end-products from Pasteurella pestis. II. Toxin yields as
influenced by conditions of growth.
K. Goodner, /. Infectious Diseases 97 246 (1955).
Studies on plague. I. Purification and properties of the toxin of
Pasteurella pestis.
Samuel J. Ajl. Jeanette S. Reedal, E. L. Durram and Joel Warren,
;. Bacterial. '70 158 (1955).
Isolation of a polysaccharide from Vibrio fetus.
S. M. Dennis, Nature 183 186 (1959).
Chemical investigation of the endotoxin of Pseudomonas aerugi-
nosa.
Fugio Egami, Michio Shimomura, Hiroshi Ishihara, J. Y. Homma,
K. Sagehashi and Seigo Hosoya, Bull. soc. chim. biol. 36 779 (1954).
Rhamnose and rhamnolipide biosynthesis by Pseudomonas aerugi-
nosa.
George Hauser and Manfred L. Karnovsky, J. Biol. Chem. 224 91
(1957).
Chemical studies on endotoxins I. Chemical composition of the
endotoxin of Shigella flexneri 2B.
Chiaki Nishimura, Masao Nakamura, Reiko Ofuchi, Shigeo Iwahara
and Yasuhiko Nozaki, Japan. J. Microbiol. 2 179 (1958).
Toxins of Pseudomonas pseiidomallei. II. Characterization.
Robert J. Heckly and Clara Nigg, /. Bacterial. 76 427 (1958).
Occurrence of poly-/3-hydroxybutyric acid in aerobic gram-negative
bacteria.
W. G. C. Forsyth, A. C. Hayward and J. B. Roberts, Nature 182 800
(1958).
Sulla composizione chimica degli antigeni delle salmonelle. Nota
III. Composizione chim. degli antigeni O delle Salmonelle tel aviv
cholerae suis e montevideo.
G. C. Nava, G. Bo and A. Defranceschi, Giorn. m.icrobiol. 4 95
(1957).
Characterization of intracellular glucosidic polysaccharide pro-
duced by Brucella suis.
N. D. Gary, L. L. Kupferberg and L. H. Graf, /. Bacteriol. 76 359
(1958).
A group of pseudomonads able to synthesize poly-/3-hydroxybutyric
acid.
M. B. Morris and J. B. Roberts, Nature 183 1538 (1959).
Production of a mannose polysaccharide by Pseudomonas fluores-
cens from low molecular weight sources.
Robert Garfield Eagen, Dissertation Abstr. 20 477 (1959).
Composition of cell walls of variants of Salmonella typhimurium.
M. Herzberg, J. H. Green and J. C. Boring, Bacteriol. Proc, 169
(1960).
Pfizer Handbook of Microbial Metabolites 626
Enterotoxin.
Kikuo Fujiwara and Tetsujiro Sugiyama, Nippon Saikingaku Zasshi
10 189 (1955).
Polyribophosphate, the type-specific substance of Hemophilus
influenzae , type B.
Stephen Zamenkof, Grace Leidy, Patricia L. Fitzgerald, Hattie E.
Alexander and Erwin Chargaff, /. Biol. Chem. 203 695 (1953).
The polysaccharide produced by Azotobacter indicum.
Clara M. Quinnell, S. G. Knight and P. W. Wilson, Can. J. Microbiol.
3 277 (1957).
Extracellular polysaccharides of rhizobium.
Beverly A. Humphrey and J. M. Vincent, /. Gen Microbiol. 21 477
(1959).
The isolation of D-fucosamine from the specific polysaccharide of
Chromobacterium violaceum (NCTC 7917).
M. J. Crumpton and D. A. L. Davies, Biochem. J. 70 729 (1958).
A galactan from Mycoplasma mycoides.
P. Plackett and S. H. Buttery, Nature 182 1236 (1958).
Circular paper chromatography of long-chain fatty acids in the
analysis of (gram-negative) bacterial lipopolysaccharides.
A. Nowotny, A. Liideritz and O. Westphal, Biochem. Z. 330 47
(1958).
The extracellular polysaccharide of Xanthomonas phaseoli.
S. Lesley and R. Hochster, Can. J. Biochem. and Physiol. 37 513
(1959).
A function for the extracellular polysaccharide of Azotobacter
vinelandii.
Michael H. Proctor, Nature 184 1934 (1959).
Lipides of the cell envelope of Azotobacter vinelandii.
Allen G. Marr and Tsuneo Kaneshiro, Bacteriol. Proc, 63 (1960).
Chemical composition of cell walls of drug resistant neisseriae.
R. P. Pradhan and W. A. Konetzka, ibid., 170 (1960).
Amino acids of red sulfur bacteria.
H. Mukherjee, Nature 184 1742 (1959).
A new amino sugar present in the specific polysaccharides of some
strains of Chromobacterium violaceum.
M. J. Crumpton and D. A. L. Davies, Biochem. J. 64 22p (1956).
Immunopolysaccharides. XI. Structure of an Acetobacter capsula-
tum dextran.
S. A. Barker, E. J. Bourne, G. T. Bruce and M. Stacey, }. Chem. Soc,
4414 (1958).
Oligosaccharide formation during synthesis of cellulose by Aceto-
bacter acetigenum.
T. K. Walker and H. B. Wright, Arch. Biochem. and Biophys. 69 362
(1957).
Bacterial levans of intermediate molecular weight.
James R. Mattoon, Chester E. Holmlund, Saul A. Schepartz, James J.
Vavra and Marvin J. Johnson, Appl. Microbiol. 3 321 (1955).
627 Appendix A.
The nature of the polysaccharides of the dextran-producing or-
ganisms Leuconostoc mesenteroides, Leuconostoc dextranicum and
Streptococcus bovis.
R. W. Bailey and A. E. Oxford, /. Gen. Microbiol. 20 258 (1959).
Characterization of dextrans from four types of Leuconostoc
mesenteroides.
Allene Jeanes, W. C. Haynes and C. A. Wilham, J. Bacteriol. 71 167
(1956).
Characterization and classification of dextrans from ninety-six
strains of bacteria.
Allene Jeanes, W. C. Haynes, C. A. Wilham, J. C. Rankin, E. H. Mel-
vin. Marjorie J. Austin, J. E. Cluskey, B. E. Fisher, H. M. Tsuchiya
and C. E. Rist, /. Am. Chem. Soc. 76 5041 (1954).
Cell wall composition of leptotrichia species.
G. H. G. Davis and A. C. Baird-Parker, Nature 183 1206 (1959).
Composition of the cell wall of Staphylococcus aureus. Its rela-
tion to the mechanism of action of penicillin.
Jack L. Strominger, James T. Park and Richard E. Thompson, J. Biol.
Chem. 234 3263 (1959).
The amino acid composition of the protein and cell wall of
Staphylococcus aureus.
R. Hancock, Biochim. et Biophys. Acta 37 42 (1960).
Composition of the cell wall of Staphylococcus aureus 209P.
Nobutoshi Ishimoto, Masahiro Saito and Eiji Ito, Nature 182 959
(1958).
Staphylococcal toxins. III. Partial purification and some proper-
ties of 5-lysin.
A. W. Jackson and R. M. Little, Can. J. Microbiol. 4 453 (1958).
The intracellular amino acids of Staphylococcus aureus: release
and analysis.
R. Hancock, Biochim. et Biophys. Acta 28 402 (1958).
Constitution of a muco-complex of Micrococcus lysodeikticus I.
Isolation and purification.
Shichiro Akiya and Otomatsu Hoshino, Yakugaku Zasshi 77 777
(1957).
Development of lysozyme resistance in Micrococcus lysodeikticus
and its association with increased 0-acetyl content of the cell wall.
W. Brumfitt, A. C. Wardlaw and J. T. Park, Nature 181 1783 (1958).
Partial acid hydrolysis of the cell wall of Micrococcus lysodeikticus.
H. R. Perkins and H. J. Rogers, Biochem. J. 69 15p (1958).
The chemical composition of the protoplast membrane of Micro-
coccus lysodeikticus.
A. R. Gilby, A. V. Few and Kenneth McQuillen, Biochim. et. Biophys.
Acta 29 21 (1958).
Products of partial acid hydrolysis of mucopeptide from cell walls
of Micrococcus lysodeikticus.
H. R. Perkins and H. J. Rogers, Biochem. J. 72 647 (1959).
The structure of a disaccharide liberated by lysozyme from the cell
walls of Micrococcus lysodeikticus.
Pfizer Handbook of Microbial Metabolites 628
H. R. Perkins, ibid. 74 182 (1960).
Synthesis of carbohydrates by Micrococcus ureae from acetic acid.
V. I. Lyubimov, Doklady Akad. Nauk S.S.S.R. Ill 881 (1953).
The biosynthesis of a streptococcal capsular polysaccharide.
Yale J. Topper and Murray M. Lipton, /. Biol. Chem. 203 135 (1953).
The production of capsules, hyaluronic acid, and hyaluronidase by
twenty-five strains of group C streptococci.
A. P. MacLennan, J. Gen. Microbiol. 15 485 (1956).
Variation in the group-specific carbohydrate of group A strepto-
cocci II. The chemical basis for serological specificity of the carbo-
hydrate.
Maclyn McCarty, /. Exp. Med. 104 629 (1956).
Production of hyaluronic acid in the resting cells of group A
Streptococcus hemolyticus.
Seiki Hayano and Haruo Iwasawa, Nippon Saikingaku Zasshi 10 269
(1955).
Examination of the L-forms of group A streptococci for the group-
specific polysaccharide and M protein.
John T. Sharp, W. Hijmans and L. Dienes, J. Exp. Med. 105 153
(1957).
Studies of streptococcal cell walls. IV. The conversion of D-glu-
cose to cell wall L-rhamnose.
W. H. Southard, J. A. Hayashi and S. S. Barkulis, J. Bacteriol. 78 79
(1959).
Studies of streptococcal cell walls. V. Amino acid composition
of cell walls of virulent and avirulent group A hemolytic strep-
tococci.
B. S. Tepper, J. A. Hayashi and S. S. Barkulis, ibid. 79 33 (1960).
Studies of streptococcal cell walls. III. The amino acids of the
trypsin-treated cell wall.
James A. Hayashi and S. S. Barkulis, ibid. 77 177 (1959).
Precipitation of the specific polysaccharide of Cryptococcus neo-
formans A by types II and XIV antipneumococcal sera.
P. A. Rebers, S. A. Barker, M. Heidelberger, Z. Dische and E. E.
Evans, /. Am. Chem. Soc. 80 1135 (1958).
The genus cryptococcus.
Rhoda W. Benham, Bacteriol. Revs. 20 189 (1956).
Immunopolysaccharides. VIII. Enzymic synthesis of 6-0-a-D-glu-
copyranosyl-3-O-methyl-D-glucose by Betacoccus arabinosaceous.
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APPENDIX B
Bacterial and Fungal Carotenes
The subject of bacterial and fungal carotenoids is confusing
because of the large number of closely related structures and,
in some cases, duplications in nomenclature. The following
tables were prepared by an authority. Professor T. W. Goodwin
of the University of Liverpool. They appeared in his excellent
book "The Comparative Biochemistry of the Carotenoids" and
are reproduced here with his permission and with the consent
of the Chemical Pubhshing Co., 212 Fifth Ave., New York City.
References
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Appendix-B.
TABLE II
Characteristic Fungal Caroienoids*
Absorption spectra maxima (m^u)
Melting
point
Pigment
Carbon
disulphide
Light
petroleum
Chloroform
Torulene'' *
185°
563-5, 520-5,
488-91
539,501,469
Torulcrhodln-
201-203°
(decomp.)
582,541,502
537,501,467
554,515,483
Neurosporene'
(See also Tetra-
124°
502.5, 470.5,
470,441.5
hydrolycopene)
439.5
Acid carotenoid'
from Neurosporo crassa
—
512-514
516, 482
Pigment III 1 from Corfinarius
—
—
520, 470
462, 405
Pigment Vlj c/nnabor/nus' —
494
—
455
Canthoxonthln 218°
500
—
462
' Pigments first reported in other organisms but also present in fungi are not recorded here.
References to Table 11
^E. Lederer, Bull. soc. chim. biol. 20 611 (1938).
2 P. Karrer and J. Rutschmann, Helv. Chim. Acta 29 355 (1946).
3 F. Haxo, Arch. Biochem. 20 400 (1949).
*Idem., Botan. Gaz. 112 228 (1950).
Pfizer Handbook of Microbial Metabolites
642
TABLE III
Fungi in Which Early Workers''^ Hove Reported fhe Presence of Carofenoids,
but Which Have Not Recently Been Investigated
Ascobolus spp. (not A. furfuraceus^)
Peziza (tochneo) scutellata
Calocerca cornea
Phragmidium violaceum
Calocerca palmata
Pilobolus crystallimus
Calocerca viscosa
Pilobolus kleinii
Chytridium spp.
Pilobolus oedipus
Co/eospoWom Pulsatilla
Polystigma ochraceum (fulvum)
Ditiola radicata
Puccinia coronata
Leotia lubrica
Saccharomyces (spp.)
Lycogola flavofuscunt
Sphaerostilbe coccaphila
Melampsora aecidioides
Spathularia flavida
Melampsora salicis capreae
Stemonitis spp.
Nectria cinnabarina
Triphragmium ulmariae
Peziza aurantia
Uredo [Coleosporium) euphrasie
Peziza (Lachnum) b/co/or
Uromyces alchemille
References to Table III
1 W. Zopf, "Die Pilze," Trewendt, Breslau, 1890.
^ F. G. Kohl, Untersuchungen iibei das Carotin und seine physi-
ologische Bedeutung in der Pflanze, Borntrager, Leipzig, 1902.
=*T. W. Goodwin, Biochem. J. 50 550 (1952).
643
Appendix- B.
TABLE IV
Fungi from Which Carotenoids Have Been Shown fo Be Absent
Agaricus [Telamoria) armillaius^
Nephoromo /usifonico'
Agaricus /oceofus'
Oidium v/o/oceum'
AUernaria so/anr'*
Paxillus ofrofomenfosos'
Amanifa muscar/o*
Penicilliopsis clavariaeformis^
Amanita pantherina^
Peziza aeruginosa^
Arthonia spp.'
Peziza echinosporo'
Ascobolus furfuracevs^
Peziza songuineo'
Bachospora c/rymo'
Phragmidium vio/oceum'
Bacidia moscorum'
Pichia spp.^
Bioforo fungidula^
Polyporus grammocephalus^
Bilimbia melaena'
Polyporus /uzonenis*
Bo/e/us /un'dus'
Polyporus rubidus^
Boletus scober'
Polyporus zonalis^
6ue//ia spp.'
Polystictus hirsutus^
C/odonia coccifero'
Polystictus sanguineus^
Clavaria fern/co'
Polystictus versicolor'
C/ov/ceps spp.^
Polystictus xanthopus^
Cortinarius bulliardi^
Pullularia spp.^
Cortinarius vio/oceus'
Rhi'zocfon/a so/Zoni^*
Daedalea flavida"
Rhizopogon rufaescens'
Fusarium iycopersici'*
Russula alutacea^
Fusarium moniforme~ *
Russula ourafo'
Fusarium oxysporium-*
Russu/o emef/co'
Ganoderma (Fames) lucidus^
Russula Integra^
Gamphidius glutinasus^
Saccobolus vio/oceus'
Gamphidius viscidus^
Sorcogyme pru/noso'
Helminthosporium sativum^'*
Taphrina deformans^
Helvetia esculenta
Thalloidima condidum'
Hydnum ferrugineum^
The/ephorus spp.'
Hydnum repandum^
Th/'e/cvio terr/co/o^*
Hygrophorus cocc/neus^
Toru/opsis lipofera''
Hygrophorus conicus'
Torulopsis /uteo/o^
Hygrophorus pun/cens'
Toru/opsis pu/cherrima^'^
Lactarius del/ciosus'
Tramefes persooni*
Lecidea spp.'
Tromefes versofi/is^
(enzf'fes subferruginea^
Zygosacchoromyces spp.^
' Only vitamin A-active carotenoids are absent from these species. Inactive carotenoids may possibly
be present.
References to Table IV
1 W. Zopf, "Die Pilze," Trewendt, Breslau, 1890.
-D. Gottlieb and G. M. Gilligan, Arch. Biochem. 10 163 (1946).
^T. W. Goodwin, Biochem. J. 50 550 (1952).
* E. M. Mrak, H. J. Phaff and G. Mackinney, J. Bacteriol. 57 407
(1949).
5 S. R. Bose, Trans. Nat. Inst. Sci. India 2 69 (1941).
^ M. F. Champeau and P. J. Luteraan, Ann. Parasit. 21 344 (1946).
Pfizer Handbook of Microbial Metabolites
644
TABLE V
Properfies of Bacierial Carofenoids
Absorption maxima in
m;u
Melting
Name
point
Light
petroleum
Carbon
disulphide
Chloroform
Sarcinene^*
—
415,440,469
Sarcinaxanthin^t
149-150"
415,440,469
464,494
423,451,480
Xanthophyll^'t (Lutein) from
Sorc/no lufea
466,499
451,480
Flavorhodene^'^J
111-113°
442,470
472,503
453,482
(Rhodoviolacein)
Rhodopurpurene''^§
162°
472,502
479,511,550
458,487,527
Rhodopin^'^
171°
440,470,501
478,508,547
453,486,521
Rhodovibrin''^
168°
517,556
Rhodoviolascin^'^
218°
496,530,573.5
476,507,544
( = Spirilloxanthin)
a-Bacteriopurpurin®' H
—
460,495,528
(in methanol)
498,532,571
/3-Bacteriopurporin''#
—
452,482,502
(in methanol)
Leprotene'
198-200°
425,452,484
477,499,517
428,460,495
Xanthophyll from
Flavobacf. esferoaroma-
iicum, F. suaveoleus and
F. faecale^
453,482,513
460,513
Carotene from F.
sulphureum^*
—
437,466,487
451,481
Xanthophyll from Erwinia
laythri^
—
478,513
458,485
Xanthophyll from E. ananas^
—
474,508
460,493
Chrysophlein^i"
—
452
487
—
* The probable identi-'y of these with neurosporene cannot be ignored,
t These may be identical.
t May be identical with e-carotene.
§ May be identical with lycopene.
II a-Bocteriopurpurin is probably one of Karrer's rhodocarotenoids.
# ^-Bacteriopurpurin is probably identical with rhodoviolascin.
References to Table V
1 E. ChargafF and J. Dieryck Naturzvissenchaften 20 872 (1932).
- Y. Takeda and T. Ohta, Hoppe-Seyl. Z. 268 1 (1941).
^B. Sobin and G. L. Stahly, J. Bacteriol. 44 265 (1942).
* P. Karrer and U. Solmssen, Helv. Chim. Acta 18 25 1306 (1935).
^ P. Karrer, U. Solmssen and H. Koenig, Helv. Chim. Acta 21 545
(1938).
•5H. F. M. Petter, Amsterdam Akad. Wiss. 34 No. 10 (1931).
^ E. Lederer, Bull. soc. chim. hiol. 20 611 (1938).
8 Y. Takeda and T. Ohta, Hoppe-Seyl. Z. 262 168 (1939).
9 G. Turian, Arch. Sci. Soc. Phys. Hist. Nat. Geneve 3 79 (1950).
^Udem., Helv. Chim. Acta 33 1303 (1950).
APPENDIX C .
The Chemical Constituents of Mycobacteria
A great many metabolites of mycobacteria have been charac-
terized, many of them incidental to the study of tuberculosis.
The following referenced list was prepared by Dr. Esmond R.
Long and appeared in his recent book, The Chemistry and
Chemotherapy of Tuberculosis. It is reproduced here by per-
mission of the author and of the Williams and Wilkins Publish-
ing Co. of Baltimore. While many of the compounds in this
list appeared earlier in the Handbook, it may be useful to see
them in aggregate as well.
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Pfizer Handbook of Microbial Metabolites 652
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Pfizer Handbook of Microbial Metabolites 658
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REFERENCES TO REVIEW BOOKS AND
ARTICLES ON CONSTITUENTS OF
MYCOBACTERIA
1. R. J. Anderson, Fortschr. Chem. org. Naturstoffe 3 145 (1939);
idem., Sigma Xi Quart. 27 39 (1939); idem., Harvey Lectures
35 271 (1939-1940); idem., Chem. Rev. 29 225 (1941); idem.,
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and Biology," Academic Press, Inc., New York, 1955, Vol. I.
4. W. F. Drea and A. Andrejew, "The Metabolism of the Tubercle
Bacillus," Charles C. Thomas, Springfield, 111., 1953.
5. P. Hauduroy, E. Chain, H. Florey, K. A. Jensen, G. Penso and
J. Trefouel, "Bacilles tuberculeux et paratuberculeux," Masson
et Cie., Paris, 1950.
6. P. W. Kent and M. W. Whitehouse, "Biochemistry of the Amino-
sugars," Butterworth and Co., Ltd., London, 1955. (Also pub-
lished by Academic Press, Inc., New York, 1955.)
7. E. Lederer, Proc. Colloq. Chemotherapy Tuberc, Dublin, 1951;
idem., Congr. intern, biochim., 2" Congr., Symposium sur le
metabolism microbien, Paris, 1952; idem., Angew. Chem. 72
372 (1960).
8. L. Negre, "Les lipoides dans les bacilles tuberculeux et la
tuberculose," Masson et Cie., Paris, 1950.
9. F. Roulet and M. Brenner, Zentr. ges. Tuberk. Forsch. 56 193
(1943).
10. F. B. Seibert, Chem. Rev. 34 107 (1944); idem., Schweiz. Z.
Pfizer Handbook of Microbial Metabolites 660
Tuberk., Separatum, Fasc. 3 1 (1950); idem., Ann. Rev. Micro-
biology 4 35 (1950).
11. B. Skowronska-Serafinowa, Wiadomosci Chem. 7 216 (1953).
12. M. Stacey, Schweiz. Z. Tuberk., Separatum, Fasc. 9 7 (1955).
13. M. Stacey and R. W. Kent, Advances in Carbohydrate Chem. 3
311 (1948).
ADDENDUM
In order to cover pertinent literature appearing as late as
December, 1960 this addendum is attached. Also included is
a little material from earlier dates which was overlooked. Ar-
rangement is by chapter title, and new compounds eligible for
inclusion often are given appropriate entry numbers, but with a
letter added to the number so that it is evident in the indexes
that such entries are located in the addendum. Due to time
restrictions these entries may be abbreviated, but references are
listed. The addendum is not indexed.
2. Alcohols, Glycols and Compounds Related to Sugars
17a Acetyl Methyl Carbine! (Acetoin)
This substance, mentioned as a co-product of butanediol,
is produced by many microorganisms. It is given off by
several streptomycetes, including Streptomyces erythreus,
an erythromycin producer. It is present in such large
quantities in some erythromycin fermentations that it
interferes with production of the antibiotic.^
A survey has been made of 44 species and strains of
acetobacter for ability to convert lactate to acetoin.^' A.
rancens and A. pasteiirianus were good producers, the
former yielding one isomer, the latter the other.
Acetoin metabolism of bacteria in general has been
studied.^"
Biosynthesis of acetoins has been reviewed.^"
47a Galactosyl Lactose
This trisaccharide was produced by Penicillhim chryso-
genum Thom on a lactose medium and assigned the
structure 0-/?-D-galactopyranosyl-(l -> 6)-0-/3-D-galacto-
pyranosyl-(l —> 4)-D-glucopyranose.^
Several papers have appeared on the mode of action of
^ V. Musilek, V. Sevcik, M. Musilkova, J. Rokos and P. Prochazka,
Experientia 14 323 (1958).
1" J. de Ley, J. Gen. Microbiol. 21 352-365 (1959).
i^Yasuhiro Maeda, Okayama Igakkai Zasshi 71 8017 (1959).
(Chem. Abstr. 55 694i)
1' H. Oberman, Postepy Biochemii 6 181-195 (1960).
2 A Ballio and S. Russi, Tetrahedron 9 125 (1960).
Pfizer Handbook of Microbial Metabolites 662
streptomycin. Its effect on Escherichia coli has been
studied.^ The cell permeability barrier was altered, remi-
niscent of detergents and of polymyxin. Preformed cells
were undamaged, but defects were caused in cell mem-
branes formed in its presence by non-resistant cells.
When C^Mabeled streptomycin was used, initial uptake
occurred only outside the cell wall and secondary uptake
depended on secondary damage to the membrane. The
growing membrane was the primary site of action of the
antibiotic.
The effect of streptomycin on the excretion of nucleo-
tides by E. coli has been investigated.'* Streptomycin en-
hanced excretion of 5'-nucleotides and prevented excre-
tion of 2'- or 3'-nucleotides. It was not clear whether
streptomycin blocked RNA synthesis de novo or whether
degradation of RNA to 5'-nucleotides was enhanced.
The same group has published on chloramphenicol-sen-
sitive and chloramphenicol-insensitive phases of the lethal
action of streptomycin.'^ It appeared that the lethal ef-
fect of streptomycin on E. coli was exerted in two phases
(1) a preparatory phase, which is markedly less lethal
and can be blocked by chloramphenicol (a protein syn-
thesis inhibitor), followed by (2) a more direct lethal
phase which is insensitive to chloramphenicol. The in-
duction process might have been due to formation of a
permease without which streptomycin could not accumu-
late in the cell in lethal concentration.
It has been found that, while penicillin inhibits growth
of Staphylococcus aureus (strain Duncan), it does not
cause rapid lysis as, e.g., in the case of E. coli. Penicillin
and streptomycin added (each at minimally bactericidal
concentrations) to exponentially growing cultures caused
rapid lysis. Only antibiotically active forms of strepto-
mycin were effective. Under anaerobic conditions lysis
was not rapid. (Streptomycin is not ordinarily effective
under such conditions.*^)
•^Nitya Anand and Bernard D. Davis, Nature 185 22, 23 (1959).
* Carmen L. Rosano, Richard A. Peabody and Charles Hurwitz,
Biochim. et Biophys. Acta 37 380 (1960).
5 Charles Hurwitz and Carmen L. Rosano, ibid. 41 162 (1960).
6R. Hancock, Nature 186 658 (1960).
663
Addendum
It has been reported that streptomycin inhibits de-
hydrogenases by influencing the apoenzyme/ The con-
clusion was made that further search for enzymatic
reactions susceptible to streptomycin should be aimed at
the study of its influence on intracellular synthetic proc-
esses, mainly the synthesis of nucleic acids and proteins.
The mode of action of streptomycin in connection with
its binding by Mijcohacterimn avium has been studied.*
The stereochemistry of neobiosamine B is as shown."
HO— CH
Neobiosamine B
CHi— NH2
Dextromycin is neomycin B and contains a small
amount of neomycin C.^" Framycetin also is identical
with neomycin B."
59a Aminocidin (Crestomycin, Antibiotic 1600, Pharmiglucin, F. I.
5853) C03H45OJ4N, (Sulfate) [aW + 51° in water. Pro-
duced by Streptomyces crestomyceticus, n. sp.^- This
antibiotic seems to be similar to or identical with paromo-
mycin.
" K. Michalska, Symposium on Antibiotics, Prague, 1959.
^Tatsuji Kinoshita, Nagoija ]. Med. Sci. 21 323 (1958).
" Kenneth L. Rinehart, Alexander D. Argoudelis, Townley P. Cul-
bertson, W. Scott Chilton and Klaus Streigler, J. Am. Chem. Soc. 82
2970 (1960).
^° Sueo Tatsuoka, Akira Miyake and Hayao Nawa, /. Antibiotics
(Japan) llA 193 (1958).
" Kenneth L. Rinehart, Jr., Alexander D. Argoudelis, William A.
Goss, Arthur Sohler and Carl P. Schaffner, /. Am. Chem. Soc. 82
3938 (1960).
^- F. Arcamone, C. Bertazzoli, M. Ghione and T. Scotti, Giorn.
Microbiol. 7 251 (1959).
Pfizer Handbook of Microbial Metabolites 664
D-Araboascorbic acid is produced by Penicillium de-
cumbens, P. chrysogenum mutant fulvescens, P. notatum,
P. meleagrinum and P. cyaneofulvum growing on sucrose,
glucose or D-gluconate."
3. Aliphatic Acids and Glycolipides
The name mycoside has been suggested to designate a
type-specific glycolipide of mycobacterial origin. To
clarify nomenclature it was proposed that Ca from photo-
chromogenic strains be called mycoside A, Gr from bovine
strains, mycoside B, and J.u from avian strains mycoside
C. Some properties are listed :^*
Mycoside A:
Nearly colorless solid, m.p. 105°, [ajn"" — 37° (in
chloroform). Anal: C 72.2, H 11.3, -OCH, 8.6, N 0.0,
P 0.0. U.V. maxima at 222, 274, 278 m^ (in hexane).
Contains 2-0-methylfucose, 2-O-methylrhamnose and 2,4-
di-0-methylrhamnose. The lipide part is a mycocerosate
of an aromatic alcohol.
Mycoside B:
Colorless wax, m.p. 25°, [a]i.-° — 22° (in chloroform).
Anal: C 76.6, H 12.0, -OCH3 4.3, N 0.0, P 0.0. U.V.
maxima at 222, 274, 281 m^. Contains only one sugar,
2-O-methylrhamnose. The lipide moiety is a diester of
2 molecules of a branched-chain acid fraction of mean
molecular weight corresponding to C22H44O2 with a
phenolic alcohol. It may also sometimes contain myco-
cerosic acid.
Mycoside C:
A peptide-glycolipide mixture. One component sepa-
rated on sihca gel had the following properties:
m.p. 200°, [a]D"'-31° (in chloroform). Anal:
Calculated for C73H133O24N., : C 59.8, H 9.1, N 4.8,
-OCH3 6.3
Found: C 60.1, H 8.7, N 5.1, -OCH3 6.0.
It contains three deoxyhexoses, one being 6-deoxytalose
and one 3,4-dimethoxyrhamnose. The peptide moiety is
"T. Takahashi, M. Mitsumoto and H. Kayamori, Nature 188 411
(1960).
1* Donald W. Smith, H. M. Randall, A. P. MacLennan and E. Led-
erer, ibid. 186 887 (1960).
665 Addendum
a pentapeptide containing 1 mole of D-phenylalanine, 2
moles of flf/o-threonine and 2 moles of n-alanine. The
lipide moiety was not entirely pure, but may be a hydroxy
acid of about C._.4H4hO:{. Two 0-acetyl groups are present
in mycoside C.
The lipoids of mycobacteria, their chemical structures
and biological effects have been reviewed.^"
132a IVIycocerosic Acid, C;{2H,.40o, isolated by Anderson and collabo-
rators,^'^ has been shown to be 2,4,6,8-tetramethylocta-
cosanoic acid:^"
CH3— (CH:),9— CH— CHj— CH— CHj— CH— CH>— CH— COOH
CH3 CH3 CH3 CH3
Indications were obtained for the presence in mycobac-
teria of normal chain acids with 22, 24, 26 and 28 carbon
atoms; 2-, 4-, 6-trimethyl-substituted acids with 25, 27
and 29 carbon atoms; and 2-, 4-, 6-, 8-tetramethyl-sub-
stituted acids with 30, 32 and 34 carbon atoms.
Succinic, fumaric and acetic acids as well as d,l-5-
carboxymethylhydantoin, shown below, have been iso-
COOCH3
/
HN —
O N O
H
lated as extracellular acids from Mycobacterium ranae
and from M. tuberculosis H37Rv.^^
15 E. Lederer, Angew. Chem. 72 372 (1960).
i«L. G. Ginger and R. J. Anderson, /. Biol. Chem. 157 203 (1945)
and preceding papers.
^' Cecile Asselineau, Jean Asselineau, Ragnar Ryhage, Stina
Stallberg-Stenhagen and Einar Stenhagen, Acta Chem. Scand. 13
822 (1959).
^^ Andrea V. Fowler, Merrill N. Camien and Max S. Dunn, J. Biol.
Chem. 235 1386 (1960).
Pfizer Handbook of Microbial Metabolites 666
Lipides of Corynebacterium ovis have been studied/"
as have the component fatty acids of Sporidesmium
bakeri Syd. Hpides.-"
The oil of wheat stem rust uredospores was found to
contain a substantial quantity of an acid not previously
reported from natural sources, cis-9,10-epoxyoctadecanoic
acid, CisH;j40:t, colorless leaflets, m.p. 58.5-59.5°, cis-
epoxide peak in the infra-red at 845 cm.'.-'
The chemistry of naturally occurring 1,2-epoxides, in-
cluding many microbial products, has been reviewed.''"
Another new fatty acid, Ci^H.joO^, containing a cy-
clopropane ring has been reported (in a preliminary com-
munication) as occurring in Escherichia coli lipides."
Bongkrekic acid, at a concentration of lO" molar, is a
potent inhibitor of oxidative phosphorylation as carried
out by mitochondrial enzymes in heart muscle tissue.-'
The direct participation of protein-bound biotin in
fatty acid biosynthesis has been confirmed.-*
Both 9- and 10-hydroxystearic acids can replace oleic
acid as growth factors for anaerobically grown yeast,
which requires unsaturated acid, and these substances
may be precursors of oleic acid in yeast. -"^
The role of vitamins in lipide metabolism has been re-
viewed.-'"'
Hydroxypyruvic acid has been isolated as the 2,4-dini-
trophcnylhydrazone from Aspergillus nigcr. It may arise
from 3-phosphoglyceric acid.'-'
i^A. Diara and J. Pudles, Bull. soc. chim. biol. 41 481 (1959).
2" L. Hartman, J. C. Hawke, Isobel M. Morice and T. B. Shorland,
Biochem. J. 75 274 (1960).
-' A. Tulloch, B. Craig and G. Ledingham, Can. J. Microbiol. 5
485 (1959).
-i» A. D. Cross, Quart. Revs. II 317-336 (1960).
" Simone Dauchy and Jean Asselineau, Compt. rend. 250 2635
(1960).
-i W. Welling, J. A. Cohen and W. Berends, Biochem. Pharmacol.
3 122 (1960).
-' S. J. Wakil and D. M. Gibson, Biochim. et Biophys. Acta. 41 122
(1960).
'-'■'W. J. Lennarz and Konrad Bloch, ;. Biol. Chem. 235 PC 26
(1960).
-"Bacon F. Chow, Avi. J. Clinical Nutrition 8 321 (1960).
-'Francis J. Behal, Arch. Biochem. and Biophijs. 88 110 (1960).
667 Addendum
The oxidative degradation of glycolic acid in £. coli
takes the following course:-"
-2H -f Acetyl CoA
HOCH COOH • OHC -COOH • HOOC -CH— CH,— COOH
— Acetyl COA |
OH
O O +H-0
-2H I -CO, l| +CoA
' HOOC -C CH —COOH > CH.CCOOH Acetyl CoA-^
-2H, -CO:
Summation: OHC COOH r O: • 2CO2 h H,0
A study has been made of the synthesis of cell mate-
rials from acetate by Aspergillus niger^-^' and by Esche-
richia coli.-''' Interrelationships of the tricarboxylic acid
and glyoxylic acid cycles were discussed.
Lactobacilli produce ^-hydroxy acids other than lactic.
Two of these have been identified as a-hydroxy-D-isovaleric
and D-isocaproic acids;-''
CH3 CH3
\, \
CH— CH— COOH CH— CH3— CH— COOH
/I /I
CH3 OH CH3 OH
D-lsovaleric Acid D-isocaproic Acid
These are growth promoters for certain strains of lacto-
bacilli.
Penicilliiim atrovenetum, a /^-nitropropionic acid pro-
ducer,'^'' was grown on C'^-labeled fj-alanine, on NaHC'^O.,
and on 4-C''*-D,L-aspartic acid.'' Since 96 percent of the
label was in the 1 -position, apparently aspartic acid was
incorporated as a unit.
2^H. L. Kornberg and J. R. Sadler, Nature 185 153 ri960).
2«' J. F. Collin and H. L. Kornberg, Biochem. J. 77 430 (1960).
^s'-H. L. Kornberg, P. J. R. Phizackerly and J. R. Sadler, ibid. 77
438 (1960).
-■' Merrill N. Camien, Andree V. Fowler and Max S. Dunn, Arch.
Biochem. and Biophys. S?> 408 ri959).
■'^'H. Raistrick and A. Stossl, Biochem. J. 68 647 (1958).
•'' A. J. Birch, B. J. McLoughlin, Herchel Smith and J. Winter,
Chem. and Ind., 840 (1960).
Pfizer Handbook of Microbial Metabolites 668
A review of naturally occurring nitre compounds has
been published.'*^
The fatty acids of B. alcaligenes faecalis, S. pullorum,
B. fluorescens, S. typhi-murium and B. natta have been
analyzed. ^^ Palmitic and unsaturated Cig-acids were the
main components. Unsaturated Cig-acids were present
to some extent, the unsaturated Cis- and Cjc-acids being
largely oleic and palmitoleic. A saturated Cig-acid was
abundant in the fat of B. natta.
