Polyketides. Biosynthesis, Biological Activity, and Genetic Engineering

281 Pages·2007·22.74 MB·English

by  Agnes M. Rimando and Scott R. Baerson (Eds.)

Polyketides: Biosynthesis,
Biological Activity, and Genetic
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In Polyketides; Rimando, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
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In Polyketides; Rimando, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
ACS SYMPOSIUM SERIES 955
Polyketides
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ber 22, oi: 10.1 Agnes M. Rimando, Editor
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Sponsored by the
ACS Division of Agricultural and Food Chemistry, Inc.
American Chemical Society, Washington, DC
In Polyketides; Rimando, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
Library of Congress Cataloging-in-Publication Data
American Chemical Society. Meeting (229th : 2005 : San Diego, Calif.)
Polyketides : biosynthesis, biological activity, and genetic engineering /
Agnes M. Rimando, editor, Scott R. Baerson, editor.
p. cm.—(ACS symposium series ; 955)
"Sponsored by the ACS Division of Agricultural and Food Chemistry, Inc."
"Developed from a symposium by the Division of Agricultural and Food
Chemistry, Inc., at the 229th National Meeting of the American Chemical
org 001 Society, San Diego, California, March 13-17, 2005"—Prelim, p.
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on 200 The paper used in this publication meets the minimum requirements of American
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In Polyketides; Rimando, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
Foreword
The ACS Symposium Series was first published in 1974 to pro­
vide a mechanism for publishing symposia quickly in book form. The
purpose of the series is to publish timely, comprehensive books devel­
oped from ACS sponsored symposia based on current scientific re­
search. Occasionally, books are developed from symposia sponsored by
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Oct7 | manuscripts are prepared in camera-ready format.
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In Polyketides; Rimando, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
Preface
Polyketides and their derivatives represent one of the most important
classes of natural products, comprising approximately 20% of the
world's top-selling pharmaceuticals, with combined revenues of over
$18 billion per year. Antibiotics such as tetracycline, erythromycin, and
nystatin are just a few of the important examples of polyketides that have
benefited our society. In addition, polyketides serve important roles in
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ub09 the essential pigments found in plant species necessary for their survival.
p://p007- As the structural complexity of polyketides often renders their pro­
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Octo7 | d duction. For these reasons as well as others, research on polyketides has
n 00 been intensive and fast-paced. The present time is thus a particularly
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d n California. The original symposium presentations addressed a wide range
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important polyketide biosynthetic pathways found in nature, mechanistic
insights obtained from studying the crystal structures of cloned polyke­
tide synthases, new approaches for the identification of genes encoding
novel polyketide synthase enzymes, and biotechnological advances
toward the development and large-scale production of novel polyketides.
We hope that this collection of chapters prepared by an international
group of experts will be a valuable resource for investigators working on
the biology and chemistry of polyketides as well as those drawn by
curiosity wishing to improve their understanding of these fascinating and
diverse compounds.
xi
In Polyketides; Rimando, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
We greatly appreciate the contribution of the authors, and we
acknowledge the valuable critiques of the reviewers.
Agnes M. Rimando
Scott R. Baerson
Natural Products Utilization Research Unit
Agricultural Research Service
U.S. Department of Agriculture
P.O. Box 8048
University, MS 38677
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xii
In Polyketides; Rimando, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
Polyketides: Biosynthesis,
Biological Activity, and Genetic
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In Polyketides; Rimando, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
Chapter 1
A Plethora of Polyketides: Structures, Biological
Activities, and Enzymes
Scott R. Baerson and Agnes M. Rimando
Natural Products Utilization Research Unit, Agricultural Research Service,
U.S. Department of Agriculture, P.O. Box 8048,
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s.orh00 University, MS 38677
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Oct7 | condensations of starter and extender units, analogous to the
n 00 biosynthesis of fatty acids. Polyketides have been shown to
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21e: active, they have also provided the basis for many important
by Dat pharmaceuticals of enormous commercial and therapeutic
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brief overview is provided on these major subject areas, to
serve as an entry point for readers exploring the subsequent
chapters in this proceedings volume.
2 U.S. government work. Published 2007 American Chemical Society.
In Polyketides; Rimando, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
3
Introduction
In their simplest form, polyketides are natural compounds containing
alternating carbonyl and methylene groups ('β-polyketones'). The biosynthesis
of polyketides begins with the condensation of a starter unit (typically, acetyl-
CoA or propionyl-CoA) with an extender unit (commonly malonyl-CoA or
methylmalonyl-CoA, followed by decarboxylation of the extender unit (1, 2)
(Fig. 1). Repetitive decarboxylative condensations result in lengthening of the
polyketide carbon chain, and additional modifications such as ketoreduction,
dehydratation, and enoylreduction may also occur (discussed below).
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09 | http://pubs.a1/bk-2007-0955. Figure 1. SGtaernteerr uanli tc Eonxtdeenndesra utinoitn reaction in polyketide biosynthesis. The starter
2002 units are attached to thiol groups of the ketosynthase (KS), and extender units to
ber 22, oi: 10.1 thiol groups of either acyl carrier protein or acetyl coenzyme A (X).
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21e: sponges (e.g., mycothiazole), algae (e.g., bromoallene acetogenins), lichens (e.g.,
by Dat usnic acid), and crinoids (e.g., polyhydroxyanthraquinones). Overall, polyketides
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drawn is between those compounds derived from unreduced polyketone chains
that are largely aromatic, and those in which the carbonyl functionalities are
mostly reduced (5).
As a result of their intensive investigation over many years, polyketides and
their derivatives have taken center stage in the quest for new antibiotics and
therapeutic agents. Approximately 1% of the 5,000 to 10,000 known
polyketides possess drug activity {4\ and polyketides comprise 20% of the top-
selling pharmaceuticals with combined worldwide revenues of over USD 18
billion per year (5). Some important examples include antibiotics such as
In Polyketides; Rimando, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2007.