Polyketide synthase gene manipulation: a structure-function approach in engineering novel antibiotics

Polyketides are produced primarily in microorganisms through a specialized metabolism that is a variation of fatty acid biosynthesis. A strong sequence and mechanistic similarity among many of the fatty acid and polyketide synthase enzymes has led to two paradigms for explaining polyketide biochemistry. In one, polyketides are formed by enzyme complexes consisting of four to seven monofunctional proteins in which the beta-carbonyl groups of the intermediates resulting from the condensation of acetate residues are largely not reduced and cyclization of the intermediates typically produces aromatic compounds. The intermediates in the other model are formed by multifunctional enzymes in which each of the initial condensation products is processed through reduction; reduction and dehydration; or reduction, dehydration, and further reduction cycles to produce highly reduced compounds from acetate, propionate, and butyrate residues. Expression of the genes encoding each type of polyketide synthase, or their mutant forms, has provided much information about the underlying biochemistry and, in some cases, resulted in the formation of novel natural products.