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Combinatorial biosynthesis: lesson learned from nature.

Polyketides produced by bacteria and fungi represent an extremely rich source of biologically active compounds that find wide-ranging applications as antibiotics, immunosuppresants, antitumor agents, and antiparasitic agents. The striking structural diversity of polyketides that gives rise to these wide-ranging applications is dictated both by the polyketide synthase (PKS) responsible for assembling the carbon backbone of the molecule, and by the tailoring enzymes (such as glycosyl transferases and hydroxylases) that modify the polyketide ring. Seminal work in our understanding of the complex polyketides came a number of years ago with the revelation that erythromycin produced by Saccharopolyspora erythraea is assembled by a modular PKS (1, 2). The first module is responsible for priming erythromycin with propionyl CoA and catalyzing a decarboxylative condensation with methylmalonyl CoA. The remaining five modules catalyze successive condensations with methylmalonyl CoA before a terminal thioesterase (TE) domain releases the aglycone, deoxyerythronolide B. The presence or absence of ketoreductase (KR), dehydratase (DH), and enoyl reductase (ER) catalytic domains within the module controls the extent to which the β-carbonyl of the growing polyketide chain is processed. In this issue of the Proceedings researchers at the University of Minnesota have revealed that a similar modular PKS is responsible for ketolide biosynthesis in Streptomyces venezulae (Fig. 1) (3).