Tolerance and specificity of polyketide synthases

Polyketide synthases catalyze the assembly of complex natural products from simple precursors such as propionyl-CoA and methylmalonyl-CoA in a biosynt hetic process that closely parallels fatty acid biosynthesis. Like fatty ac ids, polyketides are assembled by successive decarboxylative condensations of simple precursors, But whereas the intermediates in fatty acid biosynthe sis are fully reduced to generate unfunctionalized alkyl chains, the interm ediates in polyketide biosynthesis may be only partially processed, giving rise to complex patterns of functional groups. Additional complexity arises from the use of different starter and chain extension substrates, the gene ration of chiral centers, and further functional group modifications, such as cyclizations. The structural and functional modularity of these multienz yme systems has raised the possibility that polyketide biosynthetic pathway s might be rationally reprogrammed by combinatorial manipulation. An essent ial prerequisite for harnessing this biosynthetic potential is a better und erstanding of the molecular recognition features of polyketide synthases. W ithin this decade, a variety of genetic, biochemical, and chemical investig ations have yielded insights into the tolerance and specificity of several architecturally different polyketide synthases. The results of these studie s, together with their implications for biosynthetic engineering, are summa rized in this review.