Two acids, 13-methyltetradecanoic, m.p. 52.5-53°, and
15-methylhexadecanoic, m.p. 61.0-61.5°, were the main
components of the fatty acid fraction of B. subtilis.^*
A new monounsaturated, monohydroxy acid, diphthero-
corynic, C53H104O3, has been reported produced by Coryne-
bacterium diphtheriae .^^ Its relationship to related com-
pounds has been discussed.^''
4. Tetronic Acids and Other Lactones and Lactams
Tenuazonic acid ( 3-acetyl-5-sec-butyltetramic acid)
has been biosynthesized incorporating 3.9 percent of the
tracer from a medium containing CH^C^OONa.^^ Of the
total incorporated radioactivity 96 percent was present in
the C-2 and C-6 atoms. The remaining 4 percent was
shared by C-4 and C-10, and this was explained on the
basis of the manner of biosynthesis of isoleucine.
4 3 6 7
HO— C=C— CO— CH3
10 9 8 1
CH3— CH2— CH— CH C
I 5'\
CH3 N
11 H'
\
32 M. Pailer, Fortschr. Chem. org. Naturstoffe 18 55-78 (1960).
33Kunihiko Saito, /. Biochem. (Tokyo) 47 699 (1960).
^^Idem., ibid. 47 710 (1960).
3^ E. M. Gubarev and L. M. Pustovlova, Ukrain. Biokhim. Zhiir. 30
569 (1958).
3" Raoul Toubiana and Jean Asselineau, Compt. rend. 251 884
(1960).
3" C. E. Stickings and R. J. Townsend, Proc. Biochem. Soc, 36P
(1960).
669 Addendum
It might be pointed out that, formally, some of the
vulpinic acids are tetronic acids although we have not
classified them as such.
The chemistry of the tetronic acids has been reviewed.^®
5. Carotenes and Carotenoids
Another paper has been published on the incorporation
of C^Mabeled compounds into carotenes by Neiirospora
crassa.^'^ Mevalonic acid salts were the best of eight pre-
cursors used, but less than 1 percent of the 2-C'* activity
was incorporated into the carotene fraction. Phytoene, y-
carotene and its isomers (fS- and ^-), phytofluene, neuro-
sporene, spirOloxanthin and its isomers and lycopene
were isolated. The presence of much phytoene, whose
presence in the theoretical biosynthetic sequence has been
questioned, was taken as an argument against formation
of the carotenes by stepwise interconversions involving
either hydrogenation or dehydrogenation and as an indi-
cation, rather, of independent synthesis.
The major carotenoids of some ascomycetes and basid-
iomycetes have been identified. *° /^-Carotene was predom-
inant in Epichloe typhina and Helotium citrinum. Crypto-
xanthin was second in importance in Calocera viscosa.
Neurosporene was the major carotenoid in dull yellow
Cantharellus infundibiliformis with traces of lycopene
present. The reverse was true in Cantharellus lutescens.
No carotenoids, but instead pigments with quinone-Hke
reactions, were detected in the grey Cantharellus cinereus
and orange-red Giiepinius helvelloides.
A red pigmented yeast isolated from root nodules of
Lupinus luteus produced torulene, ^-carotene, y-carotene
and torularhodin.*^ Diphenylamine inhibited production
of y-carotene and torularhodin.
Rhodotorula mucilaginosa contained, in decreasing or-
38 L. J. Haynes and J. R. Plimmer, Quart. Revs. 14 292 (1960).
33 Leo F. Krzeminski and F. W. Quackenbush, Arch. Biochem. and
Biophijs. 88 287 (1960).
*o Gilbert Turian, Arch. Mikrobiol. 36 139 (1960).
" Gy. Schneider, B. Matkovics and J. Zsolt, Acta. Univ. Szegedien-
sis. Acta. Phys. et Chem. 5 55 (1959).
Pfizer Handbook of Microbial Metabolites 670
der of quantity, torularhodin, torulene, y-carotene and f3-
carotene, but no phytoene or phytofluene.*- Ultraviolet
irradiation gave stable strains varying greatly from the
parent both in quality and quantity of carotenoid content.
One of many inhibitors tested, 2-hydroxybiphenyl, inhib-
ited carotenogenesis without affecting culture growth.
Doubt was expressed that the different carotenoids are
biosynthetically mutually related.
Oil of wheat rust (Puccinia gravtinis var. tritici) uredo-
spores contained fj- and y-carotenes with minor amounts of
phytoene, lycopene, a cis-/;j-carotene and a cis-carotene.*^
Mycoxanthin is the principal carotenoid of Mycobacte-
rium battaglini.** Leprotene, a leprotene derivative, ^-
carotene, a-carotene and an a-carotene monoepoxide prob-
ably were present.
A carotenoid pigment in Spirobacillus cienkowskii
Metchnikoff, a pathogen of cladocera, resembled rhodo-
violascin or a-bacteriopurpurin.*' Astacene and astaxan-
thin also were thought to be present.
Staphylococcus citreus contains the orange carotenoid.
sarcinaxanthin, and the yellow sarcinene.**' Reference
was made to two other uncharacterized carotenoids which
have been isolated from natural sources, neoxanthin and
corynexanthin.*'
A new carotenoid has been isolated, which probably
has the structure shown below. **^
175a Bacterioruberin a, C4oHr,,50o, mauve-violet needles, m.p. 182°
(vac), U.V. 369, 385, 461, 494, 528 m^ in petroleum
ether.
"Jean Villoutreix, Biochim. et Biophys. Acta. 40 434, 442 (1960).
*-^ F. Hougen.'B. Craig and G. Ledingham, Can. J. Microbiol. 4
521 (1958).
44Aldo Gaudiano, Rend. ist. super, sanita 22 769 (1959). (Chem.
Abstr. 54 13253a)
45 J. Green, Nature 183 56 (1959).
**' Tatsuo Ohta, Toshio Miyazaki and Teruo Ninomiya, Chem. &
Pharm. Bull. (Tokyo) 7 254 (1959).
*" W. Hodgklss, J. Liston, T. W. Goodwin and Malini Jamikorn,
J. Gen. Microbiol. 11 438 (1954).
*^ Synnove Llaaen Jensen, Acta Chem. Scand. 14 950 (1960).
Gyi Addendum
)
/ 111
Halobacterium sp.
A mutant of Staphijlococcus aureus unable to produce
bright pigments incorporated the label of 2-c^*-mevalonic
acid into phytoene, which it accumulated.*''"
The biosynthesis and function of the carotenoid pig-
ments have been reviewed.*-' Also a review of cis, trans-
isomeric carotenoid pigments has been published.'^''
6. Polyenes and Polyynes, Excluding Polyene Macrolides
In a review of polyacetylenes"^^ a number of substances
not included in our list were mentioned without refer-
ences or physical properties. These are reproduced here:
193a Octa-2,6-dien-4-yn-l,8-dioic Acid, C8H6O4.
HOOC— CH=CH— C = C— CH=CH— COOH
Polyporus anthracophilus
194a Non-2-en-4,6,8-triynoic Acid, CgH402.
HC=C— C=C— C=C— C=C— CH=CH— COOH
Psilocybe sarcocephala
195a Non-2-frans-oxido-4,6,8-triynol (Biformin?), CgHgOo.
HC=C— C=C— C^C— CH— CH -CH2OH
trans
Coprinus quadrifidis {Polyporus biformis?)
*®° Ginzaburo Suzue, Biochim. et Biophys. Acta 45 616 (1960).
«T. W. Goodwin, Advances in Enzymol. 21 295-361 (1959).
^" L. Zechmeister, Fortschr. Chem. org. Naturstoffe 18 (1960).
51 E. R. H. Jones, Proc. Chem. Soc, 199-211 (1960).
Pfizer Handbook of Microbial Metabolites 672
195b Non-4-cw-en-6,8-diynoic Acid, C9Hg02.
HC^C— C=C— CH=CH— CH2— CH2— COOH
CIS
Drosophila subatrata
198a Dec-2-<rans-en-4,6,8-triynoic Acid, C10H6O2.
CH3— C^C— C = C— C=C— CH=CH— COOH
frans
Pleurotus ulmarius, Tricholoma paneolum
201a Dec-2-frans-en-4,6,8-triynol, CioHgO.
frans
CH3— C=C— C=C— C=C— CH=CH— CH2OH
Pleurotus ulmarius
200a Deca-4,6,8-triyn-l,10-dioic Acid, C10H6O4.
HOOC— C=C— C=C— C^C— CH2— CH2— COOH
Merulius lachrymans
219a Tetradec-5-cis-en-8,10,12-triyn-l,14-dioic Acid, C14H10O4.
HOOC— C^C— C=C— C=C— CH— CH=CH— CH,— CHo— CH2— COOH
CIS
Poria sinuosa
Four other polyacetylenes have been reported, complete
with physical properties : ^^
195c Drosophilin E (cis-Non-4-en-6,8-diynoic Acid), CgHgOa, light-
sensitive prisms, m.p. 35°, U.V. 279.5, 264, 250, 238, 227,
210 m/x.
CIS
HC=C— C^C— CH=CH— CH2— CHo— COOH
Drosophila subatrata
209a Drosophilin C (cis-Undec-3-en-5,7,10-triynoic Acid), CnHgOs,
colorless needles, slowly yellowing in light at 20°, m.p.
97.5-99°, U.V. 280.5, 264.5, 250.5, 238, 226.5, 210.5 m,x.
HC=C— CH2— C^C— C=C— CH=CH— CH2— COOH
Drosophila subatrata
52 E. R. H. Jones, P. R. Leeming and W. A. Remers, /. Chem. Soc,
2257 (1960).
673 Addendum
209b Drosophilin D (cis-Undeca-3,9,10-trien-5,7-diynoic Acid),
C,,HsOo, colorless plates, m.p. 21-28°, U.V. 303.5, 290.5,
274.5, 259, 217 m^.
H,C=C=CH— C=C— C^C— CH--CH— CH, -COOH
Drosophila subatrata
219b Compound 3040 (Dimethyl trans-Undeca-2-en-4,6-diyn-l,ll-
dioate), C,.,Hi404, colorless crystals, m.p. 15-16°, U.V.
304, 286, 270, 255, 222.5, 215 m/x.
CH3OOC— CH2— CH2— CH2— C=C— C^C— CH=CH— COOCH3
Drosophila subatrata
An Italian review on the chemical aspects of the basid-
iomycete antibiotics has been published. ''■^
7. Macrocyclic Lactones (Macrolides)
A new tetraene antibiotic has been reported.^*
233a Unamycin A, white needles, m.p. (dec.) 148-150°, [ajn^^ —92°
(c 1.0 in 80% methanol-water), U.V. 290, 304, 319 m/x
in methanol.
An acidic tetraene. Negative FeCl^, Million, Fehling,
Tollens tests. Positive Molisch, KMn04 and Br^ tests.
Pink Schiff test.
A second substance resembling toyocamycin was iso-
lated :
1288a Unamycin B, white needles, m.p. 236-238° (dec), [ajn^^ -43°
(c 1.0 in acid methanol), N. E. 310.
C 46.4, H 4.46, N 22.25. Gives essentially the same color
tests as unamycin A.
The unamycins were produced by Streptomyces fungi-
cidicus.
A heptaene which may be new has been reported."
256a Grubilin green-yellow, amorphous.
A non-toxic heptaene produced by Streptomyces BA-27,
s^Marcella Magliola, Annali di Chimica 50 455-490 (1960).
^* Masayuke Matsuoka and Hamao Umezawa, /. Antibiotics
(Japan) 13A 114 (1960).
" J. Uri, I. Szilagyi and I. Bekesi, Symposium on Antibiotics,
Prague, 1959.
Pfizer Handbook of Microbial Metabolites 674
and differing from amphotericin B, ascosin, airreofacin,
AYF, candicidin, candidin, candimycin, PA 150 and tri-
chomycin.
Antimycoin has been separated into A and B compo-
nents.'^'' Mevalonic acid stimulated production of these
substances by Streptoinyces aureus. Of nine other
polyene producers tested, Streptoinyces viridoflavus pro-
duction of candidin and Streptoinyces strain 3832 produc-
tion of a pentaene (antibiotic S-8) of the eurocidin type
were stimulated by mevalonic acid addition.
The mechanism of nystatin action on Candida albicans
has been studied.''' Respiration was accelerated and glu-
cose uptake diminished, apparently by alteration of cell
permeability.
A dissertation has been published (not yet received)
entitled Beitrag zur Kentitnis des Candicidins D, G.
Demuth, Math.-Naturw. Fakultat der Univ. Gottingen,
1959.
Some generalizations can be made now concerning the
structures of polyene macrolides.* Tetraenes and hep-
taenes generally seem to contain nitrogen, while pentaenes
and hexaenes do not. Moldicidin and PA- 153 are excep-
tions since they are nitrogen-containing pentaenes. All
tetraenes except PA-166 contain mycosamine. PA-166
contains an amino sugar (not a deoxy type) other than
mycosamine. Pentaenes are neutral, containing neither
amino sugars nor free carboxyl groups.
Heptaenes have been found so far to contain four dif-
ferent nitrogen-containing moieties. Two of these are
the amino sugars previously mentioned. The other two
are the aromatic amines, p-aminoacetophenone and p-
aminophenylacetone, which are released by alkahne hy-
drolysis. "
s« Robert Samuel Safferman, Dissertation Abstr. 20 4264 (1960).
'"' J. W. Hai-man and J. G. Masterson, Irish J. Med. Sci. -$78 249
(1957).
* Most of the information below on the polyene macrolides was
taken from a seminar given by Dr. Edward Borowsky, Visiting Pro-
fessor at the Institute for Microbiology at Rutgers University from
Gdansk, Poland, in August 1960 and will be published.
675 Addendum
O O
H,N— / \— C— CH3 H,N— / \— CH,— C— CH3
p-Aminoacetophenone p-Aminophenylacetone
Amphotericin B and candidin are examples of heptaenes
containing mycosamine. Candicidin, trichomycin and
PA-150 contain p-aminoacetophenone.
Hydrocandidin has yielded an oxidation fragment iden-
tified as:
HOOC— CH-(CH,)u— CH— CO— CH3
I I
CH3 CH3
Some studies on the biosynthesis of this heptaene show
no incorporation of labeled inevalonic acid, propionic acid
or methionine. It seems to be derived from acetate.
The pentaene, moldicidin A, C4;{H220i9N was omitted.
Moldicidin B is identical with pentamycin."" Can-
dicidin is identical with ascosin. The main component
of the PA-150 complex is identical with one compo-
nent of the candidin complex. Several substances listed
in the unclassified section are actually known to be
polyene macrolides. These include: 1072-aliomycin
(pentaene), 1067-akitamycin (tetraene), 1095-antibiotic
from Streptomyces fimgicidicus (tetraene), 1096-antibi-
otic from S. griseus (heptaene), 1097-antibiotic 26/1
(heptaene), 1294-substance 1404 (hexaene).
A new heptaene, perimycin (aminomycin), probably
C47H-.-,Oi4N2 and incorporating a p-aminophenyl group,
has been reported. ^"^ Another heptaene, antibiotic 2814H,
is produced together with a pentaene, antibiotic 2814P,
netropsin and aureothin by Streptomyces lA 2814 resem-
bling S. netropsis.-'-' Analytical and optical data were re-
ported on each.
•"" Hiroshi Ogawa, Teiichiro Ito, Shigeharu Inoue and Motohiro
Nishio, /. Antibiotics (Japan) 13A 353 (1960).
■''''Edward Borowsky et al.. Abstracts 1960 Conference on Anti-
microbial Agents, Washington, D. C, October 26-28, 1960.
'''■' Heinz Thrum and I-dschang Dcho, N atiirwissenschaften 20 474
(1960).
Pfizer Handbook of Microbial Metabolites 676
The complete structures of the tetraenes, lagosin and
filipin have been reported to be : ^°
CsHu— CH— OH OH OH R=OH=lagosin, C35H58O12
I I I R=H=filipin, CssHssOu
O— CO— CH (CH— CH2)5— CH— CH— R
I 1
CH3— CH— CH— (CH=CH)4— CH=C CH— OH
I I
OH CH3
Humidin (Cj2H2o04)n, colorless plates, m.p. 145-146°
(dec), [aln'* -6° (c 1.0 in ethanol), mol. wt. 550 ± 50,
823 ± 10, is an antifungal antibiotic isolated from the
myceUum of Streptomyces humidus, which also produces
dihydrostreptomycin.^^ It was not clear from the abstract
whether or not this substance was of the polyene mac-
rolide type.
Some aspects of the mode of action of polyene anti-
fungal antibiotics have been reviewed."^
A nitrogen-containing antifungal polyene antibiotic,
capacidin, produced by a streptomycete has been iso-
lated.®^- ®* The substance is levorotatory, has reducing
properties, is a primary or secondary alcohol and shows
ultraviolet absorption peaks at 318, 332, 350 m^^.
A general review of the polyene antifungal antibiotics
has been published. '^^
Two new antibiotics have been reported, one of them,
at least, apparently a macrolide.*^®
^^M. L. Dhar, V. Thaller and M. C. Whiting, Proc. Chem. Soc,
310 (1960).
**i Koichi Nakazawa, Motoo Shibata, Hiroichi Yamamoto, Toshihiko
Kanzaki, Eiji Higashide, Akira Miyake and Satoshi Horii, Nippon
Nogei Kagaku Kaishi 32 713 (1958). (Chem. Abstr. 54 22843g)
^^ E. Drouhet, L. Hirth and G. Lebeurier, Annals N. Y. Acad. Sci.
89 134-155 (1960).
83 Rachel Brown and Elizabeth Hazen, N. Y. State Dept. Health,
Ann. Rept. Div. Labs, and Research 50-52 (1959). (Chem Abstr.
54 22824h)
^Idem., Antibiotics and Chemotherapy 10 702 (1960).
«5L. C. Vining, Hindu Antibiotics Bulletin 3 37-55 (1960).
8" E. Gaumann, R. Hiitter, W. Keller-Schierlein, L. Neipp, V. Prelog
and H. Zahner, Helv. Chim. Acta 43 601 (1960).
677 Addendum
265a Lankamycin, C3cHe20i4, colorless crystals, m.p. 147-150° and
at 181-182°, "[a]ir" -94° (c 1.23 in ethanol). U.V. 289
ni/x.
Typical erythromycin color tests were obtained. It is
notable that this macrolide contains no amino sugar.
A second, unclassified antibiotic was isolated from the
same culture (Streptomyces violaceoniger (Waksman et
Curtis) (Waksman et Henrici).
n64a Lankacidin, C4,5H,;,-Oi6N2, pale yellow microcrystalline powder,
m.p. 165-168°, [aW -161° (c 0.967 in ethanol), U.V.
227 m^ (log 2.95).
Contained no N — CH3 or — OCH3 groups.
It is interesting that spiramycin contains three sugars. *^^
A paper on the mode of action of erythromycin"* reports
that, when the antibiotic was added to growing cells of
E. coli, synthesis of protein (but not RNA or DNA) was
inhibited, as was adaptive formation of ^-galactosidase.
Lactose was the substrate. Oxygen uptake of resting cells
was inhibited in some organisms but not in others, but in
no case did cytochrome oxidase appear to be affected.
The wild strain of Streptomyces kitasatoensis Hata pro-
duces leucomycin, a complex of six macrolide antibiotics,
while a mutant produces only two of these, although total
macrolide production was the same in each case.*"'^ "°- "^
Probable empirical formulas of the members of the com-
plex are shown below :
leucomycin formula melting point
Ai C46HS1 O17N
Ai C65H111O22N
Bi C36H59O13N 214.5-216.5°
B2 CssHesOieN 214-216°
B3 C34H63 0,3N 216-217°
B4 C38H59O16N 221-223.8°
^'' Raymond Paul and Serge Tchelitcheff, Bull. Soc. chim. France,
150 (1960).
^^ Hiroshi Nakagawa, Osaka Daigaku Igaku Zasshi II 3451 (1959).
(Chem. Abstr. 54 11154a)
'^^ J. Abe, Y. Suzuki, T. Watanabe and K. Satake, Nippon Kagaku
Zasshi 31 969 (1960).
■OT. Watanabe et al. Bull. Chem. Soc. Japan 33 1100 (1960).
^^ Tetsuo Watanabe, Hisao Nishida, Jinnosuke Abe and Kazuo
Satake, ibid. 33 1104 (1960).
Pfizer Handbook of Microbial Metabolites 678
Methymycin has been found to be biosynthesized prin-
cipally from propionate, although one mole of acetate
may be incorporated. '-
8. Alicyclic Compounds Other Than Terpenoids and
Steroids
An investigation of the biosynthesis of palitantin shows
that it is acetate-derived, and that neither shikimic acid
nor mevalonic acid are involved.'^
Several compounds have been isolated which may be
related to cycloheximide :
302a Niromycin B, C14H21O4N (suggested), white, hygroscopic crys-
tals, m.p. 47-67°.
A neutral substance produced by Streptomyces albusJ*
302b Niromycin A, white hygroscopic, amorphous powder, m.p. 98-
105°.
Positive 2,4-dinitrophenylhydrazine and Tollens tests.
Negative ninhydrin, FeCla, Fehlings, Benedicts, Molisch,
biuret, KMn04 tests.
The effect of cycloheximide on the metabolism and
growth of Saccharomyces pastoriamis has been studied."'^
Some substances related to sarkomycin and produced
by the same organism were overlooked.''' These were:
301a Sarkomycin Eo, C10H14O4, m.p. 179°.
301c Sarkomycin Ep Ci4HisOt, m.p. 169°.
sold Sarkomycin So, Ci4Hi,OoS, m.p. 183°, [a]n +136°.
COOH COOH
CH,— S— CH.
o o
''-A. J. Birch, E. Pride, R. W. Rickards, P. J. Thomson, J. D.
Dutcher, D. Perlman and C. Djerassi, Chem. and hid., 1245 (1960).
■■^ P. Chaplen and R. Thomas, Biochem. J. 77 91 (1960).
'* Teisuke Osato, Yutaka Morikubo and Hamao Umezawa, J. Anti-
biotics (Japan) 13A 110 (1960).
"5 Bradner Wood Coursen, Dissertation Abstr. 21 (1960).
'« Sueo Tatsuoka et al., J. Antibiotics (Japan) 9B 104 (1956).
679 Addendum
30le Sarkomycin S^, CnH,sO,;So, m.p. 161°, [a],," +145°.
COOH COOH
/ y-CHj— S— S— CH
\ /
o o
30if Sarkomycin S;;, m.p. 148°.
C 50.39, H 5.31, S 15.75.
9. Terpenoids and Steroids
A new trichothecin-like antibiotic has been isolated
from a basidiomycete."
The oil of wheat stem rust uredospores contains A'-
ergostenol (fungisterol).'*-^
Another steroidal metabolite of Poria cocos has been
isolated and characterized. It is:"
354a Pachymic Acid ( 3/3-0-Acetylpolyporenic Acid B), CasH-.^O-,, col-
' orless crystals, m.p. 296-299°, [a]D"' 17.7° (c 0.566 in
pyridine ) .
HOOC
CH3COO
Cholesterol biosynthesis is inhibited by farnesoic acid
and its analogues.'^
The conversion of mevalonate to a mixture of farnesol
and nerolidol (probably as their pyrophosphates) by a
" Ervln Glaz, Eszter Scheiber, J. Gyimesi, I. Horvath, Katalin
Steczek, A. Szentirmai and G. Bohus, Nature 184 Suppl. No. 12, 908
(1959).
'^ Shoji Shibata, Shinsaku Natorl, Ko Fujita, Isao Kitagawa and
Kazue Watanabe, Chem. & Pharm. Bull. (Tokyo) 6 608 (1958).
'^G. Popjak, Rita H. Cornforth and K. Clifford, Lancet, 1270
(1960).
Pfizer Handbook of Microbial Metabolites 680
liver enzyme preparation has suggested that 1 mole of
each is involved in the biosynthesis of squalene.®° The
condensation of these two substances would then be anal-
ogous to that of isopentenylpyrophosphate with 3,3-di-
methylaUyl pyrophosphate (or geranyl pyrophosphate).
CH=-OPO.H,
Nerolidyl Pyrophosphate
Squalene
The significant points of the chemical mechanism of
squalene biosynthesis were summarized as follows:
(a) The process is not a concerted reaction, but proceeds
in steps with well-defined stable intermediates, (b) Dur-
ing isomerization of isopentenylpyrophosphate there is an
uptake of one proton in the terminal methylene group,
and this proton appears finally in one of the terminal
methyl groups at each end of squalene, which means the
entry into each molecule of squalene of two protons not
contained originally in mevalonic acid, (c) There are no
reductive steps involved in the synthesis of geranyl or
farnesyl pyrophosphates, (d) Farnesyl pyrophosphate
and the nerolidyl derivative are the two sesquiterpenoids
condensing to the symmetrical dihydroterpene, squalene,
a stable intermediate being dihydrosqualene. (e) During
stabilization of the condensation product of the farnesyl
and nerolidyl derivatives, elimination of two protons, orig-
inally attached to C-5 of mevalonate occurs, (f) The
final step is a reduction, introducing into squalene two
further hydrogen atoms not contained originally in
mevalonic acid.
80 J. W. Cornforth and G. W. Popjak, Tetrahedron Letters No. 19
29 (1959).
68 1 Addendum
10. Tropolone Acids
More data have been published on the structure of
heliomycin (entry 1173). It is acidic (pK 5.8), forms a
diacetate and may contain a benzotropolone ring system.
Empirical formulas Ci9Hi4.i(505 or CoaHjH joOe have been
suggested.'*^
11. Phenolic Substances
p-Hydroxybenzoic acid, found earlier in Penicillium
patuhim has been isolated also from Penicilliiim griseo-
fiilviim.^- Isolated from the same culture were:
379a »j-Hydroxybenzoic Acid, CyHyO;}, m.p. 201°
and
379b Salicylic Acid ( o-Hydroxybenzoic Acid), m.p. 159°.
The same mold produces homogentisic acid, a metabo-
I lite also found in some of the higher fungl.®^
391a Homogentisic Acid, C8H8O4, m.p. 152-154°.
COOH
OH
p-Hydroxyphenylpyruvic acid and tyrosine were identi-
fied in the culture, and occasionally 1,4-hydroquinone
was present.
The production of galHc acid by Phycomyces blakeslee-
anus (sporangiophores) has been confirmed.^* It was
suggested that this substance may be the primary photo-
sensitive pigment involved in the strong negative photo-
tropic response to ultraviolet light which such organs
show.
*i Z. V. Pushkareva, N. M. Voronina, S. I. Omerchenko, L. B.
Radina and Yu. N. Sheinker, /. Gen. Chem. (USSR) 29 3469 (Eng-
lish translation) (1960).
^- P. Simonart, A. Wiaux and H. Verachtert, Bull. soc. chim. biol.
41 537, 541 (1959).
^^ Paul Simonart, Anselme Wiaux and Hubert Verachtert, Zentrl.
Bakteriol. Parasitenk. Abt. II 113 209 (1960).
*'* David S. Dennison, Nature 184 2036 (1960).
Pfizer Handbook of Microbial Metabolites 682
C^*-Labeled orsellinic acid has been prepared by using
Chaetomium cochliodes as the producer. Orsellinic acid
was known to be a metabolite of Penicillium barnense,
which also produces penicillic acid. When Penicillium
barnense was grown in the presence of the labeled orsel-
linic acid, it could be shown that orsellinic acid was a
precursor of penicillic acid in this organism. ^^ The sites
of labeling and actual modes of cleavage are shown.
HO O CH2 CH3
y C C
COOH
HC C
V/x *
h o + CO2
0CH3
Orsellinic Acid Penicillic Acid
It appears that orsellinic acid is an intermediate in the
biogenesis of the xanthone ravenehn.*'' It has been sug-
gested as an intermediate in the biosynthesis of several
other types of compounds, e.g., lichen substances, fungal
anthraquinones and alternariol.
An uncharacterized substance has been isolated from
Curvularia lunata.^^
417a Substance from Curvularia lunata, Cj 411x^0.5, colorless solid,
m.p. 195°.
Apparently phenohc. Mannitol was isolated from the
same culture.
Curvularin, also produced by Curvalaria lunata, is pro-
duced by Penicillium steckii as well.**
A new depsidone has been isolated from an Australian
Uchen and characterized as norlobaridone : *'*
85 Klaus Mosbach, Acta. Chem. Scand. 14 457 (1960).
86 Private communication from Herchel Smith.
^~ T. Krishna Murty and S. Sankara Subramanian, Indian J.
Pharmacij 20 72 (1958).
»* D. Fennell, K. B. Raper and F. H. Stodola, Chem. and Ind., 1382
(1959).
*" G. P. Briner, G. E. Gream and N. V. Riggs, Australian J. Chem.
13 275 (1960).
683 Addendum
471a Norlobaridone, C.-jHonOe, colorless crystals, m.p. 188-190°.
CH3CH,CH,CH:CO ^^^
COO OH
HO O I
CH,CH.CH,CHoCH3
A yield of 2.2% was obtained from Pannelia conspersa.
The structure of nidulin (and thus of nornidulin) has
been completed.^''' It is:
^^' COO ^^' OCH3
The chemistry of the uncommon 1-methyIpropenyl sub-
stituent is greatly modified by the neighboring chlorine
atom.
12. Quinones and Related Compounds
a. BENZOQUINONES
The growth of a mycobacterium was stimulated by
coenzyme Qio which suggests a possible role in energy
metabolism.*^"
b. NAPHTHOQUINONES
A variety of bacteria (Bacillus cereus, B. subtilis, Pro-
teus vulgaris, Sarcina flava. Staphylococcus aureus, My-
cobacterium phlei, Pseudomonas spp., Azotobacter vine-
landii, Nocardia sp.) were examined for vitamin K
content.^^ Three types were identified. Vitamin K^ was
*»" F. M. Dean, D. S. Deorha, A. D. T. Erni, D. W. Hughes and
John C. Roberts, /. Chem. Soc, 4829 (1960).
•"' James O. Norman and Robert P. Williams, Biochem. and
Biophys. Res. Comms. 2 372 (1960).
»i Bodil Kruse Jacobsen and Hendrik Dam, Biochim. et Biophys.
Acta 40 211 (1960).
Pfizer Handbook of Microbial Metabolites 684
isolated from Bacillus cereus and vitamin K^ or a related
substance from Mycobacterium phlei.
A lipide cofactor, perhaps a K vitamin or a tocopherol,
has been implicated in the conversion of L-gulonolactone
into L-ascorbic acid.^^
C. ANTHRAQUINONES
In 1955 three substances were isolated from a yellow
sterile mold and were called flavomycelin, rhodomycelin
and purpurmycelin.^^ Rhodomycelin is identical with
islandicin and flavomycelin vvdth luteoskyrin. Acetone
solutions of luteoskyrin turn purple on exposure to light,
and purpurmycelin was found to be identical with this
irradiation product.^*
The biosynthesis of the pigments of Penicillium islan-
dicum has been studied. ^^ The acetate origin of islandi-
cin, skyrin, rubroskyrin (luteoskyrin) and iridoskyrin
was established. The results of labeling experiments led
to the conclusion that, despite the close structural rela-
tionship, these pigments are not interconvertible in vivo,
but seem to be derived from a common pre-aromatic
stage. Also mutations fail to block formation of any sin-
gle pigment. Biogenesis, it was suggested, must not take
place by stepwise formations of defined intermediates
such as benzene derivatives, but should be dependent
throughout on participation of activated acetate.
An acidic substance related to herqueinone has been
isolated.^''
A review of quinones as metabolic products of micro-
organisms has been published.'''
There Jiave been two recent pubUcations on the struc-
92 I. B. Chatterjee, N. C. Kar, N. C. Ghosh and B. C. Guha, Arch.
Biochem. and Biophys. 86 154 (1960).
93 H. Nishikawa, Tohoku J. Agr. Res. 5 285 (1955).
9* S. Shibata, I. Kitagawa and N. Nishikawa, Pharm. Bull. (Tokyo)
5 383 (1957).
95 Sten Gatenbeck, Acta Chem. Scand. 14 102, 230, 296 (1960).
96 K. S. Gopalkrishnan and N. Narasimhachari, "Antibiotics,"
Council of Scientific and Industrial Research, New Delhi, 1958, pp.
176-179.
9^ J. H. Birkinshaw, Planta Med. 7 367 (1959).
685
Addendum
ture of thelephoric acid (entry 493).^^ "^ The second
publication cited reported the synthesis of thelephoric
acid and seems to establish the structure definitely as:
O
HO
HO
OH
OH
Oosporein (chaetomidin) (entry 487) is reported to be
identical with isooosporein (entry 488).^""
A reinvestigation of quinones produced by Phoma ter-
restris Hansen identified cynodontin and a small amount
of another anthraquinone, but found no phomazarin (en-
try 556).'"!
13. Tetracycline, Analogues and Related Substances
The aglycone, aklavinone, of the antibiotic aklavin has
been found to differ from rutilantinone ( e-pyrromyci-
none) only by lacking one hydroxyl group/"^
OH OH
Aklavinone C22H20O8
OH O
COOCH3
Rutilantinone C22H20O9
A biogenesis was postulated in the following sense:
0000
^^ K. Aghoramurthy, K. G. Sarma and T. R. Seshadri, Tetrahedron
Letters No. 16 4 (1960).
9»J. Gripenberg, Tetrahedron 10 135 (1960).
i°o J. Smith and R. H. Thomson, ibid. 10 148 (1960).
"ID. E. Wright and K. Schofield, Nature 188 233 (1960).
102 J. J. Gordon, L. M. Jackman, W. D. QUis and I. O. Sutherland,
Tetrahedron Letters No. 8 28 (1960).
Pfizer Handbook of Microbial Metabolites 686
A more recent publication indicates that nine acetate
units are incorporated into the rutilanlinone molecule,
but that the three starred atoms are from propionate. ^°^
Methionine would not, then, be involved in the side-chain
synthesis.
Two investigations have been made on the chlorina-
tion mechanism of Streptomyces aureofaciens in the pro-
duction of aureomycin.^"^ "^ The authors of the first
reference concluded that incorporation of the chlorine
atom does not take place on the finished tetracycline
molecule, but at an earlier stage of biosynthesis. Wang's
results lead to the same conclusion.
The influence of specific enzyme poisons on the produc-
tion of oxy tetracycline has been studied. ^•'^ Iron-contain-
ing oxidases and flavine oxidases participated in the
biosynthesis of oxy tetracycline. Phenoloxidase inhibi-
tors, on the other hand, stimulated production.
There is httle agreement on the mode of action of the
tetracycline antibiotics, and it may be that they act in a
variety of ways. Inhibition of RNA and DNA synthesis
and inhibition of enzymic conversion of uracil to thy-
mine,^°^ binding by chelation of metal ions required by
coenzymes^-"' and blocking of unspecified biosynthetic
pathways^°^ have been mentioned.
A discussion of the mechanisms of action of antibiotics
in general has been published. ^^"^
103 w. D. Ollis, I. O. Sutherland, R. C. Codner, J. J. Gordon and
G. A. Miller, Proc. Chem. Soc, 347 (1960).
i°* J. Kollar and M. Jaral, Symposium on Antibiotics, Prague, 1959.
105 E. Lin Wang, J. Antibiotics (Japan) 12A 31, 41, 50 (1959).
loo V. Sevcik, V. Musilek and I. Komersova, Symposium on Anti-
biotics, Prague, 1959.
10' T. Balakrishna Rao, D. V. Temhane, D. V. Rege and A. Sreeni-
vasan, "Antibiotics," Council of Scientific and Industrial Research,
New Delhi, 1958, p. 212.
108 E. U. Weinberg, Bacterial. Revs. 21 46 (1957).
10^ J. F. Snell, Florence Z. Thanassi and Dorothy Ann Sypowicz,
Antibiotics and Chemotherapy 8 57 (1958).
110 S. G. Bradley and L. A. Jones, Annals N. Y. Acad. Sci. 89 123
(1960).
687 Addendum
14. Aromatic Compounds Not Classified Elsewhere
The cooccurrence of anisaldehyde and junipal in
Dacdalca jutupcrina cultures has inspired the suggestion
that both substances are derived from a common acety-
lenic precursor.'"' "- An eai'lier report that Poliiporiis
beuzoiuus produces considerable quantities of anisalde-
hyde was not mentioned in our entry on that substance."^
15. Amines
Although the ordinary source of the amine, carnitine,
is mammalian muscle, a publication was overlooked in
which it was isolated from the mold Neurospora crassa
grown on a chemically defined medium."*
653a L-Carnitine, C7H]-0;iN, extremely hygroscopic crystals, m.p.
196-198°, [a],,'-" -23.5° (c 0.5 in water).
® 0
(CH3)3N— CH2— CH— CH2— COO ^
OH
This amine would not replace choline in choline-less
neurospora mutants. It was not found in E. coli. The
role of carnitine in lipide metabolism has been re-
viewed."^' ^^^
An amine related to muscarine has been isolated and
characterized by synthesis.""' "* It is:
658a ( + )-Muscaridine, C,,H..0._.NC1 (Chloroaurate), C.,H..AuCl40.N,
m.p. 129-131°, UW -f20.5° ±0.5° (c 8.3 in water).
"1 J. H. Birkinshaw and P. Chaplen, Biochem. J. 60 255 (1955).
11- K. E. Schulte and N. Jantos, Arch. Pharm. 292 536 (1959).
^^^ J. H. Birkinshaw, E. N. Morgan and W. P. K. Flndlay, Biochem.
J. 50 509 (1952).
"*G. Fraenkel, Biol. Bull. 104 359 (1953).
"' G. Fraenkel and S. Freedman, Vitamins and Hormo7ies 15 74-
115 (1957).
""E. P. Adams, P. E. Ballance and A. E. Bender, Nature 185 612
(1960).
