Polyketide synthesis: prospects for hybrid antibiotics

Abstract

Polyketides fall into two structural classes: aromatic and complex. The former are built mainly from acetate units through a reiterative process wherein the beta-carbonyl groups formed after each condensation cycle are left largely unreduced. Complex polyketides are composed of acetates, propionates, or butyrates, and the extent of beta-carbonyl reduction varies from one cycle to the next. Two themes for polyketide synthases are emerging. Aromatic PKSs are determined by four to six genes encoding mono- or bifunctional enzymes; one PKS complex is used for all synthesis steps. Complex PKSs are composed of several multifunctional polypeptides that contain enzymatic domains for the condensation and reduction steps; each domain is used at a unique step in the pathways, and the extent of beta-carbonyl processing depends on the functional domains operating at that cycle. Mutations rendering certain domains nonfunctional have been introduced into genes for complex polyketides, resulting in the production of novel molecules.