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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 metabolites 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 immunosuppressants. 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 pharmaceutical 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 ...
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