"■ F. Kogl, C. A. Salemink and P. L. Schuller, Rec. trav. chim. 79
278 (1960).
"'^C. A. Salemink and P. L. SchuUer, ibid. 79 485 (1960).
Pfizer Handbook of Microbial Metabolites 688
© CI e
(CHalsN CH,— CHo— CHo— CH— CH— CH3
I I
OH OH
Amanita muscaria
A survey of 32 fungi and nine bacteria indicated that
the production of choline sulfate is limited to the higher
fungi. ^^^ All bacteria were negative as were phycomy-
cetes. Of the ascomycetes, spharioles produced it, but
endomycetales did not. Basidiomycetes and all fungi
imperfecti examined (except Torula utilis) were pro-
ducers.
List has continued his investigations of the basic con-
stituents of higher fungi. From Polyporus sulfureus
were isolated the following non-volatile substances: ade-
nine, hypoxanthine, arginine, histidine, lysine, choHne,
histidine betaine, phenylethylamine, imidazolyl acetate,
homarine, trigonelHne, y-butyrobetaine and an uncharac-
terized hydrochloride, C9Hi6N2-2HCl.^-°
The mushroom Coprinus atramentarius was studied. ^^^
A prior report that it produced tetraethylthiuram disul-
fide could not be confirmed. Found, however, were iso-
amylamine, phenylethylamine, adenine, hypoxanthine,
urocanic acid, imidazolyacetic acid, imidazolylpropionic
acid, imidazolylethanol, histidine, arginine, choline, ly-
sine, guanidine, ergothioneine, hercynine, glycine, be-
taine, tyramine, putrescine, cadaverine, S-aminovaleric
acid, a-guanidinobutyric acid, two unidentified bases,
glycine, threonine, glutamic acid, aspartic acid, alanine,
proline, leucine, valine, isoleucine, citrulline, tyrosine
and ornithine.
A dissertation has been published on basic constituents
and amino acids of the basidiomycete, Inocybe patoul-
lardii Bres.^--
Found were methylamine, dimethylamine, ethylamine,
n-propylamine, isoamylamine, /?-phenylethylamine, cho-
line, cadaverine, putrescine, hypoxanthine, alanine, pro-
lix T. Harada and B. Spender, /. Gen. Microbiol. 22 520 (1960).
120 p. List and H. Menssen, Arch. Pharm. 292 260-271 (1959).
^21 p. H. List and H. Reith, Arzneimittel-Forsch. 10 34-40 (1960).
^2- H. Miiller, Dissertation, Naturw. Fakultat Univ. Wiirzburg,
1959.
689 Addendum
line, tyrosine, valine, leucine, cysteine, aspartic acid,
glutamic acid, histidine, imida/.ole-4-acctic acid, argi-
ninc. ornithine and the incompletely characterized basic
red pigment of the organism, C,,Ho„0,,N^,. This was yel-
low in alkali, red in acid solutions and gave positive
Bayer and Pauly diazo tests.
A study of the biogenesis of spermidine (entry 642) in
microorganisms has shown that the C4 moiety is derived
from putrescine (or ornithine) while the C;; chain has its
origin in methionine.'-'*
Biochemical pathways in legume root nodule nitrogen
fixation have been reviewed.'-*
16. Amino Acids and Related Compounds
The lysine, methionine and tryptophan contents of a
number of yeasts have been surveyed.'"
In a study of the interrelationships between folic acid
and cobalamin in the synthesis of methionine by extracts
of E. coll, it was concluded that serine is not on the route
of biosynthesis of the methyl group of methionine.'-"
Discussing the two modes of lysine synthesis by lower
fungi, Vogel has pointed out that organisms of older evo-
lutionary origin follow the bacterial route.'-' These in-
clude eubacteria, pseudomonads and actinomycetes. As-
comycetous and basidiomycetous fungi use the fungal
pathway via a-aminoadipic acid.
17. Polypeptides and Related Compounds
The ostreogrycin (E-129) complex was isolated in
1958'-^ and reported similar to streptogramin, staphylo-
mycin (A-899), PA- 11 4 and mikamycin.
E-129 A probably is identical with staphylomycin M and
123 H. Tabor, S. M. Rosenthal and C. W. Tabor, /. Biol. Chem. 233
907 (1958).
124 F. J. Bergersen, Bacteriol. Revs. 24 246 (1960).
'-'■ G. E. N. Nelson, R. F. Anderson, R. A. Rhodes, Margaret C.
Shekleton and H. H. Hall, Appl. Microbiol. 8 179 (1960).
126 R. L. Kislluk and D. D. Woods, Biochem. J. 75 467 (1960).
12" H. J. Vogel, Biochim. et Biophijs. Acta 41 172 (1960).
12^ S. Ball, B. Boothroyd, K. A. Lees, A. H. Raper and E. Lester
Smith, Biochem, J. 68 24p (1958).
Pfizer Handbook of Microbial Metabolites 690
PA-114A. E-129B may be identical with PA-114B, but
different from staphylomycin S : ^^^
770a Ostreogrycin B, (E-129B) C45H-4O9NS, colorless prisms from
methanol with solvation, colorless needles from toluene,
m.p. 266-268°, [aW -66.8° (c 0.5 in methanol).
CH--CH^CH3
N-Me-p- / ^O
Dimethylamino-
phenylalanine L-Pro
N
CH,
-N C^^ \ /
Streptomyces ostreogriseiis
This structure differs from staphylomycin only by sub-
stitution of p-dimethylamino-N-methylphenylalanine for
N-methylphenylalanine.
A similar structure has been proposed for mikamycin B,
the only difference being a hydroxyl group in the /^-posi-
'-" F. W. Eastwood, B. K. Snell and Alexander Todd, /. Chem. Soc,
2286 (1960).
691 Addendum
tion of the pyridine moiety adjacent to the carbonyl
group in the mikamycin. '-'•'"
An antiviral polypeptide, ccphaloniycin, has been re-
ported.'"' It contained leucine, alanine, valine, arginine,
glutamic acid, aspartic acid, glycine, threonine, tyrosine,
phenylalanine and three unidentified ninhydrin-positive
substances.
Some peptide sequences of colimycin have been deter-
mined.'" It resembles polymyxin B, and the sequence
L-Dia — L-Dia — D-Leu — L-Leu — L-Dia — L-Dia — L-Dia — l-
Dia — L-Thr has been established (L-Dia = a, y-L-diamino-
butyric acid).
An antibiotic named colisan has been isolated from a
bacillus.'^- '-''
Sporidesmolide I, a metabolic product of Sporidesmium
bakeri Syd., colorless needles, m.p. 261-263°, [a],,'"
—217° in chloroform (c 1.5) has the empirical formula
C33H58OSN4 and the structure : "^^
CH3 CH3
\ /
CH
CH3— CH
\
CHo
0
\
II
CH-
— c
X^D
NH
v/
CH,
\
C
„ /
"—CM 0
C
/
CH,
NH
\
CH
CH3— CH ^
]
— c-
II
1
CH3
II
0
\^°
CH3
/ \
C' CHj
CH;
-CH
\
CH.
\
CH
/ \
CH3 CH3
129a xiyoshe Watanabe, Hiroshi Yonehara, Hamao Umezawa and
Yusuke Sumiki, /. Antibiotics (Japan) 13A 293 (1960).
""Akihiro Matsumae, /. Antibiotics (Japan) 13A 143 (1960).
"^ Michel Dautrevaux and Gerard Biserte, Compt. rend. soc. biol.
153 1346 (1959).
132 R. Reitler and J. Boxer, Nature 158 26 (1946).
133 R. Reitler and A. Berner, to be published.
"3" D. W. Russell, Biochim. et Biophijs. Acta 45 411 (1960).
Pfizer Handbook of Microbial Metabolites 692
making it a new member of the depsipeptide or peptolide
class. This is the first report of L-a-hydroxyisovaleric acid
as a natural product.
A wilt toxin, culmomarasmin, which was 200 times as
active as fusaric acid or lycomarasmine, has been isolated
from Fusarium culmorura}^^ It is a crystalline polypep-
tide, m.p. 215-218° (dec), stable below 0°. It is
ninhydrin-negative and has the analysis: C 45.31, H 7.08,
O 27.56, N 10.36, S 4.76, CI 4.19, C— CH3 3.17, — OCH3
1.08. It also contains iron (1.39% inorganic residue).
The amino acids are cystine, leucine, serine, aspartic
acid, glutamic acid, alanine, valine, affo-isoleucine,
proline, glycine, threonine and ammonia.
Two dissertations on wilt toxins have been pub-
lished.i^^- ^^^
The antibacterial activities of acyclic decapeptide ana-
logues of gramicidin S have been measured."^ The mode
of action of the acyclic compounds differs from that of
the cycHc ones. While gramicidin S causes immediate
bacteriostasis, the acyclic analogues are effective only
after several cell divisions. The most active analogue
was Yio as active as gramicidin S against E. coli and Mo
as active against Staphylococcus aureus.
The mushroom toxin, phalloidin, has been reported to
act by inhibition of oxidative phosphorylation.^^* A more
recent study claims that it acts, rather, by interference
with protein synthesis.""
The neuromuscular blocking properties of various poly-
peptide antibiotics have been investigated."""
A yellow pigment has been isolated from E. coli.^*^
"*J. Kiss, Chimia 14 174 (1960).
1^5 Hans Gempeler, tjber welkakdve Inhaltsstoffe von Endopathia
parasitica (Murr.) und von Fusarium martii. Dissertation, Eidgenos-
sische Technische Hochschule, 1959.
136 Fritz Kugler, tjher welkdktive Inhaltsstoffe von Endopathia
parasitica (Murr.) und von Fusarium solani (Mart.) v. Martii, Dis-
sertation, Eidgenossische Technische Hochschule, 1959.
137 B. F. Erlanger and L. Goode, Science 131 669 (1960).
"SBenno Hess, Biochem. Z. 328 325 (1956).
"9 A. von der Decken, H. Low and T. Hultin, ibid. 332 503 (1960).
i39« R. H. Adamson, F. N. Marshall and J. P. Long, Proc. Soc.
Exptl. Biol, and Med. 105 494 (1960).
1*" K. Ishii and M. Sevag, Arch. Biochem. and Biophys. 77 41
(1958).
693 Addendum
Acid hydrolysis yielded p-aminobenzoic acid, glutamic
acid, alanine, leucine and perhaps another uncharac-
terized substance (not a pteridine) with an U.V. maxi-
mum at 360 m/t.
A total synthesis of gramicidin Jo has been achieved. ^""^
The biosynthesis of this substance has been investigated.^*^
The antibiotic was concentrated in the RNA-rich proto-
plast precipitate.
The fact that bacitracin A (especially old samples)
stimulates growth of Phycomyces blakesleanus may be
due to conversion of the thiazoline ring of bacitracin A
to a thiazole ring (bacitracin F)."^
Papers have appeared on metabolism and actinomycin
production by streptomycetes'*^ and on the citric acid
cycle and actinomycin formation. ^^"^
The cytostatic activity of actinomycins is reversed by
high concentrations of purines and pyrimidines."" The
interpretation of this effect was that actinomycin may
react with DNA to form dye-polymer complexes.
Mitomycin C causes bacteria to break down their DNA
rapidly, acid-soluble products being formed. ^■*°''
An actinomycin complex, aurantin, colorless crystals,
m.p. 255-257°, [ali,'*' - 308°, has been isolated in Rus-
sia.^*' The complex contains threonine, sarcosine, pro-
Une, valine, N-methylvaline and isoleucine. It was
separated into four biologically active components: A^
m.p. 205°, A. m.p. 225°, A3 m.p. 226° and A4 m.p. 152°.
Methionine furnishes the methyl groups attached to
the aromatic chromophore of the actinomycins as shown
by labeling wdth C^*.^*^°
1" Y. Noda, J. Chem. Soc. Japan 80 411 (1959).
142 s. Otani, I. Murakami and S. Chin, Abstr. 118th Meeting,
Japanese Antibiotics Association.
1*3 Sibor Ebringer, Naturwissenschaften 47 210 (1960).
"* Paul Prave, Arch. Mikrobiol. 32 278 (1959).
^*Udem., ibid. 32 286 (1959).
1*6 W. Kersten, H. Kersten and H. M. Rauen, Nature 187 60
(1960).
i**"'" E. Reich, A. J. Shatkin and E. L. Tatum, Biochim. et Biophys.
Acta 45 608 (1960).
1*' A. B. Cilaev, T. I. Orlova, B. C. Kuznetsova and I. B. Mironova,
Antibiotiki 3 18 (1960).
>*■» A. J. Birch, D. W. Cameron, P. W. Holloway and R. W. Rick-
ards. Tetrahedron Letters No. 25 26 (1960).
Pfizer Handbook of Microbial Metabolites 694
A general review of actinomycin structure and syn-
thesis has appeared.^*'"
A colorless, amorphous polypeptide antibiotic, edein,
has been isolated from a strain of Bacilhis hrevis}*^ It
contained arginine, glycine, glutamic acid, aspartic acid,
tyrosine and two unidentified ninhydrin-positive spots.
Two heat stable polypeptides, phytoactin and phy-
tostreptin, have been isolated from an unclassified strep-
tomycete.^*'' Both contain valine, a-alanine, proline,
leucine or isoleucine, arginine, glycine and serine.
Two peptide antibiotics not mentioned before are
coliformin^'^" and roseocitrins A and B.^^^ Coliformin has
the analysis: C 47.6, H 8.22, CI 3.31, S 0.23, P 0.47 and
O 33.15 and contains alanine, glycine, serine, glutamic
acid, aspartic acid, lysine, valine and leucine. The
roseocitrins appear to resemble streptothricin.
In a review of this class the name depsipeptide has
been suggested for substances such as amidomycin and
valinomycin, which are composed of a-hydroxy acids and
amino acids. ^'^- Synthetic methods have been devised
for both regular and irregular sequences of the two types
of acids in these antibiotics.
The biosynthesis of a,y-diaminobutyric acid in Bacillus
circulans has been studied. ^^^
The structure of amidinomycin, C9HigON4 -112804, has
been shown to be:^^^*
O NH
H2N-
-C— NH— CHo— CHo— C— NH2-H2S04
i*"''Hans Brockmann, Angew. Chem. 72 939-948 (1960).
^''^ Z. Kurylo-Borowska, Symposium on Antibiotics, Prague, 1959.
149 Jack ZifFer, S. J. Ishihara, T. J. Cairney and A. W. Chow,
Phijtopathology 47 539 (1957).
1^" Stig K. L. Freyschuss, Stig O. Pehrson and Borje Steinberg,
Antibiotics and Chemotherapy 5 218 (1955).
I'l Hisaya Kato, J. Antibiotics (Japan) 6A 143 (1953).
152 M. M. Shemyakin, Angeiu. Chem. 72 342-345 (1960).
1''^ Yelahanka Krishnamurthy Murthy, Dissertation, Purdue Univ.,
1958.
'^^'■^^ Shoshiro Nakamura, Keiko Karasawa, Nobuo Tanaka, Hiroshi
Yonehara and Hamao Umezawa, /. Antibiotics (Japan) 13A 362
(1960).
695 Addendum
The structure of the antifungal antibiotic, variotin,
CifiHo.O.N, is :'•"«"
O
II
CHaCHj— CH.— CH C— CH =C— CH=CH— CH=CH— C— NH— CH,— CH,— CH>
OH CHs
O
— C— OCH3
Thus, while it is a tetraene, it is not of the macrolide
class.
Siderochromes.
A number of microorganisms have been found to
produce iron-containing pigments which absorb in the
ultraviolet at 420-440 m^u, and have other properties in
common. It has been suggested that these be called
siderochromes.^^*
Some of these substances are antibiotic and are called
sideromycins. Others are growth factors and may be
designated sideramines. The antibiotic sideromycins
seem to function by inhibiting the growth factor sidera-
mines.
It remains to be seen how broadly the significance of
these substances will extend. Some 50 strains of strepto-
mycetes produce sideromycin-like antibiotics.^-* Of 32
common microbial species examined 10 produced
coprogen-like substances. ^^^ The sideramines seem to
perform a coenzyme-like function in many microorgan-
isms.
Grisein A and albomycin have broad antibiotic activ-
ity. In gram-positive microorganisms, but not in gram-
negative ones, their effects are inhibited by sideramines.
Ferrimycin is 10 to 50 times as effective as penicillin
against gram-positive microorganisms in animal studies.
The following table shows some of the siderochromes
which have been best characterized:
^^^" Setsuo Takeuchi, Hiroshi Yonehara, Hamao Umezawa and
Yusuke Sumiki, ibid. 13A 289 (1960).
^■* H. Bickel, E. Gaumann, W. Keller-Schierlein, V. Prelog, E.
Vischer, A. Wettstein and H. Zahner, Experientia 16 129-133
(1960).
1"'= C. W. Hesseltine, A. R. WhitehlU, C. Pidacks, M. Ten Hagen, N.
Bohonos, B. L. Hutchings and J. H. Williams, Mycologia 45 7 (1953).
Of
•o K 00
lO lO "O
o^ o
IT) >o
1
— -o
•o -o
I 0-
Ammonia, Succinic Acid
1 -Amino-5-hydroxyl-
aminopentane, 5-
aminovaleric Acid,
Cadaverine, Cryst.
compound (X max.
227, 323 m/u). Proline
and 1 unidentified
ninhydrin-positive
substance.
o i:
o
E X
3
^<
5
Methyluracil, Serine,
Ornithine, Hydroxyl-
amine
Absorption
X max.
cm.
228, 282
319, 28
425, 22
00
o &■
— CN
lO o"
-O CN
CM -"l-
a.
00 00
— 00
1^
■o
o
CO
o
1
o o
CN CO
s
X
o
c
<
0)
u.
M3
U
o
•d
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o.
CN
CN
I
o-
o
<o
u
•o
00
O;
CO
Producing
microorganism
Sfreptomyces griseo-
flavus (Krainsky)
Waksman et Henrici,
S. go/i/oeus, S.
lavendulae
S 5
S X
8 §
Actinomyces subtropicus
Kudrina et Kochet-
kova
'u
>.
E
o
4)
Ferrimycin A (may
consist of 2 com-
ponents)
<
c
'5
O
Albomycin (A com-
plex. The main
component has
been resolved
into two ports.)
en.
>o
00
>o
o»
"O
o
2 -D
-0 o
- a
4t -?
O X CO u
c .S c '^
0 £ i J!
1 c O <
<
X
.1 ^ ^ § -
JC 4, J, ii (L
1 1 m
° - -- 1: £2
•c 2 o 1 ^
o
< 0 *« •- «
:i t ^- "I <
"^^ o S S 5;
llllh
1 - O < U <
<
Absorption
X max.
E.1%
cm.
o-
CO
>W
CM
CO
o"
CO
<s
CO
•o
CO
o"
a
ii
CN
o
o
o
N.
»
0
c
<
ID
CO
<>
<)
0
CN
Z
•o
00
CN
•o
CN
d
X
o
O;
o
00
^
nI
CO
00
u
CM
O
IT)
K
■<1-
o
00
■o
O;
d
■o
E
1|
= ?
0 o
I -E
<U 0)
D> >
O <^
0) "S
D ».
-C 1=
8- m
X
o 1
^ =
"^ CO
3
8 -E
0) >
o ^
0) %
D VI
S- Uj
X
0 i!
^ =
3
O w «> 0) 3 5
S 2 g • ui "E ?
°' a i 3 £ ^ i
s .. 1 § -s ;-. -5 S
g 5 0 :i o „- "o -C
a 0 .i: . 3 g . .
d.
E
c
a.
i
0)
J)
£.
0
■a
o
4)
C
1
D
0)
o
«
11.
<
E
0
u.
CO
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c
"i
o
X
0
«
u.
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o
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U
o
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O)
4)
«
1-
Pfizer Handbook of Microbial Metabolites 698
Other less well characterized siderochromes were dis-
cussed in reference 156.
In the ferrichromes the iron is bound by coordination
with hydroxamic acid derivatives of the ahphatic acid
moieties.
"6H. Bickel, E. Gaumann, W. Keller-Schierlein, V. Prelog, E.
Vischer, A. Wettstein and H. Zahner, Experientia 16 128 (1960).
15' H. Bickel, B. Fechtlg, G. E. Hall, W. Keller-Schierlein, V. Prelog
and E. Fischer, Helv. Chim. Acta 43 901 (1960).
^""^ H. Bickel, et al., to be published.
159 D. M. Reynolds, A. Schatz and S. A. Waksman, Proc. Soc. Exp.
Biol. Med. (New York), 64 50 (1947); D. M. Reynolds and S. A.
Waksman, J. Bacterial. 55 739 (1948).
160 F. A. Kuehl, M. N. Bishop, L. Chaiet and K. Folkers, /. Am.
Chem. Soc. 73 1770 (1951).
1*^1 M. G. Brazhnikova, N. N. Lomakina and L. I. Murayeva,
Doklady Akad. Nauk. S.S.S.R. 99 827 (1954).
162 E. O. Stapley and R. E. Ormond, Science 125 587 (1957).
163 G. F. Gause, Brit. Med. J. 2 1177 (1955); G. F. Cause and
M. G. Brazhnikova, Novosti Med. (Moscow) 23 3 (1951).
164 Yu. O. Sazykin, Mikrobiologiya 24 75 (1955).
165 E. S. Kudrina and G. V. Kochetkova, Antibiotiki (Moscow) 3
63 (1958).
166 O. Mikes and F. Sorm, Symposium on Antibiotics, Prague, 1959.
16' J. B. Neilands, }. Am. Chem. Soc. 74 4846 (1952); idem., J.
Biol. Chem. 205 643, 647 (1953); idem., Bacterial. Revs. 21 101
(1957); J. A. Garibaldi and J. B. Neilands, /. Am. Chem. Soc. 77
2429 (1955); Thomas Emery and J. B. Neilands, to be published;
T. Emery and J. B. Neilands, Nature 184 1632 (1959).
16S G. E. Hall, unpubhshed.
169 C. W. Hesseltine, C. Pidacks, A. R. Whitehall, N. Bohonos,
B. L. Hutchings "and J. H. Wilhams, /. Am. Chem. Soc. 74 1362
(1952); C. W. Hesseltine, A. R. Whitehall, C. Pidacks, M. T. Hagen,
N. Bohonos, B. L. Hutchings and J. H. Williams, Mycologia 45 7
(1953); C. Pidacks, A. R. Whitehall, L. Pruess, C. W. Hesseltine,
B. L. Hutchings, N. Bohonos and J. H. WiUiams, /. Am. Chem. Soc.
75 6064 (1953).
I'O A. G. Lochhead, M. O. Burton and R. H. Thexton, Nature 170
282 (1952); A. G. Lochhead and M. O. Burton, Can. J. Botany 31 7
(1953); M. O. Burton, F. J. Sowden and A. G. Lochhead, Can. J.
Biachem. and Physiol. 32 400 (1954).
699
Addendum
Baccatine A (entry 1114) has been shown to be a
mixture of enniatins A and B.'"'
A partial structure has been advanced for PA-114-B-1
(entry 729).''- It is C^sHtjiOioNi,:
OH
/
C — L-Thre
II I
O O
I
0==C — L-a-Phenylglycine-
"-N
L-Proline
Sarcosine
p-Dimethylamino-
phenylalanine
5-Hydroxymethyl-
-D-a-Aminobutyric Acid — hydroxyproline
(perhaps)
PA-114-B-3, a minor component of this synergistic com-
plex, contains all the same components except sarcosine.
It seems to contain another N-methyl amino acid instead.
Other synergistic complexes of this sort are streptogramin,
staphylomycin, ostreogrycin and mikamycin. These were
classified as follows:
Type
Specific
compound
Synonyms
A
A,
PA-n4-A-1
Ostreogrycin (E-129) Factor A
Mikamycin A
Streptogramin main component
Staphylomycin Mi
A.,
Staphylomycin M^
B
Bi
PA-114-B-1
Ostreogrycin (E-129) Factor B
Mikomycin B
Bo
Staphylomycin S
Bs
PA- 114-8-3
Streptogramin, minor component
I'lG. E. HaU, Chem. and Ind., 1270 (1960).
I'-D. C. Hobbs and W. D. Celmer, Nature 187 598 (1960).
Pfizer Handbook of Microbial Metabolites
700
More data have been published on the purification and
physical properties of mycobacillin (entry 795).^'^
Some degradation studies of thiostreptone (entry 809)
have been reported/'* L-Threonine, L-isoleucine, l-
alanine and D-cysteine were identified, and several thia-
zole-containing fragments were isolated. A minimal
molecular weight of 1500 is required.
A structure has been proposed for a new antibiotic,
racemomycin O.^"'^ It is produced by Streptomyces race-
mochromo genus, has the empirical formula C25H44O10N8
and is thought to be :
HO CH.
l/\
CH2 CH— C
I I I
HN N C
\/ X\ /
CO N
I H
NH
NH
\
HC
HC— NH CO— CH2— CH— CH2— CH2— CH2— NH2
I
HOCH O NH2
I
HC— O
I
HC CH— CH2— CH2— O— CH2— CH— CH3
CH2— O 1 OH
A partial structure has been advanced for roseothricin
A (entry 717).^"''
^" S. K. Majumdar and S. K. Bose, Arch. Biochem. and Biophys.
90 154 (1960).
^'* Miklos Bodanszky, John Timothy Sheehan, Josef Fried, Nina J.
WiUiams and Carolyn A. Birkheimer, 7. Am. Chem. Soc. 82 4747
(1960).
i"S. Takemura, Chem. & Pharm. Bull. (Tokyo) 8 578 (1960).
1^8 T. Goto, Y. Hirata, S. Hosoya and N. Komatsu, Bull. Chem.
Soc. Japan 30 729 (1957).
yoi
Addendum
—
O—
1
r
1
CH, CH -C— CHo— NH—
1
NH N
1
1
CO—
2— CO—
1
NH
— 0—
HC
-:
— NH—
HC
1
-NH- CO CH,^CH— CH,-
-CH,— CH2— NH2
— OH—
— O— CH C
1
) NH..
— O— CH
HC
1
1
/-ij„
0
2
^n2
.
A new polypeptide antibiotic, glumamycin, has been
reported.^" It consists of colorless powder, m.p. 230°
(dec), mol. wt. ^1800 and is composed of 4-isotri-
decenoic acid, CsHi7CH=CHCoH4— COOH, L-aspartic
acid, glycine, L-valine, L-proline, D-pipecolic acid and
a,/3-diaminobutyric acid.
A number of compounds listed in the unclassified sec-
tion are known to be or thought to be polypeptides.
These include alboverticillin, antibiotic B-456, bacilipins,
bacillomycins, bacilysin, datemycin, diplococcin, dista-
mycin A, laterosporin, melanosporin, mikamycins, mito-
mycins, monilin, mycospocidin, phleomycin, pluramycins,
racemomycins, ractinomycins, roseomycin, taitomycin,
violacetin and undoubtedly others.
18. Heterocycles
C. PYRANS AND RELATED SUBSTANCES
8-Hydroxy-3,4-dimethylisocoumarin has been isolated
from cultures of a wild Oospora specimen.^"'
^'' Michitaka Inoue, Hiroshi Hitomi, Komei Mizuno, Masahiko
Fujino, Akira Miyake, Koiti Nakazawa, Motoo Shibata and Toshihiko
Kanzaki, ibid. 33 1014 (1960).
^'^ I. Yamamoto and Y. Yamamoto, Bull. Agr. Chem. Soc. (Japan)
24 628 (1960).
Pfizer Handbook of Microbial Metabolites 702
A survey has shown that a-tocopherol is the only form
of vitamin E found in bacteria."-' It was found in about
a dozen chlorophyll-containing organisms, although not
in all such bacteria which were studied. Its production
is not limited to any particular type of chlorophyll-con-
taining bacterium. Tocopherol production seemed to
parallel chlorophyll production, and it was suggested that
the same phytol precursor might be used for both.
d. XANTHONES
A labeled precursor investigation of ravenelin by Birch
and associates has shown that orsellinic acid is an inter-
mediate in the biosynthesis of xanthones.^®°
e. COMPOUNDS RELATED TO THIOPHENE, IMIDAZOLE,
THIAZOLE AND ISOXAZOLE
A comparison of the effects of D-cycloserine and of d-
alanine on the incorporation of D,L-alanine-l-C^^ into bac-
terial proteins showed that D-cycloserine acts as a d-
alanine antagonist. ^^^' ^'*-
A paper has been published on the lability of 2-acetyl-
thiazolium salts and in support of the proposed mode of
action of thiamine. ^-^
A paper on the enzymatic formation of thiamine and
phosphate esters of the pyrimidine moiety seems to be
the first of a series on the biosynthesis of thiamine."* A
dissertation on the biosynthesis of the thiazole moiety has
been published."^
i"9 J. Green, S. Price and L. Gare, Nature 184 1339 (1959).
180 Private communication from Herchel Smith.
^^^ P. Barbieri, A. diMarco, L. Fuoco and A. Rusconi, Biochem.
Pharmacol. 3 101 (1960).
182 p Barbieri, A. diMarco, L. Fuoco, P. Julita, A. Migliacci and A.
Rusconi, ibid. 3 264 (1960).
1"-* Ronald Breslow and Edward McNeils, J. Am. Chem. Soc. 82 2394
(1960).
^>** Gerald W. Camiener and Gene M. Brown, J. Biol. Chem. 235
2411 (1960).
"^ J. Vogel, Dissertation, University of Bonn, 1960.
703 Adden(lum
f. PYRROLES, PORPHYRINS AND RELATED COMPOUNDS
A dissertation has been published on a prodigiosin-like
pigment.^'"'
A partial synthesis of vitamin B,;. has been re-
ported/^"' ^'^'^
Guanosine diphosphate factor B and B diphosphate ester
have been indentified as intermediates in the biosynthesis
of vitamin Bio.^"*"
A dissertation has been published on the biosynthesis
of members of the vitamin Bj^. group/"" '"^
A report has been made on the preparation and proper-
ties of purified intrinsic factor. The purified material is
a better Bjo binder than the crude, and it is not a muco-
protein as previously believed.^®*
A publication on the biosynthesis of uroporphyrin III
from porphobilinogen reported that uroporphyrinogen I
is not an intermediate in the biosynthesis of uroporphy-
rinogen UW
A pink pigment identified as coproporphyrin III was
isolated from Mycobacterium tuberculosis avium^^* as it
had been earlier from Mycobacterium karlinski}^^
At least two kinds of chlorophylls have been shown to
be present in green bacteria.'"*^
^^•^ Roswltha Zimmer-Galler, Dissertation, Technische Hochschule,
Miinchen, 1960.
^'*' K. Bernhauer, F. Wagner, Hw. Dellweg and P. Zeller, Helv.
Chim. Acta 43 700 (1960).
iss-yy Friedrich, G. Gross, K. Bernhauer and P. Zeller, ibid. 43
704 (1960).
i**^ G. Boretti, A. dlMarco, L. Fuoco, M. Marnatl, A. Migliacci and
C. Spalla, Biochim. et Biophys. Acta 37 379 (1960).
1"" Fred Sanders, Dissertation Abstr. 18 2189 (1959).
1"^ F. Sanders and Gerald R. Seaman, /. Bacteriol. 79 619 (1960).
"- Leon Ellenbogen and William L. Williams, Biochem. and
Biophys. Res. Comms. 2 340 (1960).
^''■' Lawrence Bogorad and Gerald S. Marks, Biochim. et Biophys.
Acta 41 358 (1960).
^^D. S. P. Patterson, Biochem. J. 76 189 (1960).
195 c. M. Todd, ibid. 45 386 (1949).
^^^ R. Y. Stanier and J. H. C. Smith, Biochim. et Biophys. Acta 41
478 (1960).
Pfizer Handbook of Microbial Metabolites 704
A b-type cytochrome has been isolated from the fungus
Sclerotiana libertiana and identified. ^^^
Protoporphyrin IX has been isolated from bacterial
catalase and characterized. ^^^
Addition of S-aminolevuHnic acid to cultures of pro-
pionibacteria caused large increases in the production of
porphyrins, but no rise in vitamin Bjo production, in-
dicating divergent biosynthetic routes."^
The structure of the antifungal pigment prodigiosin
has been proved by synthesis. -°° It is
OCH
and is thus the second natural product containing a 2,2'-
dipyrrole skeleton, vitamin Bjo being the other.
A streptomycete has been found w^hich produces iso-
butyropyrrothine, orange-red antibiotic crystals, m.p.
228
o . 200a
CH3
/
S- -C=C— NH— CO— CH
sec CH3
C N O
H
CH3
Aureothricin, thiolutin, a colorless base, and a heptaene,
hamycin, also were produced.
^^" Tateo Yamanaka, Takehazu Horio and Kazuo Okunuki, Biochim.
et Biophys. Acta 40 349 (1960).
1"* Steve Miller, Davis Hawkins and Robert P. Williams, /. Biol.
Chem. 235 3280 (1960).
1^^ G. V. Pronyakova, Biokhimiya (English translation) 25 223
(1960).
'°° Henry Rapoport and Kenneth G. Holden, /. Am. Chem. Soc. 82
5510 (1960).
2oo« D. S. Bhata, R. K. Hulyakar and S. K. Menon, Experientia 16
504 (1960).
705 Addendum
g. INDOLES
The structure previously proposed for echinulin has
been confirmed, the only reservation being possible ex-
change of the groups in the 5 and the 7 positions of the
indole nucleus.-''^
926a Lysergic Acid Amide (Ergine), CieHiyONa (Monomethanolate),
m.p. 130-135° (efferv.), resolidifies 140°, m.p. 190° with
previous dec.
926b Isolysergic Acid Amide (Isoergine), CicHi-ONg.
937a Lysergic Acid Methylcarbinolamide, CisHo^OoNg, colorless
prisms, m.p. 135° (dec), [aW +29° ±2° (--1.0 in
dimethylf ormamide ) .
937b Isolysergic Acid Methylcarbinolamide, C18H21O0N3, not crystal-
Une.
A yield of about 2 g. per liter of the above alkaloids was
produced by Claviceps paspali Stevens T. Hall growing in
submerged culture.-"- A partial structure is shown for
the carbinolamide isomer corresponding to lysergic acid:
CH3
NH— C— OH
/ I
0=C H
O
N— CH3
Another new ergot alkaloid, molliclavine, has been
reported : -"^ -"*
-°^ Franco Piozzi, Giuseppe Casnati, Adolfo Quilico and Cesare
Cardani, Gazz. chim. ital. 90 451, 476 (1960).
2"- F. Arcamone, C. Bonino, E. B. Chain, A. Ferrettl, P. Pennella,
A. Tonola and Lidia Vero, Nature 187 238 (1960).
^°^ M. Abe, S. Yamatodani, T. Yamano and M. Kusumoto, /. Agr.
Chem. Soc. Japan 34 249 (1960).
^''^M. Abe and S. Yamatodani, Bull. Agr. Chem. Soc. (Japan) 19
161 (1955).
Pfizer Handbook of Microbial Metabolites 706
930a Molliclavine, CieHjgOoNo, colorless crystals, m.p. 253° (dec),
[a]i>'' +30° (c 1.0 in pyridine).
Claviceps purpurea
An antibiotic of novel structure incorporating an indole
nucleus is:
391b PA-155A, C14H15O2N3, colorless crystals, m.p. 209°, [ajp^^ -214°
(c 2.0 in methanol), U.V. 218, 273, 281, 288 m/x.
No reaction with dinitrophenylhydrazine. Negative
ninhydrin, FeCl^ tests. Blue Ehrlich's test. Decolorizes
Br2, KMn04. Streptomyces alhus''^' "'^^
i. PYRIDINES
The plant toxin, fusaric acid, was produced when
Fusarium oxysporum var. lini was grown on artificial
medium or on non-resistant flax tissues, but not when
the fungus was grown on resistant strain tissues. -°'^
A dissertation has been pubUshed on dipicolinic acid
formation and other chemical aspects of bacterial sporula-
tion.-"^
The mononucleotide of nicotinic acid has been isolated
from a fusarium specimen^°^ and from a yeast.-"*
k. PYRAZINES, DIKETOPIPERAZINES
Several diketopiperazines have been isolated from the
fungus Rosellinia necatrix Berlese.-"'' They are L-prolyl-
^•'' Koppaka V. Rao, Antibiotics and Chemotherapy 10 312 (1960).
''^" Manfred von Schach, private communication.
205 E. J. Trione, Phytopathologij 50 480 (1960).
2''« Herbert M. Nakata, Dissertation Abstr. 20 3020 (1960).
2"' A. Ballio and S. Russi, Arch. Biochem. and Biophys. 85 567
(1959).
2'« R. W. Wheat, ibid. 85 567 (1957).
2"»Yu-Shih Chen, Bull. Agr. Chem. Sac. (Japan) 24 372 (1960).
70? Addendum
L-leucine anhydride, L-prolyl-L-valine anhydride and an
apparently new diketopiperazine, L-prolyl-L-phenylalanine
anhydride (compound E) Ci^Hi.jO.jN.j, m.p. 127-128°,
[a]..-'" —99.8" (c 1.0 in ethanol). A crystalline wax, m.p.
52°, was isolated from the same culture and assumed to
be n-pentacosane, Co-H-.o. Also an uncharacterized sub-
stance, white needles, m.p. 206-208°, called rosellinic
acid was isolated.
