Engineering biodiversity with type II polyketide synthase genes.

Abstract

A very important task in the ongoing search for new clinically useful drugs is the generation of large numbers of structurally diverse compounds. The emerging field of combinatorial biosynthesis, in which nature's chemical capabilities are exploited in a combinatorial 'mix-and-match' fashion, has generated libraries of novel molecules representing great structural diversity which are not available naturally or readily generated through (combinatorial) synthesis. Novel polyketides have been generated by manipulating type II iterative polyketide synthase (PKS) systems that express a variety of combinations of a minimal PKS with ketoreductases, cyclases, and other tailoring enzymes, resulting in a set of design rules to rationally engineer new metabolites. Engineering studies with the Streptomyces coelicolor whiE (spore pigment) and the 'Streptomyces maritimus' enterocin type II PKS provide additional insight on designing diverse assemblies of aromatic, as well as nonaromatic, polyketides.