Chemistry Reference
In-Depth Information
MODULAR POLYKETIDE SYNTHASES
TONIA J. BUCHHOLZ, JEFFREY D. KITTENDORF, AND DAVID
H. SHERMAN
University of Michigan, Ann Arbor, Michigan
Polyketides constitute a large class of microbial and plant-derived secondary metabo-
lites that displays a vast array of structural diversity. These organic molecules vary
in molecular weight, functional group modification, and include linear, polycyclic,
and macrocyclic structural forms. Currently, polyketide natural products find clinical
use as antibiotics, antiparasitic agents, antifungals, anticancer drugs, and immuno-
suppressants. Given these impressive and wide-ranging pharmacologic activities, an
ever-increasing demand is placed on natural products research to uncover novel
polyketide metabolites for the benefit of human and animal health. Modular polyketide
synthases are nature's platform for the expansion of chemical diversity. This review
provides new perspectives on important biosynthetic mechanisms that contribute to
this variety. This includes control of double-bond configuration and regiochemistry,
introduction of
β
-branching during polyketide chain assembly, and other processes
that contribute to introduction of unique chemical functionality into these fascinating
systems.
Despite the promise of modern synthetic technologies to enhance pharmaceuti-
cal discovery significantly, natural products continue to be the greatest source
of all new drug leads (1). Currently, many examples of natural product-derived
pharmaceuticals are employed to benefit human health (2, 3); polyketides con-
stitute a large class of microbial and plant-derived secondary metabolites that
displays a vast array of structural diversity. These organic molecules vary in
molecular weight and functional group modification; they include linear, poly-
cyclic, and macrocyclic structural forms. Currently, polyketide natural products