L-Prolyl-L-valine anhydride had been isolated previously
from a streptomycete culture.-^" L-Prolyl-L-leucine anhy-
dride had been isolated both from a streptomycete and
from Aspergillus funiigatus.'^^
Muta-aspergillic acid, C11H18O3N2, pale yellow needles,
m.p. 173° (dec.) (subl.) with alternative structures:
CH3
CH3
/
i
CHo— CH
C— CH;
ch| j CH3
or CH3
\
1 J O"
CH-
-CHo 1 ^0
1 OH
/
OH
OH
CH3
has been reported.-"'
/. PHENAZINES AND PHENOXAZONES
Three new natural phenazines have been reported. ^^^
984b l-Hydroxymethyl-6-carboxyphenazine, C15H12O3N2, light yellow
crystals, m.p. 197-201°.
HOOC
I
.V
CH2OH
210 Y. Koaze, ibid. 22 98 (1958).
-" J. L. Johnson, W. G. Jackson and T. E. Elbe, ] . Avn. Chem. Soc.
73 2947 (1951).
2"' Seiji Nakamura, Bull. Agr. Chem. Soc. (Japan) 24 629 (1960).
2i2Koki Yaglshita, J. Antibiotics (Japan) 13A 83 (1960).
Pfizer Handbook of Microbial Metabolites 708
985a l-Methoxy-4-methyl-9-carboxyphenazine, C16H14O3N2, yellow
needles, m.p. 124-126°.
HOOC
984a l-Methoxy-4-hydroxyniethyl-9-carboxyphenazine (Griseolutic
Acid) C15H12O3N.
CH2OH
All of these compounds were Isolated from a culture of
Streptomyces griseoluteus.
An unclassified streptomycete produced two substances
which were named questiomycins A and B.-^^ These
have been identified as :
977a 6-Aminophenoxazone (Questiomycin A) CisHgOgNo, red crys-
tals, m.p. 241-244° (dec.) subl. from 150°.
NH2
o
377a 2-Aminophenol (Questiomycin B), colorless crystals, m.p. 170-
175° (subl. 120°).
NH2
OH
The suggestion was made that the aminophenol might be
the precursor of the aminophenoxazone.
A purple and a yellow pigment isolated from Brevibac-
^^^ Kentaro Anzai, Kiyoshi Isono, Kazuhiko Okuma and Saburo
Suzuki, ibid. 13A 125 (1960).
yog Addendum
teniim crystalloiodimim Sasaki, Yoshida et Sasaki have
been identified as iodinin and 1,6-dihydroxyphenazine,
respectively.-^*
m. PYRIMIDINES
Two dissertations have been pubhshed on the bio-
synthesis of pyrimidines, one with rat Uver enzymes,^^'
the other with Neurospora crassa.'^^'^
Thymidine diphosphate mannose (as well as the pre-
viously reported thymidine diphosphate rhamnose) has
been isolated from cultures of Streptomyces griseus.^^''
It is possible that this substance is an intermediate in
the biosynthesis of streptomycin B (o(-T>-mannopyranosyl-
streptomycin) which is produced by this organism along
with streptomycin.
Tritium labeling experiments indicated that in the
case cited, at least, the epimerization of N-acetylglu-
cosamine to N-acetylmannosamine, probably by way of
uridine diphosphate N-acetylglucosamine, does not in-
volve oxidation to a ketosugar, followed by stereospecific
reduction. -^^^
The structure of tubercidin, C11H14O4N4, m.p. 247''
(dec), [alo^' —62°, produced by Streptomyces tubercidi-
cus and active against Mycobacterium tuberculosis and
Candida albicans, has been reported to be:-^**"
NH2
I
4-amino-7-[D-ribofuranosyl]-
pyrrolo-[2,3-d]-pyrimidine
^
-N-^
D-ribose
Toyocamycin has a similar structure. ^^^^
2^*Tosi Irle, Etsuro Kurosawa and Iwao Nagaoka, Bull. Chem.
Soc. Japan 33 1057 (1960).
215 Richard L. Stambaugh, Dissertation Abstr. 20 64 (1959).
2i6Kamala P. Chakraborty, ibid. 20 3044 (1960).
21" J. Baddiley and N. L. Blumson, Biochim et Biophys. Acta 39
376 (1960).
218 Luis Glaser, ibid. 41 534 (1960).
218" Saburo Suzuki and Shingo Marumo, J. Antibiotics (Japan)
13A 360 (1960).
218" Kazuhiko Ohkuma, ibid. 13A 361 (1960).
Pfizer Handbook of Microbial Metabolites 710
72. PURINES
Guanosine diphosphate glucose and guanosine diphos-
phate fructose are produced by Eremotheciiim ashbyii.^^^
A dissertation reports the isolation of a new guanine de-
rivative from a riboflavin producer."""
A new purine riboside has been isolated from fusarium
species.'-^ It has been assigned the provisional struc-
ture:
2-( 1 -Carboxyethylamino )-6-hydroxy-9-D-ribofuranosyl-
purine
OH
CH;,— CH— HN
COOH
H:03P— O— CH,
OH OH
Nebularine (9-/?-D-ribofuranosylpurine), produced by
Agaricus nebularis, has been isolated from a strepto-
mycete.--^"
The nucleotides of Aspergillus oryzae have been char-
acterized.---
The mechanism of action of the antibiotic, psicofura-
nine, against Staphylococcus aureus has been studied. ^'^
A possible effect may be interference with the biosynthe-
sis of guanylic acid from xanthylic acid.
219 H. G. Pontis, A. L. James and J. Baddiley, Biochem. J. 75 428
(1960).
220Usama A. S. Al-Khahdi, Dissertation Abstr. 21 (1960).
"1 Alessandro Ballio, Carlo Delfini and Serena Russi, Nature 186
968 (1960).
'"'" Kiyoshi Osono and Saburo Suzuki, /. Antibiotics (Japan) ISA
270 (1960).
*'-- Kazuo Okunuki, Kozo Iwasa, Fumio Imamoto and Tadayoshi
Higashiyama, /. Biochem. (Tokyo) 45 795 (1958).
"•''Ladislav J. Hanka, J. Bacterial. 80 30 (1960).
yii Addendum
The antibiotic, mitomycin C, blocks DNA synthesis
completely in EschericJiia coli, but does not interfere with
RNA synthesis or protein synthesis."' Phage-infected
bacteria continued DNA synthesis, but no infective par-
ticles were produced when high concentrations of mito-
mycin were present.
A new incompletely characterized electron transport
component has been isolated from Mjicohacterium phleip-^
The mode of inhibition of electron transport by anti-
mycin A has been studied.--''
Evidence has been published for participation of a vic-
dithiol in oxidative phosphorylation.'--'
A review of ion transport and respiration has been pub-
lished."''
ATP can replace light in bacterial photosynthesis. This
discovery was made with the use of the obligate photo-
troph chromatium. An acetate medium is adequate, and
carbon dioxide is not required. ^-^
The biosynthesis of nucleic acids has been reviewed. ^^^
The biosynthesis and interconversions of purines and
their derivatives have been reviewed. ^^^
0. PTERIDINES AND FLAVINES
The prosthetic group of a chromoprotein from myco-
bacteria may be a pteridine.^"*^
In the fly, Drosophila melanogaster, labeling studies
indicate that glucose carbon atoms are specifically in-
--■* M. Sakiguchi and Y. Takagi, Biochim. et Biophys. Acta 41 434
(1960).
--=W. B. Sutton, Federation Proc. 19 31 (1960).
"«A. L. Tappel, Biochem. Pharmacol 3 289 (1960).
"' Arvan Fluharty and D. R. Sanadi, Proc. Nat. Acad. Sci. U.S.A.
46 608 (1960).
228 R. N. Robertson, Biol. Revs. 35 231-265 (1960).
22^ M. Losada, A. V. Trebst, S. Ogata and Daniel I. Arnon, Nature
186 753 (1960).
2'"' Arthur Romberg, Reviews of Modern Physics 31 200-209
(1959).
-•''^ Albert G. Moat and Herman Friedman, Bacteriol. Revs. 24 309
(1960).
232 F. B. Cousins, Biochim. et Biophys. Acta 40 532 (1960).
Pfizer Handbook of Microbial Metabolites 712
corporated into pteridines, but not into purines produced
by the organism. ^^^
The structure of "active formaldehyde" (N^N^°-methyl-
enetetrahydrofolic acid) has been proved by synthesis. ^^*
19. Unclassified Metabolites
Streptolydigin probably contains 4 carbon-carbon dou-
ble bonds conjugated v\dth a ^-diketone system. -^'^ It also
contains at least four hydroxyl groups, at least four C-
methyl groups and at least one amide group. Methyla-
mine was a base hydrolysis product of tetradecahydro-
streptolydigin.
Griseoviridin, empirical formula C22Ho9±207N3S, prob-
ably consists of three moieties. ^^'^ A 6 carbon atom frag-
ment has been identified as:
and the sulfur atom may be attached at the X-position.
The probable structure of a methanolysis product of
carzinophilin has been published. ^^^ It is:
Methyl 1 -methyl- 7-methoxynaphthalene-6-carboxylate
CH3
CH3O
CH3OOC
Mikamycin should be classified as a polypeptide of the
etamycin type. L-Proline and glycine have been char-
acterized in a hydrolysate. A monoacetate, a di-2,4-
dinitrophenylhydrazone derivative, and a decahydro de-
"3 O. Brenner-Holzbach and F. Leuthardt, Helv. Chim. Acta 42
2254 (1959).
-•^* M. J. Osborn, P. T. Talbot and F. M. Huennekens, J. Am. Chem.
Soc. 82 4921 (1960).
-^'^ Jerome Allen Course, Dissertation, Univ. of Illinois, 1959.
236 p. de Mayo and A. Stoessl, Can. J. Chem. 38 950 (1960).
237 Masao Tanaka, Teruo Kishi and Yoshiki Maruta, /. Antibiotics
(Japan) 12B 361 (1959).
713 Addendum
rivative have been prepared. The melting point of the
yellow crystals is given as 178° (dec.)-^"
Russian antibiotic 6613 may be identical with eta-
mycin.^^^
Monamycin, CooH3f5_3sO..^N, needles, m.p. 126°. Mono-
hydrochloride: m.p. 187°, [a],/^ -62 ±5° (c 0.9 in
ethanol), containing 1 N — CH;,, 3 C — CH;^ groups, no
U.V., I.R. suggestive of amide links, has been isolated
from Streptomyces jamaicensis n. sp.-*°
Teruchiomycin, Co.sH^^OioN, needles, m.p. 202-204°
(dec), a new antibiotic from Streptomyces antibioticus
has been reported."*^
A new acidic antibiotic, C-159, U.V. max. 345, 260,
280 mix, C 58.7, H 7.4, D 24.0, N 9.9% has been pat-
ented.-^-
The blue intracellular pigment of Pseudomonas lemon-
nieri has been isolated, purified and characterized.^*^
A preliminary investigation has been made of the pig-
ments of Trichophyton rubrum.^**
Rubidin, a quinoid dark red powder with acid base
indicator properties, U.V. 320, 415, 490 m^x in butanol,
C 51.9, H 5.56, O 42.54, positive FeCly and zinc dust
tests, is a substance isolated from an unclassified strep-
tomycete.-*^
A new antibacterial antibiotic has been reported. ^*^ It
had the following properties: yellow needles, m.p. 134°,
mol. wt. 397, U.V. maxima at 328.5, 314.5, 298.7 m/x.
Positive Millon, Liebermann, Schiff, FeClg and NH3-
AgNO^ tests. Probably C22H22O7 with hydroxyl, methyl
and 2 ketone groups present.
238Koichi Okabe, ibid. 12A 86 (1959).
239 M. Brazhnikova et al., Antibiotics (USSR) 4 414 (English
translation) (1959).
2*°C. H. Hassall and K. E. Magnus, Nature, Suppl. 184 1223
(1959).
241 H. Umezawa et al., Japanese Patent 850 (1958).
2*2 British Patent 814,794 (1959).
243 Werner Blau, Gladys Cosens and Mortimer P. Starr, Bacteriol.
Proc, 153 (1960).
2^Malati Bacchwal and G. C. Walker, Can. J. Microbiol. 6 383
(1960).
245 A. K. Banerjee, G. P. Sen and P. Nandi, "Antibiotics Annual
1955-1956," Medical Encyclopedia, Inc., New York, p. 640.
246Thadee Staron and Albert Faivre-Amiot, Compt. rend. 250 1580
(1960).
SUBJECT INDEX
Bold-faced numbers indicate primary microbial metabolite
entries, while Arabic numbers signify incidental mention under
such entries. Italic numbers are page numbers, and generally
indicate occurrence in a chapter or section introduction. The
appendixes and addendum are not indexed.
Abikoviromycin, 1183
Aburamycin, 1064
Acetaldehyde, 14, 17, 72, 466,
480
Acetate, 17, 48, 52, 80, 81, 91,
120, 144, 154, 155, 159,
160, 182, 187-189, 212,
232, 236, 239, 273-275, 299,
312, 398, 400, 420, 447, 555
2-C^*- Acetate, 182,274
Acetic acid, 17, 46, 69, 72, 82, 275
l-C^^- Acetic acid, 159, 182
Acetic acid (C"-labeled), 233,
236, 411
Acetoacetate, 80, 93, 190
Acetoacetyl coenzyme A, 17, 93,
155
Acetoin, 15, 17, 19, 557-560
a-Acetolactic acid, i5, 3i5
Acetomycin, 82, 150
Acetone, 18, 466
Acetopyrro thine, 914
4-Acetoxycycloheximide, 304, 309,
316
4-Acetoxyheximide, 305
Acetyl coenzyme A, 15-17, 47,
48, 53, 54, 93, 155, 424, 447
Acetylcholine, 466, 654
2-Acetyl-2-decarboxamidooxytet-
racychne, 275, 612
5-Acetyldihydrolipoic acid, 16
0-Acetyleburicoic acid, 360
Acetylenedicarboxylic acid, 108
Acetylenic acids, JOS, J 09
compounds, 107, 427
N-Acetyl-D-glucosamine, 344, 345
6-0-Acetylglucose, 37
N-Acetylmuramic acid, 343
N-Acetylneuraminic acid, 344
N-Acetyltyramine, 407
Achromycin, 613
Acidomycin, 899
Aconitase, 46
cis-Aconitic acid, 47, 49, 92
Actidione, 308
Actilin, 63
Actinobolin, 1065
Actinochrysin, 764
Actinocinin, 335, 336, 502
Actinoleukin, 1066
Actinomycin, 123, 742, 764, 770
Actinomycin I, 805
II, 811
III, 812
IV, 794
V, 803
VI, 795
VII, 793
Actinomycin B^, 794
B.., 803
C„ 794
C, 795
C.,„ 795
C3, 336, 338, 793
D, 794
El, 796
Eo, 797
Fi, 798
Fo, 799
F,, 800
F4, 801
Ii, 794
Jo, 12
nomenclature, 381, 382
Xo^, 805
X„. , 806
Xo,„ 807
Xi, 794
Pfizer Handbook of Microbial Metabolites
716
Actinomycin Bi
Xia, 802
Xo, 803
X3, 804
Zn, 808
Zi, 809
Actinomycins, 334-338, 381,
382, 1001, 1132, 1214, 1250,
1260
Z, 808
Zo, Z3, Z4, 809
Z„ 810
Actinorhodin, 234, 526, 529
Actinorubin, 737
Actiphenol, 306
Actithiazic acid, 426, 899
Active acetaldehvde, 315, 423,
559, 560
amino acids, 534
carbon dioxide, 526
formaldehyde, 549, 552, 553
formate, 549, 551
succinate 312,423
Active sulfate, 524, 525
Acyl adenylates, 525
Acyl coenzyme A, 525
Acyldehydrogenase, 53, 92
Adenine, 318, 442, 445, 483,
508-510, 529, 551, 559,
1026, 1044
Adenine-S-C^*, 557, 558
nucleoside, 445, 535
nucleotide, 526, 527
Adenosine, 1033
diphosphate (ADP), 14, 47,
54, 55, 92, 333, 450, 524,
530, 531, 535, 536, 560,
562, 564, 1038
diphosphoryl biotin, 55
-2'-phosphate, 1036
-3'-phosphate, 1037
-5'-phosphate (AMP), 53, 318,
510,530, 533, 1038
-3'-phospho-5'-phosphosulfate,
524, 525
triphosphate (ATP), 14, 47,
53-55, 92, 93, 291, 311-
313, 318, 333, 345, 425,
450, 511, 514, 515, 524-
Adenosine
526, 530, 53 J, 533, 535-
537, 1040
-5'-triphosphate, 1040
5-Adenosylhomocysteine, 553
S-Adenosylmethionine, 31 J, 525,
553
Adenosyl-5'-phosphoryl carbonate,
526
Adenylic acid, 345, 533
Adenylic acid a, 1036
3-Adenylic acid, 1037
Adenylic acid-pantoate complex,
334
Adenylo-p-aminobenzoic acid, 556
Adenylosuccinic acid, 533, 1044
Aerosporin, 780
Agaric acid, 120
Agaricic acid, 49, 120
Agaricin, 120
AgaricoHc acid, 355
Agmatine, 466
Agroclavine, 471, 944
Agrocybin, 190
Akitamycin, 1067
Aklavin, 616
Alanine, 290, 300-302, 304, 305,
309, 340-343, 435, 497, 501,
725, 756, 757, 766, 769,
773, 789, 813, 815-818, 822,
828, 829, 831, 839-841, 849,
1079
/?- Alanine, 300, 303, 309, 310,
333, 470, 535, 666, 726
D-Alanine, 310, 343, 345
L-Alanine, 343, 665, 704, 790
D-Alanine-D-glutamate aminopher-
ase, 488
D-Alanyl-D-alanine, 345, 422
Alazopeptin, 725
Albamycin, 885
Albidin, 1068
Albofungin, 1069
Alboleersin, 579
Albomycetin, 1070
Albomycin, 765, 766
Alboverticillin (hydrochloride),
1071
Alcohol, 15, 17
717
Subject Index
Alcohol dehydrogenase, 13
Alcohol fermentation (yeast), 13
Aldehydes. 564
Aldolase, 13
Aldol condensations, 16
Alectoronic acid, 187
Alicyclic compounds, 142
Aliomycin, 1072
Alkaloid biosynthesis, 459, 467-
472
Allantoic acid, 672
Aliomycin, 1022, 1073
Allophanic acid, 55
Alternaric acid, 116
Alternarine, 1074
Alternariol, 151, 185, 414, 419,
420
methyl ether, 151, 415
Altenuic acid I, 151,420
II, 151, 421
III, 151, 422
Altenusin, 151, 419
Altertenuol, 151, 416
Althiomycin, 1075
Alvein, 830
a-Amanitin, 756
/?-Amanitin, 756
y-Amanitin, 756
Amaromycin, 259
Amebacillin, 318
Amethopterin, 422
Amicetin, 21, 346, 671, 1022
B, 1020
Amide, 922
Amidomycin, 747-750, 758, 767
Amines, 290, 458, 564
Aminoacetone, 642
Amino acid decarboxylase, 485
Amino acid from Lactarius hel-
vus, 710
Amino acid racemase, 485
Amino acids, 284, 290, 299, 508
D-Amino acids, 345, 564
Amino acids (activated), 345
Amino acids (intracellular), 304,
305
Amino acid transport, 488
a-Aminoadipic acid, 301, 312
L-a-Aminoadipic acid, 694, 724
D-a-Aminoadipic acid, 421, 911
a-Aminoadipic acid e-semialde-
hyde, 3J2
S- ( a-Aminoadipyl ) cysteinylvaline,
42 J, 724
p-Aminobenzoic acid, i43, 53 J,
556, 557, 699, 1059
p-Aminobenzoylglutamic acid, 556
a-Aminobutyric acid, 341, 739,
751, 755
y-Aminobutyric acid, 300, 303,
342, 501, 673, 829
D-a-Aminobutyric acid, 704, 755
L-( + )-3;-Aminobutyric acid, 674
l-Amino-3,6-desoxyhexose, 29J
2-Amino-4,7-dihydroxypteridine-
6-acetic acid, 1049
3-Amino-l ,8-dimethylphenoxan-2-
dicarboxylic acid-4,5, 788
/:?-Aminoethanethiol, 535
2-Aminohexose reactions, 23, 64
2-Amino-4-hydroxy-6-hydroxy-
methylpteridine, 556
2-Amino-4-hydroxypteridine-6-
carboxaldehyde, 556
4-Amino-4-imidazolecarboxamide
riboside, 53 J, 898
5-Amino-4-imidazolecarboxamide
ribotide, 551
5-Amino-4-imidazolecarboxylic
acid ribotide, 53 i
Aminoimidazole ribotide, 53i
5-Amino-4-imidazole-N-succino-
carboxamide ribotide, 53i
a-Aminoisobutyric acid, 726
D-4-Amino-3-isoxazolidone, 894
8-Aminolevulinate synthetase, 485
5-Aminolevulinic acid, 435, 437,
444, 550
a-Aminomethyl-o!,/?-trans-,y,8-cis-
muconic acid, 483
2-Amino-4-methyl-5-oxy-3-pente-
noic acid, 756
2-Amino-4-methyl-3-pentenoic
acid, 757
l-Amino-2-methyl-2-propanol, 649
2-( l-Amino-2-methylpropyl)
thiazole-4-carboxylic
acid, 762
Pfizer Handbook of Microbial Metabolites
718
2- Amino-6-oxy purine, 508
6-Aminopenicillanic acid, 418,
419, 421, 897
a-Amino-^-phenylbutyric acid, 760
5- Amino- 1 -d- ( 5'-phosphoribosyl )-
4-imidazolecarboxamide, 318
6-Aminopurine, 508
l-Aminoribose-5'-phosphate, 530
p-Aminosalicylic acid, 53J
Amino sugars, 22, 120, 308
Ammonia, 290, 291, 308, 309,
466, 515, 533, 637, 729-31,
762
Amosamine, 21
Amphomycin, 833, 835
Amphotericin, 249
Amphotericin-A, 122, 233
Amphotericin-B, 20, J 22, 248
iso- Amylamine, 466
Amytal, 449
Anaerobic glycolysis, 13, 15
Anasterol, 333
Aneurin, 903
Aneurindiphosphate, 904
Angolamycin, 291
Angustmycin A, 21, 1041
C, 1042
N\N^"-Anhydroformyl tetrahydro-
folic acid, 530
Aniline, 502
Anisaldehyde, 284, 427, 619
Anisic acid, 284
Anisomycin, 1076
Anthranilic acid, 143, 186, 317,
458, 460, 492, 493, 502, 698
Anthranols, 232
Anthraquinone pigment from Gib-
berella fujikuroi, 534
Anthraquinones, i85, 190, 212,
231-233, 254, 273
bis-Anthraquinones, 2 J 4, 234
Anthrones, 232
Antibiotic 26/1, 1097
Antibiotic 289, 577
Antibiotic 446, 1098, 1197
Antibiotic 587 13, 1100
Antibiotic 720-A, 1099
Antibiotic 899, 832
Antibiotic 1037, 1101
Antibiotic 1968, J 22
Antibiotic 6270, 1102
Antibiotic 6706, 1103
Antibiotic A 246, 229, 1077
Antibiotic B-456, 1078
Antibiotic C-159, 1079
Antibiotic D-13, 1080
Antibiotic E-212, 1081
Antibiotic E.F. 185, 63
Antibiotic from Bacillus cepae,
1090
Antibiotic from Bacillus pumilis,
1091
Antibiotic from Monosporium bo-
norden, 1092
Antibiotic from Penicillium spin-
ulosum, 1093
Antibiotic from Streptomyces abi-
koensis, 1094
Antibiotic from Streptomyces fun-
gicidicus, 1095
Antibiotic from Streptomyces gris-
eus, 1096
Antibiotic HA-9, 1295
Antibiotic I.C.I. 13,959, 726
Antibiotic LA-7017, 1082
Antibiotic M-4209, 1083
Antibiotic PA-93, 885
Antibiotic T, 1085
Antibiotic X-206, 1086
Antibiotic X-340, 611
Antibiotic X-464, 1087
Antibiotic X-465A, 439
Antibiotic X-537A, 1088
Antibiotic X-1008, 1089
Antibiotic Y, 828
Antibiotic Yo, 829
Antibiotic from yeast, 828, 829
Antifungal substance, 1104
Antifungal substance produced by
Streptomyces strain No. 1037,
1105
Antimycin A, 238, 449, 848
A, 269
A.,„, 270
A„„ 271
A,, 272
A4, 273
Antimycoin, 122, 237
719
Anziaic acid, 477
Aquamycin, 5
d-Ai-abi'tol. 22
Arachidic acid, 50
Arachidonic acid. 5 J
Arginine, 300, 301, 303, 305, 308,
309, 340-342, 821, 822, 824,
830, 844, 845, 1145
L-Arginine, ()96
Argininosuccinate, 308
Argomycin, 110()
Aromatic amino acids, 143
compounds, 286
Ascorbic acid, 79, 82, 143, 460
biosynthesis, 82
Ascorbigen, 460
Ascosin, J 22, 256
Ascosterol, 343
Asparagine, 300, 303, 309, 815
D-Asparagine, 814
L-Asparagine, 669, 791, 792
Aspartate aminopherase, 488
Aspartic acid, 290, 300, 301, 303,
304, 308, 309, 311-313, 315,
340-342, 424, 516, 531, 533,
768, 769, 773, 813, 816-821,
824, 826, 831, 836-839, 841,
844, 845, 1078, 1079
L-Aspartic acid, 514, 668, 814, 834
Aspartic /?-semialdehyde, 311
Aspartic transcarbamylase, 5i4
Aspartocin, 445, 834
^-Aspartyl phosphate, 311
Aspelein, 1107
Aspergillic acid, 497, 987, 988
AspergilUn, 938
Asperthecin, 547
Asperxanthone, 890
Astacin, 162
Asterric acid, 191
Aterrimin A, 1109
B. 1109
(ATP), adenosine triphosphate, 14,
47, 53-55, 92, 93, 291, 311-
313, 318, 333, 345, 425, 450,
511, 514, 515, 524-526, 530,
531, 533, 535-537, 556, 560-
562, 564, 1040
Subject Index
(ATP), adenosine triphosphate
-phosphoglyceric transphospho-
rylase, 13
-phosphopyruvic transphospho-
rylase, 13
synthesis, 449, 450
Atranoric acid, 460
Atranorin, 460, 857
Atromentin, 235, 505
-3,6-dibenzoate, 509
Atrovenetin, 185, 570
Aurantiacin, 509, 511
Aurantiogliocladin, 236, 498, 512
Aureomycin, 608
Aureolic acid, 1110
Aureothin, 870
Aureothricin, 434, 870, 916, 1141
Aurofusarin, 584, 888
Auroglaucin, 107, 108, 189, 190,
435
Avenacein, 748
Avidin, 423
Ayfactin, J 22
Ayfivin, 814
Azafrin, 160
Azalomycin B, 1111
F, 1112
Azaphilones, 879
Azaserine, 532, 678
Azomycin ( 2-nitroimidazole ) , 893,
1197
B-73, 304, 309
Baccatine A, 1113
Bacilipin A, 1114
B, 1115
Bacillomycin, 836
A, 836
B, 837
C, 838
R, 836
Bacilysin, 1116
Bacitracin, 343
A, 814
B, 814
C, 814
D, 814
E, 814
F, 814
Pfizer Handbook of Microbial Metabolites
720
Bacitracin
Fo, 814
Fs, 814
G, 814
Bacterial carbohydrates, 338
cell walls, 310, 314, 332, 343,
344, 345, 422, 479, 514
fats, 51
pigments, 434
polysaccharides, 528
proteins, 345
spores, 310, 314
Bacteriochlorophyll a, 930
Bacterioerythrin, 181
Bacteriophage, 332, 344, 508, 509
Bacteriopurpurin, 181
Baeomycesic acid, 461
Bamicetin, 1021
Barbatic acid, 464, 861
Barbatolic acid, 452
Basidioquinone, 238
Batatic acid, 854
Behenic acid, 50
Benzimidazole, 442, 446
Benzoic acid, 618
Benzoquinones, 185, 239
Betaine, 683, 311, 466
Biformin, 196
Biformyne 1, 1117
Binaphthyls, 214
Biocytin, 426, 912
Bioluminescence, 564
Biomycin, 608
Biopterin, 555, 1051
Biotin, 54, 55, 92, 423, 424-426,
447, 471, 526, 531, 532, 900
Biotin- 1 -sulfoxide, 901
Biphenyls, 2i4
Bixin, 107
Blasticidin A, 1118
B, 1119
C, 1120
S, 1121
Blastmycin, 185, 272
B-Mycin, 760
Boletol, 537
Bongkrekic acid, 128
Boninic acid, 483
BorreUdin, 1122
Bostrycoidin, 522
Bottromycin, 760
Brevin. 826, 827
Brevolin, 827
Bromogriseofulvin, 186, 431
Bromotetracycline, 609
Bryamycin, 840, 1292
Bufotenin, 661
2,3-Butanediol, 15, 19
n-Butanol, 17, 18
Butterfly wing pigment, 554, 1048
iso-Butylamine, 466
Butyryi coenzyme A, 54
C-73, 291, 305, 295, 309
Cadaverine, 466
Caerulomycin, 1123
Caldariomycin, 143, 144, 293
Calycin, 630
Camphomycin, 1124
Candicidin A, 253
B, 254
C, 255
Candicidins, 122, 253
Candidin, J 22, 252
CandiduUn, 1125
Candimycin, 122
Canescin, 1126
Canthaxanthin, 163
Caperatic acid, 49, 80, 81, 118, 159
Caperin, 154
Capraric acid, 451
N-Carbamyl-L-aspartic acid, 514
Carbamyl phosphate, 308, 514
0-Carbamyl-D-serine, 671
Carbomycin, 21, 119, 121, 283
B,21, 119, 282
Carbon dioxide, i4-J8, 47-49, 54,
55, 92, 93, 292, 423, 424,
447, 526, 527, 53 J, 536, 550,
554, 558, 729, 731, 739
l-Carboxy-2,5-dioxybenzyl methyl
ketone, 402
l-Carboxy-2,5-dioxyphenyl acetyl
carbinol, i 85, 403
Carboxylase, 13
Carboxylation, 55
4-Carboxy-2-oxo-3-phenyLhept-3-
enedioic acid, 628
721
Subject Index
3-Carboxy-2,4-pentadienal lactol,
82, in
N- ( 2-Carboxypheny 1 ) - 1 -aminori-
bose-5-phosphate, 317, 459
Carcinocidin, 848
Carcinomycin, 847
Cardelmvcin, 885
Cardinophyllin, 1127
Carimbose, 283
Garlic acid, 148
Carlosic acid, 79, 145, 149
Carolic acid, 79, 146
Carolinic acid, 147
a-Carotene, 164
^-Carotene, 91, 161, 162, 165, 185,
186
8-Carotene, 167
y-Carotene, 94, 161, 166
TT-Carotene, 176
Carotene biogenesis, 90-94
Carotenes, 90, 93, 107
Carotenoids, 90, 94
Carviolacin, 559
Carviolin, 558
Carzinophilin, 1127
A, 1128
Catenarin, 528, 541, 542, 546, 587
6-methyl ether, 560
Catenulin, 61
Cathomycin, 885
Cell tissues, 22
walls, 22
CDP-Choline, 1016
Celesticetin, 120, 923
I, 120, 258
Celiomycin, 727
Cellocidin, 5
Cellulose, 512
Cephalin, 1016
Cephalins, 56, 135
Cephalosporin C, 421. 367, 911
N, 312, 367, 42i, 724, 905
P, 368, 368
Po, 369
P3, 370
P4, 371
Cercosporin, 589
Cerevioccidin, 1129
Cerevlsterol, 344
Cerinic acid, 124
Cerotic acid, 124
Cetyl alcohol, 47
Chaetoalbin, 592
Chaetochrysin, 590
Chaetoflavin, 591
Chaetomidin, 501
Chanoclavine, 47J, 954
Chartreusin, 439
Chartreusin-like antibiotic, 440
Chetomin, 941
Chitin, 512
Chitosamine, 33
Chlamydosporin A, 1130
B, 1131
Chloramphenicol, 284, 342, 343,
626
Chlorine-containing peptide
CssHaeO.N.Clo, 751
Chloroatranorin, 459, 489
7-Chloro-5a( 1 la)-dehydrotetra-
cycline, 607
7-Chloro-6-demethyltetracycline,
602
8-Chlorolevulinic acid, 143, 144
Chloromycetin, 626
Chlororaphine, 999
Chlortetracycline, 608, 613
Cholesterol, J 54
Choline, 135, 311, 466, 554
Choline phosphate, 56
Chohne sulfate, 686
Chromin, 122
Chromomycin A3, 1132
Chrysergonic acid, 535, 1133, 1152
Chrysocetraric acid, 632
Chrysomycin, 1134
Chrysophanic acid, 539
Chrysophanol, 538, 539, 592
Cinerubin A, 617
B, 617
Cinerubins, 276, 606, 617
Cinnabarin, 335, 502, 1001
trans-Cinnamic acid, 620
amide, 621
Cinnamycin, 420, 816, 820, 821
CircuHn A, 776
B, 777
Circulins, 776
Pfizer Handbook of Microbial Metabolites
722
Citreorosein, 545
Citric acid, 47, 48, 83, 95, 233, 466
cycle, 46-49, 92, 93, 307, 309,
445, 447, 561
Citrinin, 411, 872
Citromycetin, 185, 190, 410, 411,
873
Citrovorum factor, 1059
Citrulline, 303, 308, 423
Cladinose, 20, 278, 279
Clavacin, 867
Clavatin, 867
Clavatol, 405
Clavicepsin, 48, 466
Claviformin, 867
Clavine alkaloids, 470
Clavorubin, 535
Clavoxanthin, 553
Cleavage enzyme, 53
Clitocybin, 1135
Cobalt, 445, 446
Cobamic acid, 442
Cobamide, 442, 444
Cobamide coenzyme, 446
Cobamide-containing polypeptides,
444
Cobamine cyanide, 931
Cobinic acid, 442
Cobyrinic acid, 441
a,b,c,d,e,g-hexaamide, 442
Cobyrinic acid pentamide, 442
Cocarboxylase, 904
Coccellic acid, 464
Coelicolorin, 1136 _
Coenzyme A, 16, 47, 52, 53, 56,
310, 527, 535, 556, 1046
biosynthesis, 535-537
Coenzyme 111 (nicotinamide ribose
5'-diphosphate), 974
Q^„ 237, 238, 512
Q-, 237, 238, 513
Q.^, 237, 238, 514
Qg, 237, 238, 515
Qio, 237, 238
Coenzymes Q, 236-239, 247, 449,
512
Coliformin, 841
Colimycin, 825
Colistin, 771
oi-Collatolic acid, 488
Collinomycin, 1137
Comenic acid, 406, 863
Comirin, 824
Compound A, 551, 1052
CsHi40, 46
C9H10O7N2 from Fusarium lyco-
persici, 715
CiiH.-.OgNo, 1138
Ci.Ho^Oo, 46
D, 393
I, 823
T, 376
Condensing enzyme, 46, 93
Congocidine, 918
Coprinin, 493
Coproporphyrin, 396, 437
I, 927
111, 438, 928
Coproporphyrinogen, 438
Cord factor, 52, 55, 139
Cordycepic acid, 300
Cordycepin, 2 J, 1032
Cordycepose, 21
Corphyrin, 445
Corrin ring, 440
Corticrocin, 219
Cortisalin, 223
Corynine, 137, 55
Corynomycolenic acid, 131
Corynomycolic acid, 54, 55, 121
132
Costaclavine, 952
Cosynthetic factor-1, 1139
Coupled phosphorylation, 449
Cozymase 11, 904
2, 6-Cresotic acid, 389
Croceomycin, 1140
Crocetin, J 07
Crotonic acid, 160
Cryptosterol, 352
Cryptoxanthin, 171
Cryptoxanthol, 171
Crystallinic acid, 885
Culmorin, 889
Curvularin, 425
Cyanocobalamin, 931
Cyanomycin, 1141
723
Cycloheximide, 304, 307, 308,
309, 310. 1228
diastereoisomer, .'i09
Cycloheximides, 144
Cyclohexylamine salt, 1014
Cyclopaldic acid, 409
Cyclopenin, 493, 977, 981
Cyclopolic acid, 411
Cycloserine, 343, 345, 418, 422,
488, 671, 894
Cynodontin, 534, 544
Cystathionine, 311, 420
Cysteic acid, 300, 822
Cysteine, 305, 310, 311, 340-342,
422, 434, 447, 536, 718, 724,
756, 757
L-Cysteine, 333, 419, 420
Cysteine-S-sulfonate, 310
Cysteinylvaline, 421
Cystine, 303, 305, 420, 434, 722,
840, 848
L-Cvstinylvaline, 420
Cytidine, 509, 1010
Cytidine-5'-diphosphatecholine,
56. 512, 1016
Cytidinediphosphateethanol-
amine, 512, 513
Cytidine diphosphate glycerol,
5i3, 5i4, 1015
Cytidine diphosphate ribitol. 5i3,
5J4, 1017
Cytidine nucleotides, 512, 513
Cytidine phosphate, 56
Cytidine-2'-phosphate, 1012
Cytidine-3'-phosphate, 1013
Cytidine-5'-monophosphate,
5i0
Cytidine-5'-triphosphate, 5J5
Cytidylic acid, 509, 1012, 1013
Cytidylic deaminase, 515
Cytochrome, 436, 447, 562, 564
aa, 449, 562
fla, 562
b, 449, 562
c, 447-449, 562
C4, 448
Cn, 448
Cytosine, 508, 509, 552, 1007
Subject Index
Datemycin, 1142
Deca-tra7zs-2-irfln.s-8-diene-4,6-
diyne-l,10-dioic acid, 199
Deca-cis-2-frflns-8-diene-4,6-diyn-
l-ol, 204
Deca-fra7is-2-trans-8-diene-4,6-
diynyl dec3i-trans-2-trans-8-
diene-4,6-diynoate, 221
Decarboxylation, 309, 317, 422,
437, 447, 483, 492, 493, 502
2-Decene-l,10-dioic acid, 100
f rar2s-Dec-2-ene-4 ,6 ,8-triyn- 1 -al ,
197
tra7zs-Dec-2-ene-4,6,8-triyn-l,10-
diol, 201
7-Dechlorochlortetracycline, 273
Dechlorogeodin, 191
Dechlorogriseofulvin, 186, 432
Dechloronornidulin, 457
trarzs-a,/8-Dehydroacyl coenzyme A,
53
Dehydroaltenusin, 151, 418
Dehydrocarolic acid, 145
7-Dehydroergosterol, i54
14-Dehydroergosterol, 334
24(28)-Dehydroergosterol, 335
Dehydrofusaric acid, 479, 972
Dehydrogenase (DPNH), 449,
479-482, 561-564
5-Dehydroquinic acid, 143, 298
5-Dehydroshikimic acid, 143, 296
Dehydrotumulosic acid, 356
Dehydroustic acid, 393, 395, 412
6-Demethyltetracycline, 273, 603
Dendrolasin, 855
9-Deoxorosenonolactone, 329
3-Deoxy-3-amino-D-ribose, 21
6-Deoxy-L-gaIactose, 18
2'-Deoxy-5-methyloluridine-5'-
phosphate, 552
Deoxyribonucleic acid (DNA),
345, 508-510
Deoxyribonucleotides, 5i5
Deoxyribose, 18, 445, 515
2-Deoxyribose-l -phosphate, 5i5
2-Deoxystreptamine, 20, 52, 53,
59
5-Deoxyoxy tetracycline, 273
Pfizer Handbook of Microbial Metabolites
724
2'-Deoxyuridine-5'-phosphate,
552
3'-Dephosphocoenzyme A, 537
Depsides, 212, 213, 231, 400,
402
Depsidones, 212, 213, 231, 400,
402
Depsipeptide, 1113
Dermocybin, 562
Desertomycin, 1143
Desosamine, 20, 120, 257, 258,
263, 276-279
Desthiobiotin, 902
Dethiobiotin, 426, 902
Dethiogliotoxin, 461
Detoxication, 232
Deuterium, 480, 481
Dextromycin, 62
Diacetyl, J 5, 19
Diadenosinetetraphosphate,
1045
a,/3-Diaminobutyric acid, 834
a,y-Diaminobutyric acid, 824
L-a,y-Diaminobutyric acid, 771,
776, 777, 779, 780-785
3,4-Diaminoguaiacol, 503
2,6-Diaminohexose, 20
Diaminohexose B, 60
a,e-Diamino-8-bydroxycaproic
acid, 697
a,e-Diamino-^-hydroxypimelic
acid, 717
2,6-Diaminopimelic acid, 306,
312-314, 343, 344, 703, 719
L,L-Diaminopimelic_acid, 312
meso-Diaminopimelic acid, 312,
343
a,/3-Diaminopropionic acid, 727
d-Diaminosuccinic acid, 305, 488,
670
4,5-Diaminouracil, 516, 557, 1008
Diaporthin, 1144
Diatretyne-1, 191
-2, 192
-3, 198
Diazoacetyl-L-serine, 678
6-Diazo-5-oxoaminohexanoic
acid, 689, 725
6-Diazo-5-oxo-L-norleucine ( DON ) ,
532, 689, 725
Dibenzofurans, 2 J 2, 214, 400
Dichloroacetic acid, 284
Dichloroproline, 739
Didymic acid, 212, 40 J, 861
Diffractaic acid, 467
D-Digitalose, 439
Digitoxigenin, 398
Diglyceride phosphate, 56
Dihydroagroclavine, 950, 952
Dihydroelymoclavine, 953
5,6-Dihydroergosterol, 341
Dihydro F, 909
Dihydrofuscin, 879
Dihydrogladiohc acid, 394, 410
DihydroUpoic acid, 16
Dihydronicotinic acid, 483
Dihydroorotase, 514
L-Dihydroorotic acid, 5i4
Dihydroorotic dehydrogenase,
514
Dihydrophenazine, 502
Dihydropyrazine, 497
Dihydroshikimic acid, 299
Dihydrostreptomycin, 19, 56
Dihydrostreptose, 19
4,5-Dihydrouracil, 516
Dihydroxy acetone, 16, 483
phosphate, 14
2,6-Dihydroxyacetophenone,
388
2,6-Dihydroxybenzoic acid, 185
3,4-Dihydroxybenzoic acid, 143
2,3-Dihydroxybenzoyl glycine,
396
2 ,6-Dihy droxybutyrophenone ,
404
4-(D-er7/t/zro-l',2'-Dihydroxy-3'-
phosphopropyl)imidazole,
318
a,/?-Dihydroxyisovaleric acid, 91,
315
3,3'-Dihydroxylycopene, 172
4 ,6-Dihy droxy-3-methoxyphtha-
Uc acid, 393, 395, 412
a,^-Dihydroxy-^-methylvaleric
acid, 97
725
4 ,9-Dihydroxyperylene-3 , 1 0-quin-
one, 523
1,6-Dihydroxyphenazine, 995
3 ,4-Dihydroxyphenylalanine ,
301
2,5-Dihvdroxyphenylglyoxylic
acid, 384
3.5-Dihydroxyphthalic acid, 181,
185, 233, 386
3,5-Dihydroxy-l,4-pyrone, 72
2,5-Diketogluconic acid, 23, 25,
405, 406
a-Diketones, 422
Diketopiperazines, 346, 496, 497
2,3-Dimethoxy-5-methyl-l ,4-ben-
zoquinone, 239
2,5-Dimethoxybenzoquinone, 494
1,8-Dimethoxynapthalene, 627
3-[2-( 3,5-Dimethyl-5-acetoxy-2-
oxocy clohexyl ) -2-hy droxy-
ethyl] glutarimide, 316
yS,/?-Diinethylacrylyl coenzyme A,
92
•y,y-Dimethylallyl pyrophosphate,
156
Dimethylamine, 291, 640
6-Dimethylaminopurine, 532,
534
trans-2,4-Dimethyl-13-7z-amyl-2-
eicosenoic acid, 126
5 ,6-Dimethylbenzimidazole ,
442, 444, 446, 529
a-(5,6-Dimethylbenzimidazolyl)
cobamide cyanide, 441, 442,
931
Dimethyl deca.-trans-2-trans-8-
diene-4 ,6-diyne- 1 , 1 0-dioate,
216
Dimethyl deca-2,4,6-triyne-l,10-
dioate, 215
Dimethyl dec-trans-2-ene-4,6-
diyne- 1,1 0-dioate, 217
Dimethylhistamine, 653
/3,5-Dimethyllanthionine, 420
L-bimethylleucine, 770
Dimethyl octa.-trans-2-trans-6-
dien-4-yne-l,8-dioate, 206
3,5-Dimethyl-6-oxyphthalide,
400, 408
Subject Index
Dimethylpyruvlc acid, 8 J, 86
6,7-Dimcthyl-8(D-l'-ribityl)
lumazine, 557
Dimethylsulfone, 4
4,4'-Dioxo-/i-carotene, 163
2,6-Dioxy-5-methylpyrimidine,
509
2,6-Dioxypyrimidine, 508
2 ,4-Dioxy-6-pyru vylbenzoic
acid, 185, 398
Dipalmitoleyl-a-lecithin, 136
D-l,3-Diphosphoglyceric acid,
14, 480
Diphosphopyridinenucleotide
(DPN), 14, 47, 53, 93, 449,
479-481, 510, 511, 514, 527,
561-564, 975
Diphosphopyridine nucleic acid
(reduced) (DPNH), 449, 511,
5J4, 561-564
2,6-Dipicohnic acid, 3 J 4, 479,
714, 968
Diplococcin, 1145
Diploicin, 441
Diploschisteric acid, 444
Dlpyrromethanes, 440
Dirhizonlc acid, 467
Disaccharldes, 511
Distamycin A, 1146
Divaricatic acid, 469
5,6,7,8,9,10,10',9',8',7',6',5VDo-
decahydrolycopene, 178
Dodecyl 5-oxostearate, 12
Drosophihn A, 378
B, 1247
D-Substance, 1147
Duramycin, 420, 820
E-73, 305, 316
E-129A, 743
Eburicoic acid, 158, 355, 357
3/3-acetate, 357
Echinomycin, 760, 1089
Echinulin, 458, 460, 471, 496,
497, 943
Elaiomycin, 22, 711
Elaiophylin, 1148
Pfizer Handbook of Microbial Metabolites
726
Electron transport, 232, 233,
238, 447-450, 479, 561-564
Elymoclavine, 471,947
Embden-Meyerhof pathway, 13
Emodic acid, 536
Emodin, 188, 189, 234, 542, 562
Endocrocin, 154, 233
Endomycin A, 122, 235
B, 122, 246
Endosubtilysin, 1149
Endothianin, 580
Enniatin-A, 740, 747-750, 758,
767
Enniatin-B, 738, 747-750, 758,
767
Enniatin-C, 741, 747-750, 758,
767
Enolase, 13
Enolhydrase, 53
Enteromycin, 1150
Epanorin, 635
Episterol, 340
Epoxysuccinic acid, 49, 79
d,l-ETdm, 424
Ergobasine, 955, 956
Ergobasinine, 956
Ergochrysin, 1151, 1152
Ergoclinine, 955
Ergocornine, 465, 960, 961
Ergocorninine, 961
Ergocristine, 465, 966, 967
Ergocristinine, 967
Ergofiavine, 466, 1152
Ergokryptine, 465, 962
Ergokryptinine, 963
Ergometrine, 955
Ergonovine, 470, 955
Ergosecalinine, 957
- Ergosine, 958, 959
Ergosinine, 959
Ergostetrine, 955
A'"'-Ergosta-dien-3-one, 338, 346,
348
A^---Ergostadiene-3|8,5a,6;S-trioI,
344
A'--'-Ergostadien-3^-ol, 341
^7.24(1:8) v-Ergostadien-3^-ol, 340
/^8,24(28) ?-Ergostadien-3^-ol, 342
A8.^^(?)-Ergostadien-3y8-ol, 343
5,7,22,24 ( 28 )-Ergostatetraene-3-
/3-0I, 335
A'-Ergosten-3/3-ol, 345
Ergosterol, 154, 158, 336, 355, 466
biogenesis, i 55-158
peroxide, 339
Ergosteryl palmitate, 874
Ergot, 43, J 54, 291, 336, 343, 344,
351
alkaloid biosynthesis, 467-472
alkaloids, 291, 346, 458, 465,
472
Ergotamine, 470, 964, 965
Ergotaminine, 965
Ergothioneine, 319, 466, 708
Ergotocine, 955
Ergotrate, 955
Ergotoxine, 465, 470
Ergoxanthin, 1152
Erythrin, 468
Erythritol, 20, 468
weso-Erythritol, 20, 573
Erythrocin, 279
Erythroglaucin, 560
Erythromycin, 20, 119-121, 258,
279
B, 20, 119, 278
C, 20, 119,277
Erythronolide, J 20, 279
Erythropterin, 555, 1050
Erythrose, 398, 436
-4-phosphate, 17, 142
Erythroskyrin, 587
Escobedin, 160
Esperin, 763
Estin, 1153
Etamycin, 123, 382, 752, 769, 770
Ethanol, 14, 15, 18, 19, 466, 480
Ethanolamine, 135, 301
l-Ethoxy-l,2-ethylenedicarboxam-
ide, 8
Ethyl acetate, 6
Ethylamine, 466, 639
Ethylcarlosic acid, 153
Ethylene, 3
f-tra Tis-Ethylene oxide-a,yS-dicar-
boxylic acid, 79
Ethyl hydrogen 2,6-dipicolinate,
971
727
Subject Index
Etiocobalamine, 442
Etrusconivcin, J 22, 228
Eulicin, 712, 1183
Eumycetin, 1154
Eumycin, 836
Eurocidin, i22, 242
Evernic acid. 446, 454
Exfoliatin, 1156
Expansine, 867
Factor A, 442
ribose phosphate, 442
Factor B, 932
C, 442
D, 442
E, 442
F, 442
G, 442
H, 442
I, 442
J, 442
K, 442
L, 442
M, 442
Via, 442
Vib, 442
Fairodin, 1157
Fallacinal, 548
Fallacinol, 557
Farcinicin, 914
Farinacic acid, 485
Farnesyl pyrophosphate, 156, 157
Fatty acid biogenesis, 52-54
catabolism, 53
^-oxidation, 52
Fatty acids, 17, 22, 49, 50, 53, 93,
492
branched chain, 51
of microorganism fat, 50
of Mycobacterium tuberculosis,
51
Fatty alcohols, 23
Fecosterol, 342
Fermentation "lactobacillus casei"
factor, 1061
Fermicidin, 1158
Fermizin, 1159
Fervenulin, 1160
Filipin, 119, 120, 122, 238
Flavacid, J 22, 244
Flavacol, 496, 497, 986
Flavensomycin, 1161
Flavicidin, 910
Flavicin, 910
Flavin, 47, 92, 449
Flavine-adenine dinucleotide
(FAD), 479, 527, 560-564,
1060
Flavine biosynthesis, 557-560
enzymes, 56J
Flavines, 548
Flaviolin, 516
Flavipin, 394
Flavofungin, 122, 225, 1143
Flavoglaucin, 436
Flavomycin, 1219
Flavoproteins, 561, 564
Flavoskyrin, 550
Flavucidin, 1162
Fluoride, 13
Folacin, 1058
Folic acid, 307, 346, 444, 531,
548, 549, 552, 554, 556, 1058
Folimycin, 1163
Folinic acid-SF, 1059
Fomecin A, 1164
Formaldehyde, 552
5-Formamido-4-imidazolecar-
boxamide ribotide, 55i
Formate, 445, 516, 550, 552, 554
Formate (Ci4-labeled), 120, 159,
182, 236, 411
Formic acid, 1 7, 46, 67, 72, 466,
552, 558
Formylglycinamide ribotide, 530,
551
N-Formylkynurenine, 482
N^"-Formylpteroic acid, 1055
6-Formylsalicylic acid, J 86, J 87
N'-Formyltetrahydrofolic acid,
1059
N^--Formyltetrahydrofolic acid,
549, 550
Forocidins, 289
Forocidin A, 289
B, 289
C, 289
Foromacidins, 119, 286-289
Pfizer Handbook of Microbial Metabolites
728
Fraction A (mitomycin), 1209
B (mitomycin), 1210
C (mitomycin), 1211
R (mitomycin), 1213
W-1 (mitomycin), 1206
W-2 (mitomycin), 1207
W-3 (mitomycin), 1208
Y (mitomycin), 1212
Fradicin, 122, 243
Fradiomycins, 60
Framycetin, 63
Frangula-emodin, 542
Frequentic acid, 873
Frequentin, 302
FriedeUn, 363
epi-Friedelinol, 364
Fructigenin, 749
Fructose, 19, 407
Fructose-1, 6-diphosphate, 14,17
Fructose-6-phosphate, 14, 17, 18
N-Fructosylanthranilic acid, 318,
459
D-Fucose, 18, 22, 439, 528
Fulvic acid, J 85, 186, 190, 410,
411, 875
Fulvicin, 430
Fumagillin, 107, 318
Fumarase, 46
Fumaric acid, 47-49, 78, 483, 531,
533
Fumaromono-D,L-alanide, 712
Fumarprotocetraric acid, 470
D,L-Fumarylyl alanine, 712
Fumidil, 318
Fumigacin, 367
Fumigatin, 495
Fumaric acid, 78, 309
Fumigatin hydroquinone, 496
Fungal cerebrins, 133
Fungichromatin, 122, 239
Fungichromin, 120, 122, 239
Fungicidin, J 22, 230, 237, 304,
305, 1095
Fungisporin, 778
Fungistatin, 839
Fungisterol, 345, 346, 348
Fungocin, 836
Funiculosin, 540
Furans, 398
Furan-3-carboxyIlc acid, 851
Furfural, 466
6-Furfurylaminopurine, 1030
Furoic acid, 417
Fusaric acid, 479, 973
Fusarium wilt toxin, 715
Fusarubin, 190, 410, 520, 521
Fusarubinogen, 521
Fuscin, 878
Fuscomycin, 1165
Galactonic acid, 32
3-;8-D-Galactopyranosido-D-arabi-
tol, 39
Galactose, 22, 471
Galacturonic acid, 22
Gallic acid, 187, 382
Gangaleoidin, 449
G-Compound, 557-560, 1053
Geamine, 732, 734, 735, 773
Gentian violet, 343
Gentisaldehyde, J 87
Gentisic acid, 186, 187, 381
Gentisyl alcohol, 186, 187, 383
Gentisylquinone, 491
Geodin, 191, 213, 424
d-Geodin, 426
Geodin-like antibiotic, 429
Geodoxin, 427
Geomycin, 729, 734, 735, 773
Gibberellenic acid, 321, 322
Gibberellic acid, 323
biosynthesis, 159
GibberelUns, 321, 479
Gibberellin A, 321, 325
Ao, 321, 326
A3, 321, 323
A4, 324
X, 321, 323
Gigantic acid, 909
Glabratic acid, 443
Gladiohc acid, 408
Glauconic acid I, 317
11, 317
Glauconic acids, 144, 317
GUorosein, 499
Gliotoxin, 145, 346, 458, 460,
461, 496-498, 938
acetate, 939
729
Gliotoxin biosynthesis, 460, 461
Glomellifeiic acid, 181
D-Gluconic acid, J 8, M, 77, 405
Gluconolactone, 405
5-0-a-D-Glucopyranosyl-D-fructo-
pyranosc, 41
2-0-a-D-Glucopyranosyl-D-glucose,
42
D-Glucosamine, 18, 20, 23, 33, 59,
344
Glucosamine isomer, 732
6-Glucosamine, 19, 52
Glucose, 14, 17, 18
l-C'*-Glucose, 182, 555
Glucose-6-phosphate, 14, 17, 480,
511, 524
Glucosides, 5i2
a-D-Glucosido-a-D-glucoside, 43
Glucosone, 18, 24, 407
D-Glucuronic acid, 18, 28, 82, 109
Glucuronides, 511, 512
^rfl7is-Glutaconic acid, 84
Glutamate, 319, 435, 480, 515,
530, 533
Glutamate-aspartate aminophe-
rase, 487
Glutamic acid, 274, 290, 300, 301,
303, 304, 306-309, 312, 333,
340-342, 344, 436, 445, 501,
516, 530, 533, 549, 730, 768,
773, 813, 815, 819-821, 828,
829, 831, 836-838, 841, 848,
849, 1062, 1078
D-Glutamic acid, 343, 814
L-Glutamic acid, 92, 333, 680, 718,
722, 730, 765, 766
Glutamic acid semialdehyde, 307
Glutamine, 300, 303, 308, 318,
515, 530, 532
L-Glutamine, 681, 791, 792
L-y-Glutamylcysteine, 333
Glutamylcysteinylglycine, 718
Glutaric acid, 88
Glutathione, 307, 310, 311, 332,
333, 340, 420, 480, 718, 722
L-Glutathione, 333
Glutathione-cysteine disulfide, 722
Glutinosin, 1166
Subject Index
D-Glyceraldehyde-3-phosphate, 1 4,
17, 18, 480
L-(-)-Glyceric acid, 46, 76, 483
Glycerin, 17
Glycerol, 17, 55, 483, 501
Glycine, 300, 301, 303, 305, 309,
310, 333, 340-342, 419, 434-
437, 444, 516, 530, 550, 552,
554, 558, 663, 718, 722, 752,
754, 759, 760, 766, 768, 769,
773, 790, 815-818, 820, 822,
824, 826, 828, 829, 831, 834,
840, 841, 846, 848, 1079,
1222
Glycine-2-C^\ 435
Glycinamide ribotide, 530, 55J
Glycogen, 5J2
Glycolic acid, 72
Glycolipide from Pseudomonas
aeruginosa, 130
Glycolysis route, 13, 14, 561
Glycylcystine, 435
Glycylglycine, 436
Glyoxylate, 3i0
Glyoxylic acid, 48, 49, 87, 3 JO,
550
cycle, 48
Gramicidin, 1145
Gramicidins, 786
Gramicidin C, 788
D, 789
J:, 787
J2, 786
S, 339, 340, 788
Dubos, 789
Gram-negative bacteria, 3J4
Granatacin, 576
Granegillin, 988
Grasseriomycin, 736
Grifolin, 46
Grisamine, 1167
Grisein, 765, 766
Griseoflavin, 1168
Griseofulvin, 186, 188, 189, 213,
411, 430, 431
Griseolutein A, 502, 1004
B, 1005
Griseomycin, 265
Griseoviridin, 1169
Pfizer Handbook of Microbial Metabolites
730
Grisovin, 430
Grizein, 843
Guanidine, 2
Guanine, 22, 442, 508, 509, 529,
559, 1027, 1044
Guanine-S-C^*, 558
Guanosine, 509, 1034
diphosphate, 527, 533
diphosphate factor B, 442, 528,
529
diphosphate fucose, 528
diphosphate mannose, 511, 527,
528
nucleotide, 527
Guanosine-3'-phosphate, 1039
Guanosine-5^-monophosphate
(GMP), 5iO
Guanosine-5^-triphosphate (GTP),
511, 527, 533
Guanyhc acid, 533, 1039
L-Gulonolactone, 82
D-Gulosamine, 21, 731, 729
Gyrophoric acid, 475, 476
Haematommic acid, 2i3
Haemocorin, 573
Helenine, 1170
Hehomycin, 1171
Hehxins, 247
Helixin A, J 22, 235
B, J 22, 246
Helminthosporin, J 89, 541
Helvolic acid, 367, 368
Hematin, 925
Heme, 436
proteins, 447, 561'
Hemin-hke substance, 46
Hemipyocyanine, 994
Hemoglobin, 436
2-n-Heptyl-4-oxyquinoUne, 978
2-n-Heptyl-3-oxy-4-quinolone, 492,
979
2-n-Heptyl-4-oxyquinoHne N-oxide,
980
Hercynine, 319, 707
Herquein, 572
Herqueinone, 571, 573
Heteroxan thine, 1028
Hexacosanoic acid, 124
9-Hexadecenoic acid, 50, 106
Hexokinase, 13, 524
Hexose phosphate, 18
rz-Hexylamine, 466, 647
Hiascic acid, 476
Hiochic acid, 96
Hirsutic acid, 1172
Histamine, 466, 651
Histidine, 300, 301, 303, 305, 318,
319, 341, 342, 448, 466, 816-
819, 849
L-Histidine, 688, 814
Histidine betaine, 707
biosynthesis, 3i8, 551
L-Histidinol, 3 J 9, 691
phosphate, 319
Holomycin, 434, 435, 913
Homocysteine, 311, 419, 420, 553
Homarine, 701
Homogentisic acid, 143
Homomycin, 21, 58
amino sugar moiety, 21, 58
Homoprotocatechuic acid, 384,
387, 391
Homosekikaic acid, 478
Homoserine, 311, 312, 315
deaminase-cystathionase, 487
isomerase, 485
Hyaluronic acid, 5i2
Hydrogen transport, 232, 447—
450, 479-481, 561-564
yS-Hydronapthazin, 521
a-Hydroxy acids, 564
L-^-Hydroxyacyl coenzyme A, 53
^-Hydroxyacyldehydrogenase, 53
3-Hydroxyanthranilic acid, 482,
483
5-HydroxyanthraniHc acid, 460
Hydroxyaspartic acid, 488
Hydroxyaspergillic acid, 989
5-Hydroxybenzimidazole, 442
p-Hydroxybenzoic acid, J 43, 186,
187, 379
3-Hydroxy-y-carotene, 170
(,j-Hydroxycatenarin, 549
10-Hydroxydec-trans-2-ene-4,6-di-
ynoic acid, 205
731
Subject Index
trans-10-Hydroxydec-2-ene-4,6,8-
triynoic acid, 198
(,)-Hydroxycniodin, 515
5-Hydroxyindole, 470, 471
D(-)a-Hydroxyisovaleric acid, 338,
339, 738, 740, 747-750, 758,
767
a-Hydroxyketones, 422
3-Hydroxykynurenine, 482
3/^-Hydroxylanosta-8,24-diene-21-
oic acid, -MO
21-Hydroxylanosta-7,9( 11 )24-tri-
ene-3-one, 346
/^-Hydroxyleucine, 726
2- ( 6-Hydroxy-2-methoxy-3 ,4-meth-
ylenedioxyphenyl ) -benzof u-
ran, 858
1-Hydroxydimethoxymethylxan-
thone, 890
a-Hydroxymethyl-a'- ( N-acetylami-
nomethylene ) succinic acid,
485
6-Hydroxy-2-methylaminopurine,
532
6-Hydroxy-2-methylbenzoic acid,
389
5-Hydroxy-2-methylchromone, 868
5-Hydroxymethylcytosine, 509,
5J5, 552
5-Hydroxymethylfuran-2-carbox-
ylic acid, 852
5-Hydroxymethylfurfural, 398
;8-Hydroxy-/?-methylglutaryl co-
enzyme, A (HMG-Co A), 92,
93, 155
cleavage enzyme, 93
8-Hydroxy-3-methylisocoumarin,
397
/3-Hydroxy-^-methyl-8-valerolac-
tone, 96
D-^-Hydroxymyristic acid, 104
Hydroxymycin, 64
Hydroxy-P-481, 180
1-Hydroxyphenazine, 994
p-Hydroxyphenylacetic acid, 390
p-Hydroxyphenyllactic acid, 316
p-Hydroxyphenylpyruvic acid, 87,
235, 316
3-Hydroxyphthalic acid, 186, 187,
385
3-Hydroxypicolinic acid, 770
Hydroxyproline, 436. 756, 757,
769, 805, 807, 820
D-a-Hydroxyproline, 770
Hydroxypyruvic acid, 87
Hydroxyspirilloxanthin, 181
Hydroxystreptomycin, 19, 55
Hydroxystreptose, 19
3-Hydroxy-5-toluic acid, ,389
5-Hydroxytryptamine, 935
5-Hydroxy tryptophan, 470, 471
^-Hydroxyvaline, 419
Hygromycin A, 21, 57, 185
B, 21, 45
Hygroscopin A, 1173
B, 1174
Hygrostatin, 1112, 1175
Hyposterol, 332
Hypothamnolic acid, 463
Hypoxanthine, 442, 532, 1023
Illudin M, 1176
S, 1177
Ilotycin, 279
Imbricaric acid, 473
Imidazole, 418
Imidazoleacetol, 687
phosphate, 319
Imidazoleglycerol, 690
phosphate, 3J8, 319
4-Imidazoly acetic acid, 677
Imoticidin, 1178
Inactone, 307
Incrassatic acid, 861
Indigo, 458, 940
Indigoidine, 1179
Indole, 306, 317, 318, 471, 933
^-Indoleacetic acid, 417
Indole-3-acetic acid, 934
Indole biosynthesis, 3 J 7, 459
synthetase, 488
Indoles, 458, 496
3-Indolylacetol, 460
Indolyl-3-gIycerol phosphate, 3 J 7,
459
Inosine, 529
nucleotide, 527
Pfizer Handbook of Microbial Metabolites
732
Inosme-5'-phosphate, 510, 1035
Inosinic acid, 532, 533, 1035
meso-Inositol, 30
Inositols, 19
lodinin, 996
lodoacetate, 13
Ipomeamarone, 855
Ipomeanine, 853
Iridoskyrin, 540, 583, 587
Iron, 765, 766
Islandicin, 540, 587
Islanditoxin, 739
Isoamylamine, 291, 652
Isobutyl acetate, 9
Isobutylamine, 648
Isocitric acid, 47, 48
allo-Isocitric acid, 93
Isocitric dehydrogenase, 46
Isocitritase, 48
Isokojic acid, 404, 407, 866
Isoleucine, 80, 97, 300-302, 304,
314, 315, 342, 497, 815-818,
824, 831, 839, 840
L-Isoleucine, 693, 776, 777, 814
D-a^o-Isoleucine, 336, 793, 795-
801, 804
Isoleucine biosynthesis, 315
Isolysergic acid, 466
Isooosporein, 502
Isopenniclavine, 949
Isopentenyl pyrophosphate, i55,
J 56
Isoprene, 9, 470, 471
Isopropanol, 18
Isopropylamine, 645 '
Isopyridoxal, 484
Isorhodomycin A, 276, 597, 1180
B, 598
e-Isorhodomycinone, 276, 601
Isorhodomycinones, 276
Isosetoclavine, 946
Isovaleryl coenzyme A, 92
mycarose, 283
Isoxazole, 418
Itaconic acid, 49, 83
Itaconitin, 1181
Itatartaric acid, 89
Javanicin, 235, 520
Junipal, 427, 895
Kanamycin, 19, 20, 52
B, 53
Kanosamine, 20, 53
Keto-acids, 87, 422
/?-Ketoacyl coenzyme A, 53
a-Ketoacyldehydrogenase, 92
a-Ketoadipic acid, 312
^-Ketoadipic acid, i43, 144
a-Ketobutyric acid, 315
a-Ketocaproic acid, 87
2-Keto-3-deoxy-D-araboheptonic
acid, J 42
5-Keto-6-deoxyarabohexose, 21
2-Keto-3-deoxy-6-phosphogluconic
acid, 18
L-2-Ketofucopyranose, 21
2-Ketogalactonic acid, 27
2-Keto-D-gluconic acid, 25, 72, 405
5-Keto-D-gluconic acid, 26, 72, 405
a-Ketoglutaraldehyde, 550
a-Ketoglutarate, 319, 480
a-Ketoglutaric acid, 47, 48, 85, 87,
92, 284, 307, 309, 312, 437,
527
2-Keto-L-gulonolactone, 82
a-Keto-^-hydroxyisovaleric acid,
3J5
a-Ketoisocaproic acid, 87, 92, 316
a-Ketoisovaleric acid, 87, 3 J 5, 316,
333
5-Ketostearic acid, 112
Kinetin, 534, 1030
Kojibiose, 42
Kojic acid, 404, 405, 407, 865, 866
Krebs cycle, 46, 47
Kynurenine, 336, 337, 482, 493
Lactams, 79
Lactarazulene, 320
Lactarinic acid, 112
Lactaroviolin, 319
Lactic acid, 17, 46, 80, 466, 717
d-Lactic acid, 15, 75
L-Lactic acid, J 5
L( + )-Lactic acid, 75, 338, 339
Lactobacillic acid, 51, 114
733
Subject Index
Lactobionic acid, 44
Lactones, 79
Lactonic acid. 1239
Lagosin. i 79. i 20, 229
Lankaniycin. 119, 120
A^'-*-Lanostadien-3-ol, 352
A'-^'^'-'^-Lanastatriene-S/^, 21-diol,
348
Lanosterol, 157-159, 352
Lanthionine, 420, 815-821
Laricic acid, 120
Lateritiin-I, 740, 758, 767
Lateritiin-II, 747, 758. 767
Laterosporin, 1182
Latumcidin, 1183
Laurie acid, 104
Lavendulin, 774
Lecanoral, 488
Lecanoric acid, 443, 444, 468
Lecanorolic acid, 488
Lecithin. 1016
a-Lecithin. 136
/^-Lecithin, 136
Lecithin biosynthesis, 513
Lecithins, 55, 135
Lenamycin, 1184
Lenzitin, 1185
Leprapic acid, 633
Leprapinic acid, 633
Leprotene, 188
Leprotin, 188
Leucine, 91, 92, 300, 301, 304,
309, 314-316, 339, 341, 342,
466, 497, 759, 768, 784, 813,
815-818, 824, 828, 829, 831,
837, 838, 841, 849, 1078
D-Leucine. 771, 776, 777, 780,
785-787, 790, 825
L-Leucine, 339, 501,692, 726, 771,
781, 782, 788, 791, 792, 814
Leucine biosynthesis, 314-316
Leucomelone, 236, 506
Leucomycin, 275
Leucopterin, 554
Leucotylin, 366
Leucovorin, 1059
Leucrose, 41
a-Leucyl-L-leucine anhydride, 1195
a-Leucyl-a-proline anhydride, 1194
Levomycetin, 626
Levomycin, 753
Lichen acids, 284
Licheniformin A, 844
B, 845
C, 846
Z-Lichesterinic acid, 80, 156, 159
Lichexanthone, 891
Lignoceric acid, 50, 122
Limocrocin, 224
Linoleic acid, 50, 51
Linolenic acid, 50
Lipoic acid, 1 5- J 7, 47, 99
Lipoproteins, 50
Liposaccharides, 50, 52
Litmocidin, 1186, 1305
Lobaric acid, 480
Lomycin, 265
Longisporin, 1187
Lusomycin, 161
Lustericin, 1188
Lutein, 174
Luteol, 174
Luteoleersin, 578
Luteomycin, 577
Luteoskyrin, 587, 588
Lycomarasmine, 715
Lycopene, 94, 161, 168
Lycopersene, 94
Lycopersin, 1189
Lycophyll, 172
Lysergic acid, 466-471
Lysine, 300, 301, 303, 305, 307,
312, 313, 341-344, 426, 815-
818, 824, 831, 839, 841, 844,
845, 848
^-Lysine, 727, 729, 731, 732, 734,
735, 773, 790
L-Lysine, 306, 343, 695, 814
Lysine biosynthesis, 312, 313, 314
Lysozyme, 332, 343, 344
D-Lyxuronic acid, 21
M5-18903, 1064
Macrocyclic lactones, 118, 122
Macrolide antibiotics, 118, 190
Macrosporin, 556
Magnamycin, 119, 283
Pfizer Handbook of Microbial Metabolites
734
Malate synthetase, 48
L-Malic acid, 47, 48, 81, 483
Malic dehydrogenase, 46
Malonic acid, 71
Malonyl coenzyme A, 54, 155, 424,
446
Maltobionic acid, 44
Maltose, 44
Malucidin, 1190
Mannan, 528
D-Mannitol, 19, 35, 43, 46, 71, 329,
407, 466, 874
D-Mannonic acid, 32
D-Mannopyranosyl-l-Tneso-
erythritol, 38
Mannose, 22
Mannosidostreptomycin, 65
Marasin, 200
Marasmic acid, 1191
Marcescin, 922
Marcomycin, 1192
Matamycin, 822
trans, trans-Matricaria acid, 202
ester, 211
trans,trans-Matricarianol, 203
Mycocidin, 367
Mediocidin, 245, J 22
Megacidin, 1193
Melanomycin, 849
Melanosporin, 1196
Mellein, 399
Mesaconic acid, 445
Mesenterin, 1197
Mesoinositol monophosphate, 34
MetaboUte Co4H5o02,_1198
Metabohte A, 628
B, 628
from Curvularia lunata, 1200
of Coprinus comatis, 1199
of Eremothecium ashbyii, 1008
of Hydniim aurantiaciim, 511
Metal chelates, 436
Metamycin, 1201
Methionine, J 89, 291, 300-304,
310, 311, 337, 420, 444, 445,
461, 516, 525, 552-554, 798,
816-818
L-Methionine, 684
Methionine (C^Mabeled-CHg), 120,
159, 274, 411
6-Methoxybenzoxazolidone, 896
8-Methoxy-l-naphthol, 613, 627
p-Methoxyphenylalanine, 535
p-Methoxytetrachlorophenol, 378
4-Methoxytoluquinone, 493
2-MethyIadenine, 442, 534
S-Methyl-S-adenosylmethionine ,
292
Methylamine, 291, 466, 638
Methylaminoethanol, 646
6-Methylaminopurine, 532
Methyl anisate, 622
a-[L],^-Methylaspartic acid, 445,
516, 834
C-Methylation, 236
O-Methylation, 236
5-MethylbenzimidazoIe, 442
2-Methyl-2-butene, 7
a-Methylbutyric acid, 90
Methyl trans-cinnamate, 623
Methyl p-coumarate, 624
/3-Methylcrotonyl coenzyme A, 424
S-Methyl-L-cysteine, 305, 676
5-Methylcytosine, 509
Methyl 10-(deca-trarzs-2,trans-8-
diene-4 , 6-diyn- 1 - oyloxy ) -dec-
trans-2-ene-4,6-diynoate, 222
Methyl-2,4-dideoxy-2-aminotetro-
side, 22
N'^,N'^'-Methylenetetrahydrofolic
acid, 549
N-Methyl-L-glucosamine, 19, 54
/?-Methylglutaconase, 92
trans-^-Methylglutaconic acid, 81,
94
^-Methylglutaconyl carboxylase,
92
coenzyme A, 92, 424
1-Methylguanine, 532
2-Methyl-2-heptene-6-one, 10
Methyl 1 0-hydroxydec-trans-2-ene-
4,6-diynoate, 212
Methyl tra?is-10-hydroxydec-2-ene-
4,6,8-triyn-l-oate, 210
4-Methyl-5-(2-hydroxyethyl)-thia-
zole, 422
2-Methylhypoxanthine, 442
735
Subject Index
N-Methvlisoleucine, 337, 796, 797
/J-Methvllanthionine, 305, 704,
8 15-82 1
N-Methylleucine, 741
Methylmalonyl coenzyme A, 447
2-Methylniercaptoadenlne. 442
Methyl p-methoxycinnamate, 284,
625
Methyl 2-methoxypulvinate, 633
2-Methyl-l,4-naphthoquinone, 239
6-Methyl-l,4-naphthoquinone, 517
1-10-Methyloctadecanoic acid, 115
( + )-6-Methyloctanoic acid, 338,
771, 776, 777, 780, 781, 783-
785
S-Methylol-S-adenosylhomocy-
steine, 553
5-Methyl-2-oxo-4-imidazoUdine-
caproic acid, 902
3-Methyl-3-oxyglutaryl coenzyme
A, 155
6-Methyl-7-oxy-8-(D-Li-ribityl)-
lumazine, 557
y-Methylproline, 726
6-MethylsalicyIic acid, 185-189,
233, 236, 389
y-Methyltetronic acid, 80, 140
4-Methylthiazole, 422
Des-N-methylthiolutin, 913
3-Methyluracil, 765
5-Methyluracil, 515
N-Methyl-D-valine, 337
N-Methyl-L-vaHne, 738, 740, 747-
750. 793-812
Methymycin, 20. 119, 121, 261
Mevaldic acid, 93, 155
2-C^*-Mevalonic acid, 159, 160
Mevalonic acid lactone, 81, 91, 93,
96, 119, 154-156, 189, 190,
239, 398
Mevalonic acid dipyrophosphate,
156
5-monophosphate, 156
3-phosphate 5-pyrophosphate,
156
5-pyrophosphate, 156
Miamycin, 120, 292
Microcin A, 1202
B, 1203
Micrococcin, 761
Micrococcins, 761
Micrococcin-P, 762
Micromonosporin, 1203
Microphyllic acid, 212, 489
Mikamycin, 770
A, 1204
B, 1205
Mineoluteic acid, 49, 105
Mitochondria, 236, 238
Mitomycin C, 1214
Mitomycins, 1206-1213
Mitoquinone, 247, 511
Moldin, 1215
MoUisin, 235, 519
Monascin, 879, 882
Monascorubrin, 879, 884
Monilin, 1104, 1105, 1216
Monoacetylprotocetraric acid, 465
Mucopeptides, 343
Mucopolysaccharides, 22
Muramic acid, 343-345
Musarin, 1112, 1217
Muscaridine, 659
Muscarine, 291, 658
Muscarufin, 508
Muscle adenylic acid, 1038
Mushroom poisons, 458
Mutomycin, 1218
Myacins, 60
Mycaminose, 21, 290
Mycarose, 21, 290
Mycelianamide, 186, 411, 497, 998
MyceUn, 1219
IMO, 1220
Mycifradin, 60
Mycobacidin, 899
Mycobacillin, 813
Mycobactin, 185, 772
Mycoceranic acid, 124, 129
phthioceryl ester, 129
Mycocerosic acid, 129
Mycochrysone, 525
Mycoin, 867
Mycolic acid, 51, 55, 138
Mycolipenic acid, 125
Mycolutein, 634
Mycomycin, 218
Pfizer Handbook of Microbial Metabolites
736
Mycophenolic acid, 185, 186, 188,
189, 433
Mycorhodin, 1221
Mycosamine, 20
Mycose, 43
Mycospocidin, 1222
Mycostatin, 230
Mycosubtilin, 842
Mycothricin, 1223
A, 734
B, 735
Mycoticin, 1224
Mycoxanthin, 189
Myoinositol, 82
Myprozine, 226
Myristic acid, 50, 103, 104
triglyceride, 103
Nalgiolaxin, 566
Nalgiovensin, 567
Naphthoquinone from Mycobac-
terium phlei, 530
Naphthoquinones, J 85, 235, 248
Naramycin A, 308
B,310
Narbomycin, 20, 119, 121, 274
Natural penicillins, 905
Neamine, 60, 61, 63
Nebularine, 1031
Necrosamine, 662
Nemotin, 208, 209
Nemotinic acid, 108, 209
xyloside, 108, 109, 220
Nemoxynic acid, 478
Neobiosamine C, 60_
NeohydroxyaspergiUic acid, 990
Neoinosamine-2, 21
Neomethymycin, 20, 119, 262
Neomins, 60
Neomycin, 20, 63, 64
Neomycins, 60
Neomycin A, 60
B, 60, 62
C, 60
Neophromin, 561
Neosamine C, 20, 60
Neospiramycins, 289
Nephromopsic acid, 80, 81, 159
Nephrosteranic acid, 154, 155
Nephrosterinic acid, 154
Netropsin, 346, 435, 918
Neuraminic acid, 344
Neuraminopeptides, 344
Neurosporaxanthin, 187
Neurosporene, 94, 175
Neutral nitrogen-containing com-
pound, 877
Ngaione, 855
Nicotinamide, 480, 563
ribose 5'-diphosphate, 974
Nicotine, 435
Nicotinic acid, 479, 483, 974, 1054
biosynthesis, 482, 483
Nidulin, 212, 466
Nigericin, 1225
Nisins, 420, 816
Nisin A, 816
B, 817
C, 818
D, 819
Nitrogen-containing compound,
876
2-Nitroimidazole, 893
p-Nitrophenylserinol, 284
^-Nitropropionic acid, 73, 310
Nitrosporin, 257
Nivemycins, 60
Nocardamin, 713
Nocardianin, 1226
Nocardorubin, 1227
Noformicin, 730, 915
Nonactin, 1228
( — )-Nona-3,4-diene-6,8-diyne-
l-ol, 200
trans-Non-2-ene-4,6,8-triyn-l-al,
193
f rans-Non-2-ene-4 ,6 , 8-triyn- 1 -ol,
194
(2d,3d)-Nona-4,6,8-triyn-l,2,3-
triol, 195
2-(n-A'-Nonenyl)-4-oxyquinoline,
982
2-7i-Nonyl-4-oxyquinoline, 983
N-oxide, 984
Nordin, 1153, 1229
Norherqueinone, 571, 573
Nornidulin, 456
737
Norstictic acid, 447
Norvaline, 755
Notatin, 850
Novaose. 21
Novobiocin, 21, 343, 885
NTCC 7197, 1116
Nucleic acids, 508, 524
Nucleocidin, 1043
Nucleoproteins, 508, 5J0
Nucleosides, 509
Nucleotides, 509
Nudic acid A, 1230
B, 192
Nybomvcin, 1231
Nystatin, 20, 122, 230
Obtusatic acid, 454
Ochracin, 399
Ochrolechaic acid, 442
Octacosan, 11
d-2-Octadecanol, 50
d-3-Octadecanol, 51
7.8,ll,12,12Ml',8',7'-Octahydro-
lycopene, 177
Octapyrrole, 440
Odyssic acid, 108, 209, 214
Odyssin, 209, 213
Oleandomycin, 20, 119, 121, 276
Oleandrin, 118, 119
Oleandrose. 20, 119, 276
Oleic acid, 50, 51
Oligomycin A, 1232
B, 1233
C, 12.34
Olivetoric acid, 212, 486
Ommatins, 1001
Ommochromes, 335
One-electron transfer, 446
Oosporein, 501
Ophiobalin, 1235
Oregonensin, 1236
Orientomycin, 894
Ornithine, 300, 307, 308, 312,
423, 436, 820, 1078
D-Ornithine, 786, 787, 814
L-Omithine, 339, 666, 685, 786-
788, 791, 792
Orosomycin, 1295
Subject Index
Orotic acid, 52 5
riboside, 1014
Orotidine, 1014
Orotidine-5'-phosphate, 515
Orotidylic decarboxylase, 515
pyrophosphorylase, 515
Orsellinic acid, 81, 186, 190, 213,
233, 392, 401
4-methyl ether, 81
Orygmaeic acid, 504
Oryzacidin, 1237
Oryzasizine, 1237
Ostreogrycin A, 743, 770
Oxalic acid, 49, 68, 466
Oxaloacetic acid, 47, 48, 80, 81,
87, 308, 309, 423, 483, 527
Oxalosuccinic acid, 47
decarboxylase, 46
Oxamycin, 422, 894
Oxidase (cytochrome a^), 449
Oxidative phosphorylation, 524
L-4-OxopipecoHc acid, 755
Oxoproline, 802, 803
2-Oxy-6-aminopyrimidine, 508
3-Oxyanthranilic acid, 502, 1054
3-Oxy-^-carotene, 171
4-Oxy-/3-carotene, 171
Oxychlororaphine, 501, 998
(-)-3-Oxydecanoic acid, 338, 723,
759
2-Oxy-5-hydroxymethyl-6-amino-
pyrimidine, 509
Oxyjavanicin, 521
i-3-Oxykynurenine, 337, 1054
3 a-Oxylanost a-8 , 24-diene-2 1 -oic
acid, 350
methyl ester-acetate, 349
S-Oxy-L-lysine, 697
2-Oxy-5-methyl-6-aminopyrimi-
dine, 509
3-Oxy-4-methyl-anthranilic acid,
336, 337
3-Oxypalmitate, 80
4-Oxyquinolines, 492, 493
Oxytetracychne, 273-275, 306,
610, 670, 1302
Oxytetracycline-X, 274, 275
Pfizer Handbook of Microbial Metabolites
738
P-481, 179
PA 94, 894
105, 276
106, 1076
107, 1076
108, 280
114A, 743, 754, 770
114B, 744, 755, 770
114B-3, 745, 770
121, 614
128, 1238
132, 1239
133A, 260
133B, 264
147, 141
148, 281
150, 122, 250
153, 122, 240
166, 122, 227
Pachybasin, 538
Palitantin, 144, 302, 303
cis-Palmitenone, 13
Palmitic acid, 50, 51, 54, 55, 104,
108, 121, 124
Palmitoleic acid, 106
Palmitone, 14
Panmycin, 613
Pannaric acid, 859
Pannarin, 453
Pantetheine, 334, 536, 720
Pantetheine-4'-phosphate, 536
Pantethine, 721
Pantoic acid, 333, 535
Pantothenic acid, 333, 334, 536,
537
d-Pantothenic acid, 716
Pantothenic acid 4'-phosphate,
536
■Pantothenylcysteine, 334, 536
Paraconic acid, 485
Parellic acid, 442, 450
Parietin, 2J2, 555
Parietinic acid, 554
ParmeUn, 460
Paromamine, 59
Paromobiosamine, 59
Paromomycin, 20, 59, 61
Paromose, 20, 59
Patulin, 186, 188, 867
biosynthesis, 82
Penatin, 850
^-Penetrin, 417
Penicidin, 867
Penicillamine, 419, 420, 911
Penicilhc acid, 81, 144
biosynthesis, 81
Penicillin, 3ii, 337, 343, 345, 346,
716, 970
B,850
F, 910
G, 906
K, 907
X, 908
Penicillins (biosynthesis), 418-
421,435
Penicilliopsin, 585
Penitrinic acid, 423
Penniclavine, 948, 949
Pentacosanoic acid, 123
Pentaenes, 119
Pentamycin, i22, 241
Pentose, 405
phosphate, 18
oxidative cycle, 13, 17, 18
Peptolide, 1113
Perlatolic acid, 482
Peroxidase, 436
Perylenequinones, 235
Phagolessin A 58, 1240
Phalamycin, 1241
Phalofacin, 1242
Phalloidin, 458, 756
Phalloin, 757
Phenanthrenequinone, 233, 234
Phenazine, 502, 997
Phenazine-1-carboxamide, 999
Phenazine- 1-carboxylic acid, 997
l,6-Phenazinediol-5,10-dioxide, 996
Phenazines, 501
1-Phenazinol, 994, 1000
Phenol coupling, 191, 213, 214,
234, 400-402, 502
Phenohc substances, 185, 212,
213, 236, 502
Phenoxazones, 50J, 502
Phenylacetic acid, 417
739
Phenylalanine, 143, 182, 300, 301,
303, 305, 306, 316, 342, 461,
470, 497, 815. 820, 821, 849
D-Phenvlalanine, 339. 778, 779,
781-783, 786-788, 791, 792,
814
L-Phenylalanine. 705, 755, 778,
787, 791
Phenylalanine biosynthesis, 316
/:J-Phenyl-/^-alanine, 739
ytf-Phenyl-^-aminopropionic acid,
751
/3-Phenylethylamine, 291, 466, 656
Phenylpyruvic acid, 143, 235, 284,
'316. 493
Phleomycin, 1243
Phloroglucinol, 188
Phoenicin, 500
Phomazarin, 569
Phosphate, 18, 56, 450, 480, 524,
530, 531, 533, 560, 562-564
Phosphatides, 51, 52
Phosphoenolpyruvic acid, 14, 142,
527
6-Phosphogluconic acid, 17, 18
D-2-Phosphoglyceric acid, 14, 77
D-3-Phosphoglyceric acid, 14, 310
Phosphoglyceromutase, 13
Phosphohexoisomerase, 13
Phosphohexokinase, 13
2-Phospho-4-hydroxy-4-car-
boxyadipic acid, 98
3-Phosphohydroxypyruvic acid,
310
Phospholipide biosynthesis, 52
Phosphohpides, 50
Phosphoribose pyrophosphokinase,
524
5-Phosphoribosyl-l-pyrophos-
phate, 317, 515
Phosphoric acid, 14, 17, 333
Phosphorylase, 485, 487
Phosphoserine, 310
Phosphotidylethanolamine, 513
Photosynthesis, 436, 564
Phthienoic acid-Coy, 126
Phthiocerol, 66
Phthiocerol dimycoceranate, 66
Phthiocol, 518
Subject Index
Phthioic acid, 51, 124
Phthiomycin, 728
Physarosterol, 353
Physcion, 2] 2, 555, 560, 573
anthranols, 563, 564
Physetohc acid, 106
Physodalic acid, 465
Physodic acid, 485
Phytoene, 94, 177
Phytofluene, 178
Phytomonic acid, 114
Phytonivein, 1244
Picoline, 752
Picrocin, 20, 263
Picrolichenic acid, 437
Picromycin, 20, 119, 121, 263
Picrorocelhn, 497, 992
Pigment I, 417
II, 417
A, 1002
Pigment B (fois-anthraquinone),
581
(phenazine), 1003
C, 582
R, 182
Y, 183
Pimaricin, 20, 119, 121, 122, 226
Pimelic acid, 426
Pinastric acid, 632
PinicoUc acid A, 347
Pipecohc acid, 338
D-a-Pipecohc acid, 314, 834
Piricularin, 1245
Pleocidin, 733, 734, 735
Pleomycin, 1246
Pleuromutihn, 1247
Pleurotin, 1248
Phcacetin, 1020
Pluramycin A, 1249
B, 1250
Poin, 1251
Polyacetylenes, 109
Polycycline, 613
Polyene macrolides, i20
Polyenes, J 07
cts-Polyisoprene, 9
Polymyxin, 671, 780
A, 780
Bi, 781
Pfizer Handbook of Microbial Metabolites
740
Polymyxin
B.,, 782
C, 783
D, 784
E, 785
Polypeptide antibiotics, 332
biosynthesis, 332, 345, 346
Polypeptides, 299, 332, 508, 511
(intracellular), 332, 340-342
Polypeptin, 779
Polyporenic acid A, 359
C, 354
Polyporic acid, 235, 504
Polysaccharide, 922
Polysaccharides, 22, 511
Polystictin, 1001
Porphobilinogen, 437-440
deaminase, 439, 440
Porphyrilic acid, 857
Porphyrin byosynthesis, 436-440
enzymes, 447-450, 561
Porphyrinogens, 440
Post-oxidation, 236
Prephenic acid, 143, 301, 316, 493
Primycin, 1252
Proactinomycins, 266
Proactinomycin A, 266
B, 267
C, 268
Prodigiosin, 435, 436, 919
precursor, 435, 436, 920
Prodigiosin-like pigment, 436, 924
Porphyrins, 310, 434, 444, 447,
448
Proline, 300, 301, 303, 304, 307,
342, 435, 436, 796, 797, 799,
801, 803-807, 813, 815-818,
820, 821, 831, 837, 839, 844,
845, 849, 1078
L-Proline, 336, 339, 679, 754, 755,
766, 786-788, 791-795, 812,
834
L-ProUne (C^Mabeled), 435
1,2,3-Propanetriol, 17
Propionate, i20, 447
Propionic acid, 46, 74, 447
acid-l-C^*-H3, 120
Propionyl coenzyme A, 424, 447
2-Propionylthiazole-4-carboxylic
acid, 762
Propiopyrro thine, 916
zso-Propylamine, 466
7i-Propylamine, 466, 644
Propynoic acid, 108
Protein biosynthesis, 332, 343,
345, 346, 534
Protoactinorhodin, 527
Protocarbomycin, 121
Protocatechuic acid, 380, 382
Protocetraric acid, 119, 213, 451
Protocidin, 122, 232
Protoleucomelone, 510
d-Protolichesterinic acid, 157
Z-ProtoHchesterinic acid, 157, 159
Z-afio-Protolichesterinic acid, 158
Protomycin, 1314
Porphyria, 438
Protoporphyrin, 437, 926
IX, 438, 447
Protoporphyrinogen, 438
Psalhotin, 1253
Pseudoneamine, 64
Pseudopsoromic acid, 455
Psicofuranine, 1042
Psilocin, 936
Psilocybin, 458, 936, 937
Psoromic acid, 450
Pteridine, 554, 558, 1063
biosynthesis, 555-558
pigment, 1063
Pteridines, 548
Pterin-hke substance, 1049
Pteroproteins, 549
Pteroylglutamic acid, 554, 1058
Pteroyl-y-glutamyl-y-glutamyl-
glutamic acid, 1061
Pteroylhexaglutamylglutamic acid,
1062
Puberulic acid, J 82, 373
Puberulonic acid, i82, 183, 375
Pulcherrimin, 991
Pulcherriminic acid, 496, 497, 991
Pulvic anhydride, 2i2, 629
Pulvilloric acid, 1254
Pulvinic acid, 235, 236
Pumilin, 1255
741
Purine biosynthesis, 424, 530-533,
558
nucleoside, 559, 560
nucleotides, 529, 559
Purines, 308, 310, 318, 422, 508,
524-538, 557-559, 564
Puromycin, 21, 534, 535, 1047
Purpurogenone, J 90, 411, 874
Putrescine, 291, 292, 466, (>50
Pyo compounds, 492
Pyocyanine, 50i, 1000
Pyolipic acid, 107
Pyoluteorin. J 85, 435, 917
Pyrans, 404-407
Pyrazines. 496
PyTidomycin, 752, 770
Pyridoxal-5-phosphate, 92, 310,
312, 437, 484, 487, 969
Pyridoxamine, 484
phosphate, 484
5-Pyridoxic acid, 484
Pyridoxine, 310, 479, 484-487,
970
phosphate, 484
Pyridoxol, 484
Pyrimidine biosynthesis, 514
nucleotides, 509, 510
Pyrimidines, 309, 508
Pyrocalciferol, 337
Pyroclavine, 951
Pyrogallol, J 86, 187, 377
Pyrogens, 52
Pyrones, 404, 405, 407
Pyrophosphate, 53, 333, 511, 515,
524, 526, 533, 560
Pyrroles, 434, 458
gi.pyrroline-5-carboxylic acid, 307,
435
Pyrromycin, 606
7/-Pyrromycin, 615
e-Pyrromycinone, 606, 616, 617
^-Pyrromycinone, 605
r/-Pyrromycinone, 604
Pyrromycinones, 275, 276
Pyruvate, J5-i7, 80, 81, 309, 315,
560
Pyruvic acid, 14, 18, 46-48, 70,
80, 87, 309, 312, 313, 315,
316, 423, 559
Subject Index
Q,.7,, 247. 511
Quadrilineatin, 401
Quinhydrones, 232
Quinic acid, 143
Quinocyclines, 275, 276, 614
Quinolines, 492
Quinones, 23 J, 449
Quinonoid compounds, 4J0
Racemomycin A, 790, 1256
B, 790, 1257
C, 790, 1258
Ractinomycin A, 1259
B, 1260
Radicalisin, 586
Radicinin, 413, 871
Raisnomycin, 1261
Ramalic acid, 454
Ramalinic acid, 451
Ramalinolic acid, 474, 471
Rammacin, 1262
Ramycin, 1263
Rangiformic acid, 49, 117
Raromycin, 1264
Roseomycin, 1265
Ravenelin, 886
Resistomycin, 575
Resorcinol, i88
Respiratory chain, 447-450, 561—
564
Reticulin, 55
Rhamnose, 723
Rhizobacidin, 1266
Rhizocarpic acid, 636
Rhizoic acid, 464
Rhizopin, 934
Rhizopterin, 1055
Rhodocidin, 1267
Rhodocladonic acid, 212, 565
Rhodomycetin, 529, 1271, 1305
Rhodomycin, 22, 275, 276
A, 276, 596, 1180
B, 276, 598
/3-Rhodomycinone, 276, 599
y-Rhodomycinone, 276
e-Rhodomycinone, 276, 600
Rhodomycinones, 275, 276
Rhodophyscin, 595
Rhodopin, 169
Pfizer Handbook of Microbial Metabolites
742
Rhodopurpurene, 168
Rhodosamine, 22, 276, 615
Rhodovibrin, 180
Rhodoviolascin, 184
8-Ribityl-6 , 7-dimethyllumazine ,
1053
8-Ribityl-6-methyl-7-oxylumazine,
1052
Riboflavin, 516, 529, 555, 1056
biosynthesis, 557-560
Riboflavin-5'-phosphate, 560, 1057
9- ( ^-D-Ribof uranosyl ) purine , 1031
Ribonucleic acid (RNA), 345,
508-510, 526, 532, 534
Ribonucleoprotein , 1170
D-Ribose, 18, 59, 60, 317, 318, 483,
560
Ribose-5-phosphate, 17, 318, 458,
524, 530
Ribose-5-phosphate-l-pyrophos-
phate, 524, 530
5-Ribosyluracil, 509
Ribulose-5-phosphate, 17
Rifomycin B, 593
Rimocidin, 122, 231, 1095
Ristocetin A, 1268
B, 1269
Roccellic acid, 49, 50, 110
Rosenonolactone, 160, 328, 330
biosynthesis, 159, 160
Roseonine, 731, 732, 734, 735, 790
Roseopurpurin, 558
Roseothricin A, 21, 729, 732
Rosololactone, i59, J 60, 330
Rotaventin, 1270
Rotiorin, 879, 883 "
Rubidin, 1305
Rubiginic acid, 72, 406, 864
Rubiginol, 72, 406, 862
Rubixanthin, 170
Rubrofu sarin, 887
nor-Rubrofusarin, 890
Rubroglaucin, 560
Rubromycin, 1271
Rubropunctatin, 880
Rubroskyrin, 587
Rugulosin, 580, 586
Ruticin, 1272
Rutilantinone, 276, 606
SA, 247, 511
Saccharic acid, 29
Sacromycin, 1022
Salazinic acid, 448
Salmotin, 905
Sambucinin, 750
Sarcidin, 1273
Sarcinaxanthin, 186
Sarcinene, 186
Sarcolactic acid, 75
Sarcosine, 310, 337, 664, 770,
793-812
Sarkomycin, 294
Saxatilic acid, 448
Sclererythrin, 1152
Sclerocristallin, 1152
Sclerotiorin, 411, 881, 883
Scleroxanthin, 1152
Scopularic acid, 455
Secaclavine, 954
Secalonic acid, 1152, 1274
Sedoheptulose-1 ,7-diphosphate,
142
Sedoheptulose-7-phosphate, 1 7
Sekikaic acid, 454, 471
Seligocidin, 1275
Senecioyl coenzyme A, 92
Serine, 300, 301, 303, 304, 309-
311, 341, 342, 419, 435, 461,
471, 497, 516, 552, 739, 759,
773, 813, 816, 822, 824, 826,
836, 839, 841
D-Serine, 422, 671, 766, 784
L-Serine, 317, 459, 667, 723, 727,
734, 735, 751
Serotonin, 458, 935
Serratamic acid, 723
Setoclavine, 945, 946
Shikimic acid, 143, 297, 3J7
biosynthetic route, J 42, 143,
181, 188, 236, 284, 316, 317,
458, 493
5-phosphate, 3i6
Sinanomycin, 918
Sirenin, 1276
Sistomycosin, 122, 234
Skyrin, 234, 580, 582, 587
SLR Factor, 1055
Soframycin, 63
743
Solanorubin, 168
Solorinic acid, 574
Sorbicillin, 107, 117, 423
Spurassol, -10()
Spermidine, 291, 292, G55
Spermine, 291, 292, 660
Sphaerophoric acid, 462
Sphaerophorin, 472
Spheroidenone, 182
Spheromycin, 885
Spiculisporic acid, 49, 50, 105, 109
Spinulosin, 145, 497
Spiramycins. 21, 119, 286-288
Spiramycin I, 286
II, 287
III, 288
Spirilloxanthin, 184
Sporidesmin, 1277
Squalene, 154, 157-159, 351
Squamatic acid, 461, 462, 861
Stachydrine, 702
Staphylomycin M, 742, 754, 770
M.., 755, 770
S, 755, 770
Stearic acid, 50, 51, 113
Stearyl alcohol, 49
Stereocaulic acid, 480
Sterigmatocystin, 892
Steroid glycoside, 118
Steroids, 154, 157
Sterol esters, 50
Sterols, 46, 93, 158, 160
Stictaic acid, 455
Stictic acid, 455
Stictaurin, 2J2
Stipitatic acid, 182, 372
Stipitatonic acid, 182, 183, 374
Strepogenins, 333
Strepsilin, 856
Streptidine, 19, 54
Streptimidone, 315
Streptobiosamine, 54
Streptocardin, 1278
Streptogramin, 746, 770, 832
Streptolidine, 729, 731
Streptolin A, 729
Streptolins, 729
Streptolydigin, 1279
Streptomycete antibiotics, 19
Subject Index
Streptomycin, 19, 54, 63-65
B, 65
Streptomycins, 19
Streptonivicin, 885
Streptose, 19, 54
Streptothricin, 21, 729, 731, 732-
737, 790
Streptothricin BI, 60
BII, 60
Streptothricins, 60
Streptovaricin A, 1280
B, 1281
C, 1282
Streptovitacin A, 311
B, 312
Co, 313
D, 314
Streptozotacin, 1285
Strophanthin, 118
Substance 1404, 1286
Subtihn, 420, 815, 816
Succinate, 17, 447, 483
Succinic acid, 47, 48, 80, 313, 466,
550
Succinic dehydrogenase, 46, 449,
561
Succinyl coenzyme A, 47, 424,
437, 446, 447, 527
transferase, 93
N-Succinyl-L-diaminopimelic acid ,
719
N-Succinyl-L-glutamic acid, 714
Sucrose, 24
Sugar nucleotides, 22
Sugars from streptomycete anti-
biotics, 19
Sulcatic acid, 450
Sulfocidin, 1288
Sulfactin, 1287
Sulfanilamide, 531
Sulfate, 310, 524, 525
Sulfokinase, 525
Sulfur, 310, 427, 461, 498
Sulfur bacteria, 930
Sulochrin, J 9 J, 428
Sumiki's acid, 398, 852
Suprasterol, 154
Synnematin B, 312, 421, 724, 905
Pfizer Handbook of Microbial Metabolites
744
T 1384, 918
Tabtoxinin, 717
Taitomycin, 1291
D-Talose, 21, 45
Taraxerene, 362
Tardin, 1292
L( + )-Tartaric acid, 82
Tartronic acid, 72, 80
Taurine, 301
Telomycin, 769, 770
Teloschistin, 557
Tennecetin, 122, 236
Tenuazonic acid, 80, 151
Tenuiorin, 484
Teropterin, 1061
Terpene biosynthetic route, 81,
159, 160, 239
Terphenylquinones, 235, 236
Terramycin, 274, 610
Terramycin-X, 274, 612
Terrecin, 1293
Terreic acid, 492
Terrein, 295
Terrestric acid, 152
Tertiomycin A, 284
B, 285
Tetracosanoic acid, 122
Tetracycline, J 85, 190, 273, 613,
1139
biosynthesis, 273-275
Tetracyclines, 273
Tetracyn, 613
2,3,4,6-Tetradeoxy-4-dimethyla-
minohexopyranose, 21
Tetrahydrofolic acid, 310, 311,
333, 515, 530
6,7,6',7'-Tetrahydrolycopene, 175
Tetrahydronicotinic acid, 483
Tetrahydroxybehenic acid, 121
Tetrahydroxybenzoquinone, 490
4,5,4',5'-Tetrahydroxy-l,l'-dina-
phthyl, 524
l,4,7,8-Tetrahydroxy-2-methyl-an-
thraquinone, 551
3,4,3',4'-Tetraoxo-y3-carotene, 162
Tetraphenylhydrazine, 502
Tetrapyrrole, 440
Tetronic acid, 79
acids, 79, 398
Tetrose phosphate, 18
Thamnolic acid, 121
Thelephoric acid, 507, 511
Thermophillin, 568
Thiactin, 1294
Thiamine, 418, 422, 423, 560, 903
Thiamine diphosphate, 904
Thiamine pyrophosphate, 15, 16,
47, 92, 315
Thiazole, 418
/?-(2-Thiazole)-/:?-alanine, 760
Thiazolidine-4-carboxylic acid, 422
Thioaurin, 1294, 1295
6,8-Thioctic acid, 99
Thiolutin, 434, 914
Thiomycin, 1296
Thiophene, 418
Thiostrepton, 831
Thiosulfate, 310
Thiourea, 1
D-Threitol, 20
Threonine, 300-302, 303, 304,
305, 310-312, 315, 341, 342,
444, 752, 755-757, 759, 762,
769, 773, 831, 836, 839, 840,
1079
L-Threonine, 675, 771, 776, 777,
780-785, 793-812, 825
Threonine synthetase, 485
Thymidine diphosphate rhamnose,
1019
Thymidine-5'-phosphate, 552
Thymine, 422, 445, 509, 515, 516,
529, 552
Tiglic acid, 417
Tobacco mosaic virus, 5iO
a-Tocopherol, 438
D-L-Tocopherol, 239
Torularhodin, 161, 185
Torulene, 161, 185
Totomycin, 1297
Toxin of Helminthosporium victo-
riae, 768
Toxin of tobacco wild-fire disease,
717
Toxoflavin, 1029
Toyokamycin, 1104, 1105
745
Toyocamycin, 1298
Trametenolic acid, -MO
Transaminase, 92, 485
Transamination, 290, 291, 485,
486, 493, 550
Transhydrogenase (TPN-DPN),
449
Transmethylation, 311
Transpropionation, 447
Trehalosamine, 20, 40
Trehalose, 43
Trehalose phosphate, 511
Tricarboxylic acid cycle, 46, 47
Trichomycin, J 22, 251
Trichothecin, 160, 327
biosynthesis, 159, 160
Triglycerides, 50
Trigonelline, 700
2 ,4 ,5-Trihydroxyphenylglyoxylic
acid, 387
Trimethylamine, 291, 466, 643
( + )-2,4L,6L-Trimethyltetracos-2-
enoic acid, 125
Triose, 405
Triose phosphate, 14, 18, 317, 458,
459
Triosephosphate dehydrogenase,
13
isomerase, 13
Triphosphopyridinenucleolide
(TPN, Codehydrase II), 17,
47, 54, 93, 449, 479, 480,
510, 550, 976
Triphosphopyridine nucleotide (re-
duced) (TPNN), 315, 449,
528, 553
Triseclavine, 946
Triterpenes, 93, 154, 157
Tritisporin, 549
Tropolone acids, 181
biosynthesis, 181-183
Tryptophan, 143, 299, 301, 302,
305, 306, 317-319, 336, 337,
342, 458, 470, 482, 483, 493,
756, 757, 789, 815, 831, 839
^-C'*-Tryptophan, 470, 471
L-Tryptophan, 459, 460, 471, 709,
790, 792
Tryptophanase, 306
Subject Index
Tryptophan biosynthesis, 317, 318
synthetase, 485
Tubercidin, 1299
Tuberculin, 342
Tuberculostearic acid, 115, J22,
124
Tubermycin A, 997
Tumulosic acid, 356, 358
Tylosin, J J 9, 290
Tyramine, 466, 657
Tyrocidine, 1145
A, 791
B, 792
Tyrocidines, 786
Tyrosine, J 43, J 82, 305, 316, 341,
342, 466, 497, 813, 824, 826,
836-839
D-Tyrosine, 1078
L-Tyrosine, 706, 791, 792
?neta-Tyrosine, 461
Tyrosine biosynthesis, 316
Tyrothricin, 786, 787, 789, 791,
792
Ubiquinone, 247, 511
UDPG, 1018
Umbilicaric acid, 479
Umbilicin, 39
Unclassified compound, 1300
Undec-3,5,6-triene-8,10-diynoic
acid, 207
10-Undecenoic acid, 101, 102
2-n-Undecyl-4-oxyquinoline N-
Oxide, 985
10-Undecylenic acid, 102
10-Undecynoic acid, 101
Ungulinic acid, 119
Unnamed antibiotic, 1301
Unsaturated Co acids, 50
Uracil, 22, 508, 529, 552, 1006,
1044
Urea, 308
cycle, 308
Ureidosuccinic acid, 5J4
Uric acid, 1025
Uridine, 1009
diphosphate, 510-512
Uridinediphosphateacetylglucosa-
mine, 5J0, 5J2, 1018
Pfizer Handbook of Microbial Metabolites
746
Uridinediphosphate-L-arabinose,
511
Uridinediphosphategalactose, 510,
511
Uridinediphosphateglucose, 520-
512, 1018
Uridinediphosphateglucuronic
acid, 511
Uridinediphosphate-D-xylose, 511
Uridine nucleotides, 343, 510-512
Uridine-3'-phosphate, 1011
Uridine-5'-phosphate(UMP), 510,
515
Uridine-5'-pyrophosphate, 343
Uridine-5'-triphosphate, 510-512,
515
Uridylic acid, 1011
Urocanic acid, 305
Uroporpliyrin III, 438, 440, 929
Uroporphyrinogen, 438, 439
III, 440
isomerase, 439, 440
Uroporphyrins, 438
UrsoHc acid, 361
Usnarin, 460
Usnetic acid, 480
Usnic acid, 159, 212, 400, 401,
454
d-Usnic acid, 460, 860
/-Usnic acid, 462, 857, 860
Ustic acid, 393, 395, 412
Ustilagic acids, 127
Ustilic acid A, 127
B, 127
Ustin, 456
II, 457
cis- Vaccenic acid, 51, 111
Valine, 91, 301, 303, 304, 309,
314-316, 340-342, 466, 497,
724, 759, 768, 798, 799, 802-
810, 815-818, 820, 821, 828,
829, 831, 838, 839, 841, 845,
846, 849, 1078
D-Vahne. 337-339, 419, 758, 767,
778, 790, 793-795, 811, 812
L-Valine, 337-339, 419, 682, 758,
760, 778, 786-788, 790-792,
834
D-Valine-1-C^*, 338
L-Valine-1-C^*, 338, 420
Valine biogenetic pathway, 81,
314, 315
Valinomycin, 123, 337-339, 747-
750, 758, 767
Vancomycin, 1302
Variolaric acid, 442
Variotin, 1303
V-Compound, 557, 560, 1052
Vengicide, 1304
Ventosic acid, 121
Verdazulene, 321
Versicolorin, 543
Vertimycin C, 1305
Vicanicin, 445
Victoxinine, 768
Vinacetin, 594
Vinactane, 727
Vinactin A, 727
Viocin, 727
Violacein, 458, 942
Violacetin, 1306
Violarin, 1307
Viomycin, 727, 729, 734, 735
Viridicatic acid, 153
Viridicatin, 493, 977, 981
a-Viridin, 1308
yS-Viridin, 1309
Viridogrisein, 770
Virtosin, 1310
Viruses, 508
Viscosin, 723, 759
Vitamin A, 239
Vitamin B, 1058
conjugate, 346, 1062
Vitamin Bi, 903
diphosphate, 904
Vitamin B.., 1056
Be, 970
Bjo, 311, 434, 436, 440-444,
446, 447, 516, 528, 529, 552,
554, 931
pseudo-Vitamin Bj^, 442, 445
Vitamin Bj., analogues, 442
Vitamin C,"l43
D.., J 54
D3, J 54
E, 438
747
Vitamin C
H, 423
K, 237-239, 512
K...A, 5:n
K.,,B. 5:{2
K...C. 5.-{:{
K,„ 531
d-Volemitol, '56
Volucrisporin, 503
Vulcamycin, 885
Vulpinic acid, 631
Waksman's actinomycin B, 12
Watermelon wilt toxin, 1244
Wortmannin, 1311
Xanthicin, 1312
Xanthine, 532, 559, 1024
Xanthocillin-X, 284, 434
Xanthocillin-Y, 434
Xanthommatin, 235, 336, 1001
Subject Index
Xanthomycin4ike antibiotic,
Xanthomycins, 1314
Xanthones, 185
XanthophvU, 174
Xanthopterin, 554, 556, 1018
Xanthothricin, 1315
Xanthylic acid, 532, 533
Xyhndein, 528
L-Xylose, 88, 109
Xylulose-5-phosphate, 17
Yeast adenylic acid, 1037
cerebrin, 134
Zaomycin, 219, 835
Zeaxanthin, 173
Zeaxanthol, 173
Zeorin, i 57, .36.5, 635
Zymonic acid, 80, 142
Zymosterol, 7 59, 331
1313
EMPIRICAL FORMULA INDEX
This index lists the known empirical formulas of microbial
metabolites as an aid to future characterizations. Boldfaced
numbers are entry numbers, while italic numbers are page
numbers reflecting occurrence in a chapter or section introduc-
tion. The appendixes and addendum are not indexed.
NHg, 637 C,H704N, 668
CHoOo, 67 C^HsO.., 6
CH4N0S, 1 C4H^03N.., 669
CH5N, 638 C4HSO4N.., 670, 671
CH5N3, 2 C4HSO4N4, 672
C0H0O4, 68 C4H9O0N, 673, 674
C0H4, 3 C4H9O3N, 675
C0H4O2, 69 C4H9O3NS, 676
C0H5O0N, 663 C4H106, 18
CoHeO, 15 C4H10O0, 19
CoHeOoS, 4 C4H10O4, 20
C.,H,N, 639, 640 C4H11N, 648
C0H7ON, 641 C4H11ON, 649
C3H3O0N3, 893 C4H10N0, 650
C3H4O3, 70 C-,H40-., 1068
C3H4O4, 71 C5H4ON4, 1023
C3H40,„72 C-,H402N4, 1024
C3H,,04N, 73 C;H403, 851
C h'C N^'894 C,H403N4, 1025
C3He03, 16, 75 ^•^JJ^^^' ^f
C,U,0„ 76 C5H5N5, 1026
C3H7ON, 642 C5H5ON5, 1027
CgH.OoN, 664, 665, 666 CgHeOoNs, 677
C3H7O3N, 667 C5H6O3, 140
C3H,07P, 77 - C5H6O4, 83, 84
C3H8O3, 17 CgHeOg, 85
C3H9N, 643, 644, 645 C5H7O4N3, 678
C3H9ON, 646 CgHgOo, 417
C4H4O2N,,, 5, 1006, 1184 CHgOoClo, 293
C4H4O3N0, 1184 CgHsOa, 86
C4Hr,ON3, 1007 . C5HSO4, 88
C4H4O4, 78 C,HsOe, 89
C4H4O,, 79 C5H.,N3, 651
C4H6O2N4, 1008 C,H,OoCa/2 • 2H..0, 21
C4H,,04, 80 C.H^O.N, 679
C4H6O5, 81 C,H904N, 680
C4He06, 82 C5H10, 7
749
Empirical Formula Index
C-,H,„0.., 90, 417
C,H,„0,N.., 681
C,H,„0^. 91
C-,H„O..N, (i82. 683
C,H,,O..NS, 681
C-,H,..O..N.., 685
C,H,.0-„ 22
C,H,,N, 652
C-,H,.ANS, 686
C.jH^b-,, 863
C.-H^O^;, 490. 864
C,.H-,O..N,, 1048
C,,H„O..N4, 1028, 1029
C^-H.jO^, 141, 786,377
C,;H,.,Oj, 852, 865, 866
C,.,H,;0-„ 142
C,jH,.0,„ 92, 93
C^HsO-.N., • HCl, 687
C,;Hs04, 94
CfiH.O,,, 143
CoHsO,, 95
CgHgOoN,, 688
CC.H9O3N3, 689
(CcHioOo)n, 1148
CeHioO.,, 96
CeH,„0,N,, 8
CfiHioOaNo • HCl, 690
CgHioOe, 24
CeHioO^, 25, 26, 27, 28
CeHi„0«, 29
CeHuON;, • HCl, 691
CgHnO^N, 694
CgHioO.,, 9
(CeHio6oN.),s.io, 773
C6H10O3N4, 731
CgHi-.O^, 97
CgHioOe, 30
C,jH,.0-, 31, 32
CeHigOiN, 692
CgHigOoN, 693
CgHisO-.N, 33
C6H13O9P • 3HoO, 34
CeHi^OoNo, 695
CfiHi^OoN^, 696
C6H14O3N., 697, 737
C6H14O6, 35
CeHi^N, 647
C^H^OXl^, 378
C^H-.O^N, 968
C-H,;O..N..S.„ 913, 1295
C.II.At, 186, 379, 491
C-H,jO,, 186, 380, 381, 492, 867
C,H,;0,„ 382
C;H-O..N, 186, 698, 699, 700, 701
C^H.O.N-,, 1160
C^HsOi, 186, 294, 383
C,HsO-„ 296
C-H.,0,N, 712
C,H,„0,, 297
C-H,„0,;, 298
C-H,, ,.,0.„ 1218
C^HhOuP, 98
C,H,.0-„ 299
C-HioOfi, 300
C7H13N3, 653
C7H13O0N, 702
C7H14O4N0, 703
C7H14O4N0S, 704
C7H14O5N0, 717
C.Hi^O,, 36
C-H17O3N, 654
C-H10N3, 655
CgHga.N, 192
CgHgOoN, 190
C8H5O3N, 191
CgHgOS, 895
CsHgO^, 186
CsHeO,, 186, 372, 384, 385
C.,H«Oe. ^85, 373, 386, 387
CgH^N, 933
CgH.OgN, 896
C8H7O4N5, 1049
CsHsOo, 619
C.HsOoNoSo, 914
C,sH,,03, 186, 388, 389, 390, 493
CsHsO^, J 86, 391, 392, 494, 495
CgHsO,, 497, 1164
CsHgO.N.S, 1091
CSH1063, 295
C,sH,,A, 144
C8HioO,;NP, 969
CsH,iN, 656
CsH„ON, 657
CgHuOaN, 970
Pfizer Handbook of Microbial Metabolites
750
CgHioOsN.S, 897
CsHi,0,N, 1237
C,hHi40, 10, 46
C^Hi40..S.>, 99
CHi^O,, 37
CsHi-,ON-„ 915
CsHieO.N.., 713
C9H4O, 193
CH^Ofi, 374
C9H4O7, 375
Cc,H„0, 194
CgHyO., 620
CgHsOs, 195
C9Hh04, 145
CgH.Os, 393, 394, 412
CoHsO-, 395
CoHcON, 621
CcHcO^N, 971
CgH^O-.N, 396
CgHgO.N-,, 1050
CoH^o6.,N..So, 916
C9H10O,, 622, 853
CoH.oO^, 146
C<,Hj„0„, 147
Cc,HiiO.,N, 705
Cc,H„0,N, 706
C,,HnOHN,-i, 1051
(C.,Hi.O:iN.),„ 1066
Cc»Hio6«N., 1009
Cc,Hi.O;N., 715
CoHijA^N;,, 1010
Cc,Hi30,N, 714
Cc,Hi:A.N,P, 1011
CgHiA-.N^, 898
CoHiAsN.jP, 1012, 1013
CoH^.A.Na, 707
Cc,H,50.N,S, 708
CcjHi.A^NS, 899
Ci,Hi,07N3, 715
C.,H,,Or.N, 716
CgHiA.N, 658
CcH.oOo, 1117
C^H.-O-NCl, 659
C.,H.,,04N,, 737
CioH.iO, 197
CoH.O.s, 198
Ci,H,04, 199
CioHeO,, 516
CioHsO, 200
CioH,0„ 201, 202
Ch,HsO,, 397, 868
CjoHsOfi, 185, 398
CioHh04-CioHi„04, 376
CioH.,ON-„ 1030
Ci„H.,O..N, 934
Ci„H,„d, 203, 204
CioHu.O,, 623
Ck,Hu,0-.N.., 920
CtoHioOg, 205, 399, 400, 624, 869
Ci„Hi„04, 206, 401
C,oH,„0-„ 186, 402
CioH^.Ai, 148, 185, 301, 403
CjoH^At. 186
CioH„O..N, 972
CioH.iOeN, 417
C10H1..ON.., 935
CioH,o03, 404, 405
C,oH,..04, 406, 498, 854
Ci„Hi.,04N.., 1054
Ci„H,o04N4, 1031
CioH,..0,;, 149
Ci„H,..OsN.., 1014
C,oH,,0-N, 407, 973
Ci„H,:AsN-., 1032
CioHi,,04N,, 1033
CioHi^O.-^N.,, 1034
CioHi30,N4P, 1035
CioH,404, 499
CioHi40„ 150
CioHi40,N,P, 1036, 1037, 1038
CioH^40sN,P, 1039
CioHiA^N, 151
CioH,oO,N..S, 900
C,„H,«0„ 417
C,oH,,.04, 100
C,oH,fi04N..S, 901
Ci„H,,O.N„ 717
Ci„Hi,,0i:iN-,P3, 1040
C^oH,,0.iN.HS, 718
CioHiAaN,., 902
Ci(,Ho,)Oc,, 38
Cn,H.,,.N4, 660
C„H,0,sNCl,, 917
CiiHA'., 207, 208, 517
751
Empirical Formula Index
CHH^O,. 210. 518
C,..H,,0,N.., 989, 990
C„H,„6.., 211
C,..H.,„0,N... 991
C„H,oO,, 209
C,..H.,,0,..N,P.., 1015
CnH,„0-„ 108
C,..H...,0,„N, 40
C,,H,„0,-,. 109
C,..H.,.,0„, 41,42, 43
C,,H,..0.,N.., 709
C,..H.,..0,.., 44
C,,H,..0;, 212. 025
Ci,H,b..N.., 997
C„Hi..O-„ 410
Ci.,H.,ON.,, 998
C„H,.,0,N..CL, 626
C,,H,„0.„ 218
Cl,H,.,0,;, 411
C,,H,..N..O, 1000
C„Hi.,0,, 412
C,,H,,0,, 1144
CnH,,O.N • H..SO,, 1183
C,.tH,,0,N..S.., 938
CnHi,0,N-„ 1041
C,,H,,0,, 872
C„Hi40„ 152
C,,H,-,0-,N, 1312
CnH,,0,N4, 1299
C,,H,sO,.N„ 1053
C,,H,-,0,. 1292
C,,H.,„.,..0,;N.., 1065
CnH,,0.,N, 1125
C,,H....6,sN,S.., 722
Ci,H,-,0-,N-,. 1042
C,,H.,,0,N.., 1173
C,,H„0,N,;S, 1043
C,,H..,Oi,N,P.„ 1016
Ci,HihO„N..P.., 974
Ci,H..,0-,N, 723
CnH,;0,N. 1301
Ci,H..,.0,N.., 711
CiiH,sO.., 101
Ci4Hio04Cl.., 519
CnHisO^N... 710
Ci4Hu,0-„ 4"l4, 886
CiiHisO.N.,, 719
C,4Hi„0-,N.., 1001
CnH.,„O.N 102
C,4Hi„0,„ 416, 500
CnH.,„0,.N.,. 1138
Ci4Hi„0:, 534, 873
C„H.,..0,N..S, 719
Ci4Hi„0s, 501, 502
C,,H....O,,„ 39
Ci4H„0..N, • 2H..0, 1002
C,..HsbN, 994
Ci4H,..04N4S4, 1295
Ci.H.O.N.., 995
Ci4H,..0-„ 874
Ci.HsO^N.., 996
C,4H,..0,, 628
C,..Hi„0.., 213
C14H1..OH, 186, 875, 1246
C,..H,„0„ 215, 216
C14H1..O,,, 535
Ci..H,„0-„ 413
C14H14O4, 219
Ci..HnO..N.,, 1123
C,4Hi,.0,, 417
Ci..Hi.,0„ 627
Ci4i,H,,0,N3, 1139
C,.,H,..0,, 214
Ci4Ht,0i.>N,, 1285
Ci.,Hi.,0„ 217
Ci4H,sO-„ 1200
Ci.,H,.,0-„ 871
Ci4HisO„N,P, 1044
Ci.,Hi,04N-„ 1298
C14H1CO4N, 1076
Ci-HifiON.., 661, 936
Ci4H.,„0„ 1230
Ci.Hh-.ON.S, 1199
Ci4H.,o04, 302
Ci-.H^jOfi. 153
C14H..0O4N0S, 910
CjoHieO.N^, 1052
C,4H.,oO,N,,, 1121
CioHi.O^N.-P, 937
C,4H..i04N, 1158, 1159
Ci.,HihON4C1..S, 903
CuH.iOoN.S, 905
Ci-.HisO.N^SP.. • HCl, 904
C14H....O4, 303
Ci.,H..uON.„ 986
Ci4H.,..04N..S, 909
CioHooOoN.., 987, 988
Ci4H.,40-„ 1111
Pfizer Handbook of Microbial Metabolites
752
4Ho,06N3S, 724
4Ho50i,N3Po, 1017
4H08O.,, 103
4Ho,03, 104
^HgO^, 536, 537
.HioOg, 538
,Hio04, 539
,Hio05, 540, 541, 542, 551, 856
^HioOg, 543, 544, 545, 546
,Hio07, 549
5H10OS, 547
,HnOoN, 977
-.HioO.N.,, 1141
5H10O4N6, 1055
5H10O5, 415, 550, 887
sHjoOe, 418
,Hi..O,, 551
5H14N4S..OP,, 1075
5H14O, 3'l9
5H14OP., 419, 520
5H14O,, 521, 1126
-,H,40s, 420, 421, 422
5H15O6N3S, 1003
5H16, 320, 321
gHieOoNo, 304
,U,,0„ 878
gHieO.NoS.,, 939
5H17O4N, 3"05
gHi^O-.N, 423
,H,o03No, 1216
5H,o04, 1172
,Hoi04N, 307
gHoiOgN,, 725
,H.,..0, 855
,H.>o03, 855
5H.,.,04, 1177
5H.,304N, 308, 309, 310
5H03O5N, 311, 312, 313, 314
,H..40.., 46
5H.,40i7N..Po, 1018
gHogOo, 889
.HogOgNo, 1174
gH^gOioN,, 45
-,H3oO.)N.., 1192
eHioOoN.., 940
eHioO,Cl4, 441
eHioOe, 548
6H10O7, 442, 552, 553, 554, 857
eHioO.CL, 424
6H10O5, 555, 556, 858
eHjoOe, 557, 558, 560, 561
gHjoO^, 562, 859
6H14O4, 563, 564
6H14O4N.,, 1231
6H14O.,, 890, 891
fiHi^OgClo, 1153
,H,40„ 443
6H14OS, 444
6Hi,04N3So, 941
eHi.No, 944
eHisON.,, 945, 946, 947
gHisO,, 220
oHmOoN.., 948, 949
6H18O4N0S, 906
,H,sO,, 425
gHisO.NoS, 908
eHic03N3S3, 762
cHooN., 950, 951, 952
gHooONo, 953, 954
eH,,o04, 1191
eH_ooO,, 425
gHoiON, 978
eHoiOoN, 979, 980
eHoiOgNgS, 911
6H03O4N, 315
gHogO^N, 314
eHo604NoS, 907
eH.oO^, 105
6H..6O14N0P.,, 1019
gHogOo, 46
6H08O4N4S, 912
6H30O.,, 106
6H30O,, 107
6H30O0, 108
r,H340, 47
,Hi4No03, 1245
^HjoOoN., 1300
VH12O7CL, 426
^HioOgCL, 427
-H10O.J, 5"65
,Hi403N., 981
7Hi40,Clo, 445
7Hi40«No, 1004
.HieO.No, 997
,Hi60„No, 1005
7H16O7, 428, 446, 1092
^HiPeBr, J 86, 431
753
Empirical Formula Index
C,,H,-0,.C1. 186, 430
C,„H,40„, 455
C,;H,,0,., 186, 432
C,.,H,,0-,C1,, 456
C,;H.,„0,i. 186, 433
C,.,H„-,0-,Cl.., 457
C,;H..„0,,N^, 1056
C,.,H,,A^ 1308, 1309
C,:H..iO.»N^P, 1057
C,.,H„,0,,, 458
C,;H..-A;N, 316
C,„H,-OsCl, 459
Ci;H..,04, 154
C,.,H,;OsN, 569
Ci:H.,sO,i, 109
C,«Hi,0,, 570
Ci;H..„ON, 768
Ci,Hi,0„ 571
C,,H,„0,, 155
CioHisOs, 460, 461
Ci,H„OsN-,. 729
CioHisO.,, 462
Ci7.isH,i.,,0,sN,„ 727
Ci.,H,sO,o, 463
Ci;H.,o04, 110
Ci<,H,.,0,iN7, 1058
Ci,H,,0-,N,o(S04).., 730
Ci,H..„0„ 464
CisHioO^, 629
C,„H,,A, 572
CmHioO-,, 630
CioHo,0(5N3S..Cl • CCI4, 1277
CmH,oO..N.>, 434
Ci.>H....03, 435
CmHi-O^, 503, 504
Ci<,H....O(,, 322, 323
CisH,..0,,, 505, 892
C,.,H.,.A>N3, 955, 956
CmHioO-, 506
C,.,H.,40-„ 324, 327
C,sH,..0„ 447
CiaH,40«, 325
CisH.oO^o, 448
Cic,H,eO«, 326
CisHu03N,, 1245
CioHoyO.N • HCl, 598
CmHi^O-Cproposed), 522
CigHogOg, 436
Ci.HuO^Clo, 449
C19H30O4, 156, 157, 158
CisHi40s, 450
CieH3404, 159
C1SH14O9, 451
C,,H,,0,, 114
CisHi^Oio, 452
CicHj.O.N, 1252
CisHjA,, 567
C19H3SO,, 115
CisHisOeCl, 453, 566
C<>qHjo04> 523
CigHifiO^, 860
CooH^oO,,, 507
CisHieO^Clo, 1229
C00H13O3N3, 942
CisHisO^, 454
C00H14O,, 599
CisHisOg, 568
C00H14O,, 525
C,,Hoo,06, 317
C20H15O,, 1189
C^sHofA, 317
CooHieO,, 221
CmHogON, 982
CooHieOg, 632, 633
CisHo-.ON, 983
CooHicO,, 559
CisHo-,O..N, 984
CooHieOio, 465
Ci.H.eOaNio, 918
CooHi^O-.Cls, 466
C1SH07O4N, 1303
C.>oH.,oO-, 573
C18H34O0, 111
CooHooOc, 601
C1SH34O3, 112
C.-oH.oO^No, 992
C1SH34O16, 48
C..„H >0-„ 1248
CmH3,0„ 1224
C.,oH.,.,0„ 467
CisHgeOo, 113
C..oH.,..On, 468
CisHaeOnN^, 52
CoH-.A^N^, 1059
CisHggO, 49, 50, 51
CooH..-,ON3, 919
C19H14O5, 631
C2oH,oOeN„ 257
Pfizer Handbook of Microbial Metabolites 754
CooH.sOs, 328 C20H04O6N, 634
C>oH..,Oic,N,oP, 1045 C02H04O8N., 613
CoHogOoN, 985 C00H04O9N.,, 610
C..0H..9O7N • HCl, 596 CooHogO.,, 861
Co^HogOgN, 1180 CooHofiOg, 471
C,„Ho90,sN • HCl, 597 CooHogO-.No, J 86, 993
C00H30O0, 329 CooHoqO-.N^, 1047
C20H30O3, 330 CoHooO^NgS, 1169
C00H30O7N4, 1167 C..o.o4H3o.340,s 9, 1307
C.,oH3..0s, 1236 C00.03H30.34O11, 1132
(aoH3..09No)„, 1222 C...H34O,, 1247
aoH3609Ns, 731 C00H36O6, 1233
C.0H44N0, 662 Co.,H3.s06, 119
CoiHis04, 222 C.-.H^sOeNo, 738
C01H00O3, 223 C.,..H3904N,, 1129
C01H00O7, 574 C....H40O-, 120
C.iHoiOgNoCl, 602 C....H40OSN4S.., 719
CnH^oOg, 880 C0..H44O6, 121
C2iHo<,05Cl, 881 C..3H00O6, 611
C01H00O7, 1176 C.,3H.,40-„ 883
CoiH^oOg, 600 C.,3H..-,0,N • HCl, 612
CoiHooOgNoCl, 603 C^H.-oO,, 884
C01H04O7, 469 C.,,H ,,0,, 474
C21H26O,, 882 C23H.,80,, 472, 473
C21H27O14N7P2, 975 C03H..9O1.N, 57
C.,H„„0,-N.P„ 976 r H n t\t isi.
C21H08O17N-P3, 976
CsiH.gOnN, 1297
C2.sH29-3l6,N3, 1314
^21-29-11-, — / C23H4,Oj4N5, 59
CoiHgoOg, 116 C.,3H4,.OioNp., 60
C2iH3,08N, 1180 C" H O 475
C2.H3eO,N, 1276 C H o" 476
C.oiH360,eN,SP3, 1046 T H O N T 7fi9
C.1H38O6, 117 C24H23O5N5S4, 762
C:;H38o!, 118 C24H2SO4N4, 957
C"oiH390ioN„ 54 C2,H2909Nio, 1304
C01H39O13N,, 55 C24H30O7, 477
C21H41O12N7, 56 - C24H3oO,s, 478
CooHifiOe, 575 C24H3iO-N,Clo, 739
C22H16O7, 604 C..4H33O2N-, 9'22
G22HieOi2, 470 C24H36O9N2S, 923
C-HigOe, 1140 C.4H36 40O9N0S, 258
C22H20O,, 1134 C24H;sOio, 1193
C21.H20O8, 605 C24H40O6, 1232
C2i.H2o09, 606 C24H41O6N, 268
C22H20O10, 576 Co4H4.,06No, 740, 741
C22H2iO,N2Cl, 607 C:.4H4:0,N:, 750
C22H230,N, 870 Co4H4;0-„ 122
C22H230,N2Br, 609 C:,4H5oO;N8, 742
C02H23O8N2CI, 608 C.>4H4oO-N2, 750
755
Empirical Formula Index
C.^H^.OhN,, 729
C..4H-,„0.,, 1198
C..-,H,„0., ■ H..O, 508
C..-,H..„0,iN.., 614
C..,H....O„„ 479
C..-,H..-,0,;N, fi-iS
C..-,H..sO^, 480
C..-,H,oO,, 437
C.,,Hi„0.. 481
C..-,H,,0,;N,. 743
C..,H,.,0:, 482
C..-,H,..0,. 483
C..-,H,-,ON,. 924
C..-,H,,0,N-„ 1020
C..,H,,,0,N-,C1.>- 751
C..-,H,.,0,N, 259
C..-,H4„0:, 1087
Co-,H4,0„N, 260
C05H43O-N, 261, 262, 263, 1106
C^H^^O.N.., 748
C.>-,H4-,OioN, 264
Co,H,60sNCl, 265
C..-,H,,Oi,N-„ 64
C..-,H-,oO.., 123
C..,,Ho,Oio, 484
C.,,H,,.06No, 224
C.,.H;^„Os, 485
aeH^.Os, 486
C26.l'tH3oO,kN,, 752, 1103
C.,,.H3,0,N;^, 746
CooH3,Oi,,N, 577
C0CH34O7, 318
C,oH„.0<,N., 270, 272
C,6H3,0,;N, 628
CogHasO;, 578
C..,,H,„07, 579
C.iH^.Os, 1262
C,,H,,.,,0,N,, 749
C,eH„;0,N., 747
Co,,H4,0,;R., 1113
C..,;H,,.0.., 124
Co,H3,0i,N,Po, 1060
C.7H3SO4, 160
C,,H3,0,„N,„ 753
C,;H4oO,N,sS3, 1287
C,-H4,A.N.'. 1310
C27H40O1GCI, 1156
C.HnO, 331
C..-H,.,0, 332
C.-H^.O, 332. 333
C..;H,-OhN. 266
C..;H,.,0,-N:, 65
C.-Hv.O.., 125, 126
C..sH.,.iO,,N, 636
C.H.sO,.., 1151
C.,sH,..0„ 1235
C..,H.,.,0.„ 487
C..sH,,jOsN.„ 754
C..sH,-O..N„ 943
C.,sH,,0,„N,;, 1167
C..sH,„O..N.., 269, 1099
C..sH,oO„N,;, 1021
C.,sH,.,0, 334, 335
CsH^AiN, 1122
C.H.^O, 336, 337, 338
CsH^.O,, 339
Co^H4,.0, 340, 341, 342, 343
C..hH4,.03, 344
asH4,Ai, 1234
CosH^hO, 345
C..sH4<,0,N, 274
C.sH^cAsN, 267
C9sHr;g, 11
Co,H..oO,„, 1107
C.^H^Ar-Ng, 1061
CkjH^^O.,, 488
CocH.eO,,, 489
CoH^.N^SOe „ 1102
C.^HasO-NgS, 1089
C0CH40O-, 128
CKtH^.O-NgS^Cr, 1313
Co^H^.OgNfi, 1022
C09H44O9, 1073
CgH^eOo, 1244
C.>9H-,oO.., 438
C3,HisOio, 580
CsoHisOii, 581
CsoH^sOi,, 582
C;{oHihO]s, 583
C3„H..„0,.., 584, 888
C.3oH....O.s, 585
C3„H...,Oio, 586
C30H....O1.,, 587, 588
C3oH.,,Oi4, 1152
CaoHo.Oio, 589
C-30H28-30O11, 592
Pfizer Handbook of Microbial Metabolites 756
C30H34O4N4, 243 C,,H,,0,N4Fe®0He, 925
CsoHggOnN, 615 C^.H^.O^N^, 926
CaoHg.OsN,, 958, 959 C,,H,,.,,0,,N, 1280, 1281, 1282
C3oH3,OiiN, 616 C,,H,,Oj,N, 226
C30H46O0, 346 C3,H,,0s, 1088
C30H46O3, 347 C.,4H,,N0c,, 1162
C30H48O0, 348 C34H,,,OioN3, 921
C30H48O3, 349, 350, 361 C3-,H,c,0,N,, 966, 967
C30H48O,, 225, 1228 C3r,H4(.09NgS, 757
CsoH-^o, 351, 362 C3,-,H,,OioNsS, 756
C3oH,oO, 352, 363 C3,H,oOioNo, 1279
CgoH.oOioN.., 1112 C3,H530i4N (proposed), 227
C30HV.O, 364 C3,H5c06Ns, 786
C30H50O0, 365 C35HeoOi3, 239
CaoH.oOa, 353, 366 (C35HeoOi4No)„, 1217
CgiHo'eOn, 591 C3,H,i0^oN, 276
C3iH;o.3'^Oi4, 1274 C36H3SO8N4, 927, 928
C3iH3e6„N.., 885 C36H4,Oi4N9S, 1241
C3iH390,N-„ 960, 961 CgeH^Oj^N, 228
C3iH3,Oc,N3, 1204 C36H,gOio, 1187
C31H46O4, 354 C3oH,oOioN4, 758
C31H4SO3, 355 CgeHenOigN, 277
C31H48O4, 356 C36H66O10N6, 759
C3iH,o03, 357 C3eH,403, 66
C3iH,o04, 358, 359 C3,H4gOo, 161
C31H60O, 13 C37.46Hci-750a3-16N, 1238
CgiHo-.O, 14 C37H61O14N (proposed), 240
CaiHeoOo, 129 CsTHeo^eOi,, 127
CgoHooOg, 509 C37H67O12N, 278
C32H26-3oC)l4' 526 P H O N 27Q
^S2"-28^U^ ^A" p TT f) j^ 7Ke
r" 14 n 11^^ '-'38-39"47-48^9^^6' ' -'-'
*--32J^30 32'-'l4. A*^^ P H O IV «! 1987
C30H32O14, 439, 527 C38H55U7^Jn=»4, 1^87
C3IH34O14, 440 C3.,H57.6i07.8N7S, 760
C3oH4iO,N5, 962, 963 C3SH63O14N, 280
C30H40O8, 367 - CgsHo^Oi^N, 281
C32H4e09No, 1279 C39H51O14N, 593
C32H4HOS, 368 C39H58O4, 512
C32H,40c,N, 1070 C39H6,OnN5, 763
C32H54O10, 238 C39H690„, 1225
C32H(joOi4, 130 P H O N 929
'-'32^62'^3' ^-^A r" T4 n lfi9
PHD 1^9 ^40'^4S^4) ^"'^
'--32rt64^3, '-^-^ P T4 n Ifi^
C33H3oO,4N3, 1259 C40H52U0, 163
CooHo.O.N,, 964, 965 C40H,,,, 164, 165, 166, 167, 168
C33HV.,04, 360 C4oH,eO, 169, 170, 171
C33-38H54-660n-i3N, 275 C4„H,,02, 172, 173, 174
C33H60-62O14N, 1143 C4oH,70iiN„ 764
C34H.>60n, 528 C40H60, 175
757
Empirical Formula Index
C4oH,..iO,oN,oSFe, 765
C40H,,,, 176, 177
C4oHli40l3' 11^8
C40.412Hot.7iOh>N, 1083
C4oH(;s, 178
C,oHe,OioN„ 767
C^oH.oOsNP, 136
C4iH-,^0.., 532
C4,H-,,0, 179
C^iH-.^O... 180, 181, 182
C41H00O, 183
C4iH6c.ToO,4, 229, 1077
C4oH,.,0„;N, 284
C4..H,;oO.., 184, 185
C^oH^-Oi-.N, 282
C4oHfiT0ie,N, 283
C4oH:30ieN, 1084
C4oH,-,0-,N, 133A
C4oHs-,0eN, 133B
C43H-1O17N (proposed), 285
C44H-,90a8N±CHo, 617
C44H,oOioNs, 770
C44H6-,0,N<„ 787
C44Ho„04, 513
C44HS9O5N, 134
C45H5sO„Ns, 1205
C4,H,sOi-,N.., 286
C4,H,90i,N, 290
C45Hs50ioN,3, 771
C46..2H8.10N4.T, 1118
C46H30O10, 511
C46H64O0, 531
C46H730o„N (tentative), 248
C46H7-O19N (tentative), 230
C46H80O13, 1086
C4vH,,OioN5, 772
C4,HsoO,fiNo, 287
C48H6oOie, 1166
C4sHs..0ifiN.,, 288
C4c,H6i0..4Ni3, 1062
C4c,H630i8Ni3S, 774
C49H74O4, 514
C49-50H87.9lOi8N, 291
C,oH„oO,oN,,S,, 775
Cn2H,,,0,..N„, 744
C52H,0404, 137
C,.3Ho303,N,„ 1243
C,3Hi,,,0,3Ni„, 776, 777
C54HciO,s,Ni3, 1214
C54H8,04, 515
C54H8.O18N0 (proposed), 250
C55Hv40,;N4Mg, 930
C56H,,0,N,H, 778
CsgHsoO,, 533
CceHyeOiaNi., 779
CseHae-y^OiaNie, 781, 782
(C56-6oH96.iy40.9.3i ),Mg, 1110
C56-63Hu,5-ll-Ooo.22N3, 1196
C57H86O10N10, 811
CggHssOieNi,, 798
C58Hio20,N4, 1142
CggHseOieNjo, 812
C59H87O17N10, 802
C59H88O16N10, 806
CsoHooOifiNi,, 800
CeoHooOieNi,, 799
CeoHgoOiyNio, 788
C60H128O32N00, 790, 1257
C61H89O17N10, 803
CeiHgoOieNio, 794
C61H90O17N10, 805
CeiHgoOieNi,, 801
CeoH^oOieNio, 795
C6,HssOi4Ni4PCo, 931
C64H9„Oi6N:o, 793
C,,H,,0,,N,,, 807
C,,H,,0,,N,., 796
C65H8,03oNi3, 813
CesHasOieN.o, 797
C65-67H96-104O:,Ni8, 1226
CeeHse^isJ^iS' 791
CecHioaOir.Ni.S, 814
Ce8H880:3Ni4, 792
C84Hi7404(±5CHo), 138
Ci4sH,,„0,,N„„ 375
Ci86H366O,7(±10CH,), 139
MICROORGANISM INDEX
Boldfaced numbers are entry numbers of metabolites pro-
duced by a microorganism. Italic numbers are page numbers
and indicate mention in a chapter or section introduction. The
appendixes and addendum are not indexed.
Absidia ramosa, 934
Acetobacter acetosum, 72
melanogenum, 21, 25
spp., 31, 32
suboxydans, 16, 26, 82
xylinum, 512
Acremonium sp., 501
Actinomyces atroolivaceus var.
mutomycini, 1218
fiavochromogenes var. helio-
mycini, 1171
(Streptomyces) ftavus, 12
genus, 118
globisporus, 1097
longispori, 1187
Actinomycetaceae buchanan, 713
family, 118
order, 118, 119
Actinomycete, 14, 334, 1252
Actinoplanaceae family, 118
Actinoplanes genus, 118
Aerobacter aerogenes, 19, 143,
306, 317, 449, 528, 532
Agaricus campestris, 707
(Clitocybe) nebularis Batsch.,
1006, 1007, 1023, 1031, 1033
Agrobacterium tumefaciens, 51,
111, 114
Agrocybe dura, 190
Alectoria sp., 860
implexa (HofFm.) Nyl. f. fuscid-
ula Arn., 452
japonica Tuck., 487
ochroleuca (Ehrh.) Nyl., 363
ochroleuca Mass., 467
sarmentosa Ach., 487
zopfi Asahina, 450
Aleuria aurantia, 164, 165
Algae, 24, 35, 43, 212, 213, 231,
301
Allomyces sp., 1276
arbiiscula, 166
javanicus, 165, 166, 168
macrocygna, 166
moniliformis, 166
Alternaria radicina, 871
solani Ell. and Mart., Jones and
Grout, 116, 1074
tenuis Auct., 151, 415, 416, 418,
419, 420, 421, 422
Amanita mappa, 661
muscaria (Linn.) Fries, 43, 74,
508, 537, 641, 650, 658, 659,
707, 1023, 1024
phalloides, 11, 47, 343-345, 351,
652, 756,757, 1198
Amphierna rubra, 29
Anaptychia hypoleuca, 365
speciosa, 365
Anthomyces renkaufi, 29
Anthurus aserioformis, 168
muellerianus, 638
Anzia gracilis, 477
leucobatoides f. hypomelaena,
477
opuntiella Miill. Arg., 477
Armillaria mellea, 20, 537
Arthrobacter sp., 1179
Ascomycetes, 1056
Ashbya gossypi, 557, 558, 721,
1056
Aspergilli, 19,418, 1049
(white), 81
Aspergillus amstelodami (Man-
gin) Thom and Church, 546,
552
candidus, 872, 1125
chevalieri, 555
citricus (Wehmer) Mosseray,
516
759
Microorganism Index
Aspergillus amstelodami
clavatiis, 105, 852. 8(i7
elegans. 1107
flavipes (Bainier and Sartory)
Thorn and Church, :^91, 429
flavus, 24, 73. 865, 910. 986-989
fimiigatus Fres., 79, 318, 335,
336, 339, 496, 497, 938
fumigatus mut. Jielvola Yuill,
367
giganteus, 867
glaucus, 435, 436, 555, 560, 563,
564, 852, 865
itaconiciis, 1181
mangini, 435
vielleiis Yugawa, 399
nidulans, 50, 456, 457, 466, 547
niger, 29, 31, 42, 68, 82, 84, 88,
92, 95, 143, 334, 852, 890, 901,
934, 302
niveus, 872
ochraceiis, 144, 399
onjzae, 73, 312, 537, 683, 694,
702, 852, 865, 927, 1025, 1237
parasiticus, 24
quadrilineatus Thorn and Raper,
401, 547
ruber (Man gin) Raper and
Thorn, 555
sclerotiorum, 990
spp., 35, 78, 86, 310, 404, 435,
436, 778
sydoivi, 135, 686
tamarii, 865
teireus mutant, 89
terreus Thorn, 20. 80, 83, 295,
394, 424, 426, 427, 492, 867,
872, 1293
ustus, 412
versicolor, (Vuillemin) Tira-
boschi, 543, 892
wentii, 17, 852
Auxotrophs, 143
Azotobacter vinelandii, 237, 448,
514
Bacillus aerosporin, 780
alvei, 830
anthracis, 703
Bacillus aerosporus
brevis, 531, 786. 787. 789. 791.
792, 826,827, 1157
brevis var. Gause-Brazhnikova,
788
bruntzii, 436
cepae, 1090
cereus var. mycoides, 971
cereus var. terminalis, 968
circulans, 776
circulans mucoid variant, 779
coli, 17, 18
colistinus, 825
krzemieniewski, 779
laterosporus, 1182
licheniformis, 814, 844-846
megatherium, 37, 440, 714, 968
mesentericus, 19, 238, 763
polymyxa, 19, 785
prodigiosum, 919
pumilis, 762, 1091, 1255
pyocyaneus, 1000, 492
sphaericus, 479, 968
spp., 306
subtilis, 17, 19, 185, 396, 422,
483, 814-816, 836-839, 842
1078, 1115-1117, 1151, 1157,
1269
subtilis var. aterrimus, 1109
Bacteria, 14, 15, 17, 35, 87, 154,
185, 237, 290, 291, 308, 316,
332, 333, 436, 480. 488, 492,
496, 508, 509. 531, 532, 969,
1060, 1062, 1040
Baeomyces fungoides Ach., 461
roseus Pers., 461
Basidiomycete, 1085
B-841, 220
Basidiomycetes, J 07, 238, 291,
427
Blastomyces brasiliensis, 3
dermatitidis, 3
Boletus appendiculatus, 638, 652
badius Fr., 537
chrijsenterou Bull., 537
edulis Bull., 2, 638, 641, 643, 650,
652, 656, 707, 934, 1023, 1026,
1027
elegans, 650
Pfizer Handbook of Microbial Metabolites
760
Boletus appendiculatus
luridus Schaeff. ex Fries, 537,
652
luteiis, 650, 656
qiieletii, 652
regius, 652
sanguineus, 652
satanas Lenz, 537
spp., 78, 305
subtomentosus Linn, 537
versipellis, 641
Botrytis alii, 302
cinerea, 1
Buellia canescens (Dicks.) De Not,
441
Caldariomyces fumago, 293
Calicium chlorinum Korper, 631
hyperellum. Ach., 636
Calocera viscosa, 345
Calonectria sp., 997
Caloplaca elegans (Link), 555
Candida flareri, 558
guillermondi, 558
parapsilopsis, 558
pulcherrima (Lindner) Win-
disch, 991
Cantharelhis cibarius, 164-167
cinnabarinus , 163, 165
multiplex Underw., 507
spp., 168
Carpenteles brefeldianum Dodge
(Shear), 430
Cephalosporium sahnosynnema-
tum, 312, 367-371, 905, 911
spp., 368
Ceratostomella fimbriata, 620, 851,
853-855
Cetraria collata Miill. Arg., 488
crispa Nyl. ( = C. tenuifolia
Howe), 158
crispa (Ach.) Nyl., 363
cucullata (Bell.) Ach., 363
delisei (Bory) Th. Fr., 363
hiascens, Th. Fr., 363, 476
islandica (L.) Ach., 157, 363,
470
islandica Ach. var. orientalis
Asahina, 158
Cetraria collata Miill. Arg.
islandica F. tenuifolia, 156
japonica, Zahlbr., 489
juniperina Fr. var. tubulosa
Schaer, 631
juniperina L. (Ach.), 632
nivalis (L.) Ach., 363, 364
pinastri (Scop.), 631, 632
pseudocomplicata Asahina, 487
sanguinea, 477
sp., 860
tubulosa (Schreb.), 632
Chaetoniium affine Corda, 539,
542, 592
aureum Chivers, 501
cochlioides, 392, 941
indicum Corda, 284, 628
Chlorobacteria, 930
Chlorobiiim spp., 166
Chlorophyll-containing bacteria,
438
Chlorosplenium aeruginosum
(Oeder ex Fries) De Not, 528
Chromatium species, 172, 179-
181, 184, 237, 238
Chroniobacterium iodinum, 996
violaceiim, 942
Circinella species, 78
Citric acid-forming fungus, 502
Citromyces spp., 68
strains, 873
Cladonia alpestris L. Rabh, 363
amaurocraea, (Fl.) Schaer., 464
bacillaris Nyl., 464
bellidiflora var. coccocephala
Ach., 462
coccifera (L.), 464
deformis Hoffm., 4, 362, 365
digitata, 458
evansii. Abb., 473, 482
floerkeana Sommerf., 464
impexa Harm., 22, 361, 463, 473,
482
macilenta (Hoff.) Flk., 464
mitis Sandst., 117
nemoxyna (Ach.) Nyl., 478
papillaria (Ehrh.) Hoffm., 157
pityrea Flk. f. phyllophora
Mudd, 478
761
Microorganism Index
Cladonia alpestris L. Rabh
polydactijla Flk., 158
pseiidoevansi Asahina, 473, 482
pseudostellata Asahina, 463
rangiferina (L.) Web.. 470
ravqifonnis HofFm., 117
species, 212, 458, 565, 860, 861
squaj7iosa HofFm., 462
strepsilis, 856
sylvatica L. Harm., 361, 470, 664
uncialis (L.) Web., 462
Clasterosporiiim spp., 17, 81
Clathrus ruber, 640, 643
Claviceps purpurea, 43, 48, 291,
336, 341, 344, 351, 465, 47J,
535, 553, 639, 643-645, 647,
648, 651, 652, 654, 656, 657,
668, 673, 693, 944-967, 1133,
1151, 1152, 1274
Clitocybe Candida, 1135
diatreta, 191, 192, 198
illudens, 1177
Clostridia, 237, 449
Clostridium acetobutylicum, 18
butylicum, 30
propionicum, 74
propylbiitylicum, 18
saccharobutylicum, 18
tetanomorphum, 445, 446
Coccifera bellidifiora, 365
pleurota, 365
Coleosporium senecianis, 164-166,
168, 170
Collybia dryophila, 672
Coprinus comatis Gray, 651, 652,
657, 708, 1026, 1027, 1199
miraceus, 672
quadnfidus, 193-195, 201
similis B. and Br., 493
Cordyceps militaris (Linn.) Link,
1032
sinensis (Berkeley) Saccardo,
300
Coriolus sanguineus Ft., 1001
Cornicularia diverqens Ach., 486
pseudosatoana Asahina, 486
Corocyneamembranacea (Dicks.),
859
Corticeum croceum Bres., 219
saliciuu 771 Fries, 223
sasakii, 390
sulfureum (Ft.), 219
Cortinarius cinnaharinjis Fries,
562
cin7iamomea, 638
sanquineus (Wulf.) Fries, 542,
562
Corynebacteria, 51, 54, 121, 437
Corynebacterium diphtheriae, 13,
16, 51, 106, 131, 132, 137, 168
314, 343, 518, 674, 698, 703,
873, 928
insidiosum (McCulloch) Jen-
sen, 1179
michiqanense, 163, 168
michiganense mutants, 165
ovis, 132
sp., 548, 1061
Cryptococcus laurentii, 142, 165,
166
luteolus, 165, 166
Cunninghamella species, 78
Curvularia lunata, 1200
sp., 425
Cyanococcus chromospirans, 1000
Cyphelium chrysocephalum Ach.,
631
Dacromyces stillatus, 164-166, 171,
173, 176
Daedalea juniperina Murr., 619,
895
Daldinea concentrica (Bolt) Ces.
and De Not, 388, 404, 523,
627, 869
Debaryomyces hansenii, 142
Dermatocarpon miniatuTTi (L.)
Mann, 36
Dermocybe (Cortinarius) Cinna-
momea, 638
Dimelaena oreina, 365
Diploschistes bryophilus (Ehrh.),
444
scruposiis (L.), 444
Discomycetous inoperculate fun-
gus, 525, 526
Pfizer Handbook of Microbial Metabolites
762
Drosophila semivestita, 207
suhatrata (Batsch. ex Fr.) Quel.,
378
Endoconidiophora coerulescens
Miinch, 9, 10
virescens Davidson, 10
Endothia fiuens Shear and Stevens,
580, 586
parasitica (Murr.) Anderson
and Anderson, 580, 586, 1144
Enterococcus stei, 556
Erevtothecinvi ashbyii, 516, 529,
557, 558, 560, 1008, 1052,
1053, 1056
Erwinia chrysanthemi, 1179
Escherichia coli, 98, 104, 143, 237,
238, 290, 296-298, 301, 306,
307, 310, 312, 314, 341-343,
423, 483, 509, 527, 531, 532,
537, 554, 556, 557, 662, 674,
691, 703, 898, 933
Aerohacter aerogenes type of
bacterium, 841
mutant, 99, 344, 444, 460
Evernia divaricata L., 469
mesomorpha f . esorediosa Miill.
Arg., 469
prunastri L., 406, 446, 459
sp., 860
vulpina L., 631
Fistulina hepatica, 22
Flavohacterium marinotypicum,
186
sulfureum, 186
Fomes fomentariiis, 338
juniperimis (Polyporus), 1164
laricis, 120
• officinalis, 120
Fremella mesenterica, 165
Fungi, 15, 35, 68, 81, 83, 90, 95,
i54, 185, 212, 213, 231, 232,
291, 299, 303, 532, 564, 683,
702, 1058
Fusaria species, 78, 335, 336, 479,
738, 741
Fusariiim bostrycoides Wr. and
Rkg., 522
bulbigemim, 1244
Fusarium bostrycoides Wr. and
Rkg.
bulbigenum Cke. et Mass. var.
lycopersici (Bruchi) Wr. et
Rkg., 973
culmoriim (W.G. Sm.) Sacc,
584, 887
gravtinearum Schwabe, 887
heterosporum Nees, 973
javanicum Koorders, 520
lateritiiim, 740
lycopersici, 301, 715, 1189
moniliforme, Vl%
orthoceras App. et Wr., 973
orthoceras var. enniatinum, 740
oxysporum, 80
scirpi Samt. et Fautr., 740
solani (Mart.) App. and Wr.,
521
sporotrichiella var. poae, 1251
vasinf ectum Atk., 973, 1189
Ganoderma oregonense, 1236
Geaster fimbriatus Fr., 345
Gibberella baccata, 1113
fujikuroi (Saw) Wollenweber,
321, 324-326, 534, 852, 972,
973
saubinetti, 82, 887
Gliocladium fivibriatiim, 938
roseiim Rainier, 498
sp., 236
Gluconoacetobacter liquefaciens,
72, 405, 862-864
roseum, 407, 865, 866
spp., 404
Gram-negative bacteria, 342
-positive bacteria, 119, 342, 344
Grifola confluens, 46
Gyranoasciis spp., 867
Gyvinosporavgiiini juniperi-virgi-
vianae. 164-166
Gyrophora deiista (L. ), 479
esculenta Miyoshi, 475
polyphylla (L.), 479
proboscidea L., 475
vellea (L.), 479
Haematomma coccineum, 365, 857
leiphaermim, 365
763
Microorganism Index
Haematomma coccineum
porphiiriutu (Pers.), 365, 857
sp., 8(i()
ventosinu, 121
Hauscnula auomala, ()99
suhpclliculosa, 142
Helicohasidium monpa, 83
HelmintJiosporium avenae Ito and
Kurib.. 544
catenarium Drechsler, 541, 546
cynodontis Marignoni, 541, 544
eiiclaevae Zimmermann, 544
grammeum Rabenhorst, 541,
546
leersii Atkinson, 579
ravenelii, 886
triticividgaris Nisikado, 541,
546, 549
velutiniim Link, 546
victoriae, 544, 768
Histoplasma capsulatum, 3
Hijdnurn aspratum Berk., 2
aiirantiaciim Batsch., 509, 511
imbricatum L., 345
spp., 507
Hydrogenornonas species, 238
Hypholoma capnoides, 537
Hypochniis sasakii Shirai, 390
Inocybe patoullardii Bres., 1138
Kloeckera brevis, 142
Lactariiis deliciosus, 319-321,
638
helviis, 638, 710
rufus Scopol., 112
spp., 9, 305
turpis, 537
vellereus, 537, 638, 641
Lactobacilli, 51, 75, 87, 119, 154,
449, 513, 561
Lactobacillus acidophilus, 1019
arabivosus. 111, 114, 514, 556,
931, 1015, 1017, 1038
casei. 111, 114, 333
helveticiis, 334
leichmannii, 445, 516, 552
pastorianus var. quinicus, 299
Lecanora atra (Hudson) Ach., 488
cpatwra Ach., .365, 635
gangaleoides Nyl., 22, 449
gru7uosa (Pers.) Rohl, 488
parella Ach., 442
sordida, 365
sp., 110, 860
sulfurea, 365
thiodes, 365
Lentiniis dactyloidcs, Cleland, 357
degener Kalchbr., 493
lepideus Fr., 619, 622-625
Lenzites spiaria (Wulf), 1185
thermophila, 568
Lepiota clypeolaria, 638, 641
Lepraria candelaris Schaer., 630
citrina, 633
fiava (Schreber. ) f. quercina,
632
latebrarum, 365
Leuconostoc mesenteroides, 41
Lichens, 35, 68, 80, 121, 154, 157,
190, 212. 213, 231, .336, 400-
402, 4,92, 496, 1059
Lobaria oregana Mijll. Arg., 455
pulmovaria (L.) Hoffm., 22,
447, 455, 507
pulmonaria, HofTm. f. tenuior
Hue., 484
pidmonaria, var. meridionalis
(Wain.) Zahlbr., 475
retigera Trev., 507
Lycoperdon gemmatum, 652
piriforme, 652
pratense, 537
"M-14" strains, 1142
Macrosporium porri. Elliott, 556
Marasmivs comgenus, 1191
gramineiim Lib., 517
peronatus, 652, 656
ramealis, 200, 397
Merulius lacrymans, 210, 212,
215
Metarrhiziiim glutinosum, 1166
Micrococcus lysodeikticus, 174,
305, 537
sp., 306, 761
Pfizer Handbook of Microbial Metabolites
764
Micrococcus lysodeikticus
tetragenus (pink type), 168, 170
varians, 680
Micromonospora genus, 118
globosa, 334
sp., 1203
Microsporum canis, 1063
gypseum, 1063
Mitrida paludosa, 165
Molds, 14, 43, 50, 154, 308, 313,
315, 316, 436, 492, 496,
969, 970, 975, 976, 1018, 1040,
1060
Mollisia caesia, Sacc. sensu Sy-
dow, 519
gallens Karst., 519
Monascus purpureus, Wentil,
882, 884
rubTiginosus Sato, 882
rubropunctatus Sato, 880, 882
Monilia formosa, 79
sitophila, 165
Monosporium bonorden, 1092
Mucor species, 78
hiemalis, 91
mucedo, 303
ramannianus , 1263
stolonifer, 80
Mushrooms, 43
Mutinus caninus, 638, 652
Mycobacteria, 43, 51, 55, 121, 188,
237, 531
Mycobacteriaceae family, 118
Mycobacterium avium, 50, 556—
558
battaglini, 189
genus, 118
laticola, 162, 1049
marianum, 189
phlei, 50, 160, 164-166, 168,
171, 173, 174, 176, 177, 178,
185, 187, 188, 530, 697, 772
sm.egmatis, 238, 558, 931
tuberculosis var. hominis, 34,
50, 51, 66, 115, 122-126, 129,
138, 139, 238, 342, 407, 518,
533, 703, 708, 928, 1050
Mycococcus genus, 118
Mycotorula lipolytica, 699
Myoporum spp., 855
Nectria cinnabarina (Tode) Fr.,
973
Nematoloma fasciculare, 656, 657
Nematospora coryli, 142
Nephroma antarcticum, 365
arcticum, 365
laevigatum, 365
parile, 365
Nephromium lusitanicum, 561
Nephromopsis cilialis Hue., 487
endocrocea Asahina (= Cetraria
endocrocea (Asahina) Sato),
154, 155, 552
stracheyi f. ectocarpisma Hue.,
118, 156, 159
Neurospora crassa and inutants,
91, 97, 143, 164-168, 175-178,
184, 187, 238, 291, 301, 305,
310-312, 482, 512, 525, 532,
641, 646, 649, 655, 660, 676,
687, 690, 1014
crassa mutants, 164, 176, 311,
312
sitophila, 178
Nocardia acidophilus, 218
formica, 730, 915
gardneri, 266-268
genus, 118
lurida, 1269
mesenterica, 893, 1098, 1197
narasinoensis, 1227
rugosa, 528
sp., 893, 1226, 1278
Ochrolechia pallescens, 475
Ochromonas malhamensis, 1051
Oidiodendron fuscum Robak,
878
Oospora colorans van Beyma, 501
sulfurea-ochracea, 428
Ophiobahis miyabeanus, 1235
Oxidative bacteria, 44
Pachybasium candidum (Sacc.)
Peyronel, 538, 539
765
Microorganism Index
Pachiima hoelen Rumph., 358
Paecilomyces, 726
Paecilorntices variotis Bainier
var. antiJ)ioticus, 1303
victoriae V. Szilvinyi, 393, 395,
412
Ponaeolus cmyipamilatus, 935
Pannaria fidvescens Nyl., 453
lanuginosa Korb., 453
lanuginosa Ach., 859
lurida Nyl.. 453
Parmelia abyssinica Kremp., 448
acetabulum Duby., 447
borreri Turm., 443
caperata (L.), 118, 451
cetrata Ach., 448
conspersa Ach., 448
formosana Zahlhr., 891
furfuracea Ach., 459, 485
glomellifera Nyl., 481
hypotrypella, Asahina, 465
latissima Fee, 22, 443
leucotyliza, 365, 366
marmariza, Nyl., 448
olivetorum Nyl., 486
perlata Ach., 473, 482
physodes Ach., 459, 465, 485
saxatilis Ach., 448
scortea Ach., 443
sinodensis Asahina, 157
sp., 213, 860
tinctorum Despr., 443
Parmeliopsis spp., 458
Patella vulgata, 683
Paxillus atromentosus (Batsch.)
Fr., 505
Pellicidaria sasakii, 390
Peltigera horizontalis, 365
malacea, 365
propagulifera, 365
Penicilliopsis clavariaeformis
Solms-Laubach, 585
Penicimum, 28, 497
Penicillium spp., 17, 35, 78, 133,
336, 528, 778, 850
albidum Sopp., 430, 1068
aurantio-virens Biourge, 80,
182, 373, 375
Penicillium spp.
baannmse, 144
brefeldianum, 875
atrovcnetuni G. Smith, 570
brevi-compactinn Dierckx, 16,
20, J 85, 386, 398, 402, 403,
433
canescens, 1126
charlesii G. Smith, 140, 146-
149
chrysogenum, 122, 302, S12,
345, 422, 426, 537, 686, 724,
897, 902, 910, 1035, 1037,
1038
chrysogenum. (myceUum),
5 JO, 1044
chrzaszszi, 872
cinerascens Biourge, 145, 497,
938
citreo-roseum Dierckx, 545
citreo-sulfuratum, 872
citrinum, 872
claviforme, 867
crateriforme Gilman and Ab-
bott, 109
cyclopium Westling, 20, 81,
144, 302, 303, 409, 411, 536,
545, 977, 981
cyclopiwm-viridicatum, 373, 375
digitatum, 3, 6
divergens Bainier and Sartory,
381, 383
equinum, 867
expansum, 867, 872
fellutanum, 140
flexuosum, 389, 875
frequentans Westling, 302, 873
funicidosum Thorn, 71, 540,
1170
glabrum, 873
gladioli McCull. and Thom,
400, 408, 410
glaucum, 317
griseofidvinn Dierckx, 186,
302, 381, 389, 392, 4J0, 430,
432, 867, 875, 993
herquei Bainier and Sartory,
555, 572, 573
implicatum Biourge, 872, 881
Pfizer Handbook of Microbial Metabolites
766
PenicilUum spp.
islandiciim Sopp, 71, 385, 539,
540, 546, 550, 551, 580, 583,
587, 588, 739, 751
islandiciim N.R.R.L., 581, 582
janczexvski Zal., 430, 432
jenseni, 381, 938
johannioli Zaleski, 373, 375
leucopus, 867
lilacinum, 50, 106
lividum, 872
melinii, 430, 867
minioluteum Dierckx, 105, 109
multicolor G. M. P., 881
nalgiovensis Laxa, 566, 567
nigricans (Thorn and Bainier),
430
notatum Westling, 49, 90, 100,
337, 417, 423, 434, 850, 910,
934
novae-zeelandiae , 867
oxaliciim, 68
palitans Westling, 303
patuhim Bainier, 186, 377, 379,
389, 430, 491, 867
paxilli var. echinulatmn, 1153,
1229
pfefferianum, 873
phaeojanthinellum, 872
phoeniceum van Beyma, 500
puberuhnn, 144, 373, 375, 1298
pulvillorum Turfitt, 1254
purpurogenum Stoll, 317, 874
pnrpurogenum Stoll var. rubri-
sclerotiiim Thorn, 32, 93
racihorskii Zal., 430'
raistrickii, 295, 430
resticulosiim, 712
. roquefortii, 303
roseopurpureum Dierckx, 558
roseo-purpiirogenum, 873
rubrum O. Stoll, 500
rugulosum Thorn, 580, 586
sclerotiorum van Beyma, 164-
166, 881, 883
soppii, 50
spiciilisporiim Lehman, 109
spinulosum Thom, 50, 497,
1093
PenicilUum spp.
terlikoiuski Zaleski, 938, 939
stipitatum Thom, 182, 372,
374, 376
stoloniferum Thom, 398, 402,
403
tardiim, 580, 586, 1292
terrestre Jensen, 152
thomii, 144
urticae Bain., 389, 430, 867
viniferum, 79
viridicatuni Westling, 153, 977
wortmanni, Klocker, 580, 586,
1311
Peniophora filamentosa (B. and
C.) Burt, 504
Pertusaria amara (Ach.) Nyl.,
437
Pertusaria spp., 458
Phallus impudicus, 640, 643, 652
Phlegmacium mellioleus, 652,
656
Pholiota mutahilis, 638, 641, 656
Phoma terrestris Hansen, 569
Photosynthetic bacteria, 437,
438, 926, 927
Phycomijces blakesleeanus, 91,
122, 124, 164-166, 168, 176,
178, 380, 382
Physarum polycephaluin, 353
Physica caesia, 365
endococcina. 365, 595
Phytomonas spp., 25
Pilobolus bleinii, 165
Piriciilaria oryzae, 86, 1245
Placodium saxicolum, 365
species, 213, 555
Pleurotus griseus, 1248
mutilus, 1247
ulmarius, 197, 210
Polyporus anthrocophilus Cooke,
199, 202, 203, 205, 206, 211,
212, 216, 217, 221, 222, 357,
360
australiensis Wakefield, 356,
358
benzoinus, 354
betulinus Fr., 119, 354, 356,
358, 359
767
Microoigai>ism Index
Poliiporus anthrocophilits
hi for mis. 19(i. 1117
ciunabariuus, 1001
cocci ne us Fr.. 1001
confliu'us Fr., 46, .'{45
eucahiptorum Fr., 357
fumosus Pers. Fries, 494
guttalatus, 204
hispidiis (Bull.) Fr., 357
iuuiperirms, 1164
leucomelas Pers. ex Fr., 506,
510
nidiilans Fries, 504
officinalis ( = Fomes officinalis,
Fomes laricis.), 120, 355, 357
pinicola Fr., 346-348, 354
puniceus Kalch., 1001
rutilans (Pers.) Fries, 504
sanguineus L., 1001
squamosus, 537
sulfureus, 291, 345, 357, 537,
638-641, 644, 652, 656, 677,
700, 701, 707, 1023, 1026
tumulosus Cooke, 356, 358, 384,
387, 391
Polijstictus cinnaharinus (Jacq.),
1001
sanguineus L., 1001
semisanguineus Lloyd, 1001
versicolor (L.) Fr., 507
Polystigma rubrum, 169
Poria cocos (Schw.) Wolf, 356-
358
corticola, 208, 209, 213, 214
tenuis, 208, 209, 213, 214
Proactinomyces cyaneus var. an-
tibioticus n. sp., 1186
Propionibacteria, 74, 87, 447, 931
Propionibacterium shermanii,
440, 932
Proteus immunitatis anticarcino-
matosa n. sp., 1301
vulgaris, 30
Psalliota xanthoderma, 1253
Pseudomonas aeruginosa (Bacil-
lus pyocyaneus), 130, J 85,
448, 492, 501, 917, 979, 980,
982-985, 994, 1000, 1002
Pseudomonas aeruginosa
aeruginosa strain T-359, 979
aestumarina, 171. 173
antiuiycetica, 824
aureofaciens Kluyver, 997
beijerinchii Hof, 490
chlororaphis, 998, 999
cocovenenans, 128, 1029
fiuorescens, 30, 85
forrnicans n. sp., 67
hydrophila, 19
indigo f era, 1179
pyocyanea, 107
saccharophila , 70
spp., 25, 27, 44, 306, 501
tabaci, 717
viscosa, 759
xanthochrus, 171, 173
Psilocybe aztecorum Heim, 937
caerulescens Murr. var. ma-
zecatorum Heim, 937
mexicana Heim, 937
sempervirens Heim et Cail-
leux, 937
sp., 936
zapotecorum Heim, 937
Psoroma crassum. Korber, 450
Puccinia coronifera, 164-166
graminis Pers. var. tritici Eri-
kas. and Henn., 7
Ramalina boninensis Asahina,
483
calicaris Rohl., 471, 474
farinacea, 451
geniculata Hook et Tayl., 22,
471, 474
intermediella Wain., 471, 474
pollinaria Wests., 446, 454
scopulorum (Retz.) Nyl., 22
sinensis, 22
sp., 860
spp., 454
tayloriana, 22
usneoides Mont., 474
Rhizocarpon geographicum L.,
464, 636
viridiatrum Flk., 636
Pfizer Handbook of Microbial Metabolites
768
Rhizopus nigricans, 497, 934,
1055
saponicus, 345
Rhizopus sp., 75, 78
suinus, 934
Rhodopseudomonas spheroides,
182, 183, 438, 926, 928-930
spheroides mutant, 177
Rho do spirillum fulvum, 930
rubrum, 172, 177, 179-181,
184, 238, 930
Rhodotorula glutinis, 165, 168
glutinis var. lusitanica, 101,
102
rwfcra, 161, 164, 165, 168, 175,
185
sanniei, 161, 165, 168
sp., 50
Rhodovibrio sp., 930
Roccella fuciformis Ach., 992
fuciformis DC, 468
montagnei Bel., 20, 110, 171,
468
tinctoria (L.), 110
Russula alutacea, 640
aurata, 640
cyanoxantha, 640
foetens, 652
grisia, 640
lepida, 640
maculata, 641, 652
olivacea, 640
sardonia, 640
spp., 638, 643
turci, 640, 641, 652 _
vesca, 640
Saccharomyces anamensis, 927
carlsbergensis, 336
cerevisiae, 69, 237, 238, 512,
722, 927
fragilis, 238
Salmonella typhi, 306
Sarcina aurantiaca, 165, 168
[utea, 174, 186
species, 90
Schizophyllum commune mu-
tant, 940
Scleroderma vulgare, 638
Scopulariopsis brevicaulis, 302
Serratia species, 723
marcescens, 19, 30, 143, 435,
919
marinorubrum, 919
Solorina crocea (L.) Ach., 574
Sparassis ramosa, 406
Sphaerophorus coralloides Pars.,
472
fragilis Pers., 472
melanocarpus , 472
Sporidesmium bakeri Syd., 1277
Sporobolomyces roseus, 165
salm.onicolor, 142, 165
Staphylococcus, 343
Staphylococcus aureus, 167, 168,
170, 173, 174, 304, 343, 642
citreus, 186
Stemphylium radicinum Sterad,
413, 871
Stereocaulon exutum Nyl., 480
nabewariense Zahlb., 455
paschale (L.) Fr., 363, 480
Stereum hirsutum, 1172
Sticta aurata Ach., 629, 630
colensoi Bab., 504
coronata Muell., 504
crocata Ach., 630
spp., 643
fuliginosa, 638
sylvatica, 638, 640
Streptobacterium plantarum, 537,
654
Streptococci, 5J
Streptococci (Group A), 5J2
Streptococcus albireticuli, 1150
cremoris, 816-819
faecalis, 17, 304, 556
lactis, 816-819
spp., 106, 111
Streptomyces abikoensis, 1094
achromogenes, 1285
acidomyceticus, 1072
afghanensis, 1291
akitaensis, 1067
albo-niger, 1047, 1139
alboreticuli, 242, 283, 284
albulus, 304, 305, 309, 316
a/bus, 1070, 1081, 1139, 1178
769
Microorganism Index
Streptornyces abikoensis
«//;// ,s-rcscmbling, 1315
fl//;//.s-similar, 1-U5
alhus var. fu7igus, 1069
amhofaciens. 292, 918
atiti})ioticus (Waksman et
Woodruff) Waksman and
Henrici, 27(). 334, 335, 617,
79'?. 791. 931
arable us, 1140
aureofacietis Duggar, 306,
603, 604, 607-609
aureofaciens strain W-5, 1139
flz/rez^s-resembling, 1242
aureus Waksman and Curtis,
237, 1066
bikitiiensis, 54
bobiliae. 1222
bottropensis, 760
cacaoi, 1129
caelestis, 258
caeruleus. 1123
caespitosus, 1214
calvus n. sp., 1043
canesciis, 256
canus, 833, 1079
carcinomycicus , 847
catenulensis, 61
celestis n. sp., 923
cellulofiavus n. sp., 916
cellulosae, 239
chartreiisis , 439
chattanoogensis, 236
chibaensis, 5
chromogenes, 918
chrysomallus, 334, 764, 793-
795, 802, 803, 805-807, 811,
812
cinnamonensis, 899
cinnamoneus f. azacoluta,
820, 821
coelicolor (Miieller, Waksman
and Henrici), 526, 1136
colliniis, 1137, 1271
crystallinus, 1297
diastatochromogenes, 1286
diastatochromogenes-Tesem-
bling, 1234
Streptornyces abikoensis
echinatus n. sp., 775
endus, 246
erythreus, 277-279
enithrochromogenes, 294
ETH 1796, 306
eurocidicus, 284, 285
eurytherinus, 291
exfoliatus, 1156
fasciculatus, 1022
feZZezzs, 263
fervens, 1160
filipinensis, 238
fiaveolus, 334, 577
flavochromogenes, 259, 1102
fiavofungini, 1143
flavovirens, 334
fiavus, 244, 334, 335
/Zaz^MS, 0-2, 1147
fiavus-parvus, 335
floridae, 727
fradiae, 60, 243, 290, 306, 335,
802, 803, 805-810
fulvissimus, 758
fungicidicus, 1095
fuscus, 1165
galiloeus Ettlinger et aZ., 617
garyphalus, 894
genus, iJ8
glaucus, 923
gr amino faciens, 746
griseocarneus, 55
griseochromogenes, 1120, 1I2I
griseofiavus, 1167, 1168
griseolavendus, 736
griseolus, 265, 1076, 1106, 1158
griseoluteus, 1004, 1005
griseoplanus, 725
griseoviridus, 1169
griseus (Krainsky) Waksman
et Henrici, 54, 65, 238, 253-
255, 307, 308, 311-314, 407,
440, 529, 765, 766, 885, 91,3,
931, 1096, 1132, 1139, 1159,
1169
griseus var. spiralis, 834
grisews-like strains, 843
hachijoensis n. sp., 251
halstedii, 282, 283
Pfizer Handbook of Microbial Metabolites
770
Streptomyces abikoensis
haivaiiensis, 840, 1294
hepaticus, 711
humidus, 56
hygroscopicus var. angustmy-
ceticus, 1042
hygroscopicus, 45, 57, 235, 246,
1041, 1083, 1111, 1112, 1139,
1174, 1192
hygrostaticus n. sp., 1175
K-300, 894
kanamyceticus, 52, 53
kentuckensis , 1261
kitasatoensis, 275
kitazawaensis, 848
lactis, 1145
lavendulae, 731, 733-736, 894,
899, 1100, 1223
lavendulae -xesevnbMng, IIQ, 774
limosus, 224
iipwanzi-resembling, 1295
lucensis, 228
luteochromogenes n. sp., 728
lydicus, 1279
mashuensis, 54
matensis, 822, 1201
mediocidicus n. sp., 245
mediterranean, 593
melanogenes, 849
melanosporus (sine melanos-
porofaciens) n. sp., 1148,
1196
michiganensis , 335
misakiensis, 997
mitakaensis, 1204, 1205
nagasakiensii n. sp., 894
narboensis n. sp., 274
natalensis, 226
nayagaiwaensis n. sp., 1163
netropsis, 918
nitrosporeus , 257
niveoruber Ettlinger et aZ., 617
niveus, 885
noboritoensis, 58
nodosus, 248
noursei, 230, 308
noursei variant, 1241
n. sp., 240, 250, 1099
Streptomyces abikoensis
olivaceus (Waksman) Waks-
man and Henrici, 306, 440,
576, 744, 745, 931, 1290
olivochromogenes, 1310
orchidaceus, 894
orientalis n. sp., 1300
parvullus, 335, 794
parvus, 334
paucisporogenes, 64
penticus, 241
phaeochromogenes var. c/iZo-
ronz2/ceficus-resembling,
1296
p^a/oc/?rornogenus-resembllng,
1215, 1260
phoenix, 1267
platensis, 1139
pleofaciens, 1246
plicatus, 1020-1022
polychromogenes, 671
puniceus, 727
purpurascens , 275, 1180
purpurochromogenes, 1154
purpurochromogenes-
resembling, 1306
pyridomyceticus , 752
racemochromogenes n. sp.,
790, 1258
ramulosus n. sp., 150
resistomycificus, 575
reticuli, 1270
reticuli var. latumcidus, 1183
reticidi var. aqiiamtjceticus, 5
rimosus, 231, 274, 275, 306, 610,
612, 670, 1139
rimosus form paromomycins, 59
roc/iei, 1122
roseochromogenes, 732, 931,
1265
roseoc^roTnogenes-resembling,
1275
roseodiastaticus , 924
roseofiavus, 1219
roseus, 1287
rwber, 1224
ruber (Krainsky, Waksman
and Henrici), 924
771
Microorganism Index
Streptomyces abikoensis
rutgersetisis var. castelarense
n. var.. 1124
rutgersensis-resemhhng, 1272
sahachiroi, 1127. 1128
sakaieusis, 12 Hi
siudeuensis, 1022
sp., 8. 40. 222, 141, 229, 232,
233, 247. 2(iO. 261, 275, 280,
281, 286-289, 310. 334, 335,
439, 440. 594, 611. 613-616,
621, 634. 689. 729. 742, 753,
755. 769, 796-801, 831. 1065,
1071, 1077, 1081, 1086-1089,
1101, 1103, 1104, 1110. 1129,
1134, 1154, 1158, 1167, 1188,
1193-1195, 1217, 1221, 1231,
1239, 1240, 1262, 1264, 1278,
1288, 1313. 1314
sp. No. 7017, 1082
sp. No. 14420, 1162
sp. PRL 1642, 767
sp. -resembling S. fradiae, 62
sp. -resembling S. lavendulae, 63
spectahilis, 1280-1284
spheroides, 885
spp., 60, 253-255, 604-606, 737,
914, 1064, 1076, 1228
strain No. 4738, 1141
subtropicus, 765, 766
tanaschieiisis related to s. a7i-
tibioticiis, 577
tanaschiensis type, 1161
thioluteus, 870, 995
toyocaensis, 1298
vendargensis, 1304
venezuelae, 626
verticillaUis, 1305
verticillis, 1243
vinaceus, 727
vinaceus-drappus, 1022, 1080
violaceaniger, 1225
violaceus, 834, 1307
virginiae, 899
viridoflavus , 252
viridosporus, 234
xanthochromogenes n. sp., 1312
xanthophaeus, n. sp., 773
Streptomyces abikoensis
zaomyceticus, 249
zaomyceticus n. sp., 835
Streptomycctaccac family, 118
Streptomycetes, 190, 212, 225, 237,
261, 262, 332, 334, 434, 436,
492, 501,502, 678, 1046, 1075,
1184, 1239, 1313
Streptosporangium genus, 118
Stropharia cubensis Earle, 937
Teloschistes exilis Wainio, 555
flavicans (Sw.) Norm., 445,
555, 557
Thamnolia subvermicularis
Asahina, 461, 462
vermicularis (Sw.) Schaer.
458
Thelephora palmata, 507
spp., 507
Thermoactinomyces genus, 118
Thiocystis violacea, 930
Tilletia laevis, 643
tritici, 643
Torula mellis, 142
utilis, 351,513, 515,900
Torulopsis sp., 50
utilis, 537
Trachypus scaber, 652
versipellis, 638
Trametes cinnabarina (Jacq.)
Fr., 1001
odorata (Wulf) Fr., 349
suavolens (Finn.) Fr., 619,
622
Treponema spp., 933
Trichoderma viride, 302, 938,
1308, 1309
Tricholoma nudum, 641, 1230
Trichosporon capitatum, 142
Trichothecium roseum (Link),
J 59, 327-330
Umbilicaria pustulata L. Hoffm.,
22, 39, 475
Urceolaria cretacea, 365
Usnea
barbata, 452
diffracta Wain., 467
Pfizer Handbook of Microbial Metabolites
772
Usnea
japonica Wain., 447
jesoensis Asahina, 446
longissima Ach., 464, 467
sp., 860
Ustilaginales spp., 127
Ustilago maydis, 301, 302, 643,
695, 896
sp., 38
sphaerogena, 94
zeae, 83, 127, 412
Ustulina vulgaricus, 28
vulgaris, 80
Variola amara (Ach.), 437
Verticilliiim alho-atriim, 1
psalliotae, 501
Vibrio adaptatus, 171, 173
Volucrispora aurantiaca, 503
Wheat rust, 304
Xanthoria fallax (Hepp.) Arn.,
548, 555, 557
parietina (L. ) Th. Fr., 554
parietina (L.) Beltram, 555
Xerocomus hadius, 641
sanguineus, 652
suhtomentosus, 652
Yeasts, 13, 15, 17, 17, 19, 30, 43,
50, 53, 77, 96, 99, 134-136,
i54, J57, 159, 308, 310,
314-316, 318, 331-333, 335,
336, 340-344, 351, 352, 422,
426, 436, 447, 480, 496,
508-512, 525, 528, 532,
534, 548, 618, 655, 660, 686,
716, 718, 721, 858, 900, 903,
904, 912, 926, 927, 933, 934,
969, 970, 974, 975, 976, 1009-
1012. 1013, 1016, 1018, 1028,
1030, 1034-1040, 1045, 1046,
1051, 1057-1060, 1062, 1190
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