Intermodular Acyltransferase Complementation for Type I Polyketide Synthase

Multimodular polyketide synthases (PKSs) are large proteins that catalyze the biosynthesis polyketide antibiotics via an assembly line mechanism. Biosynthetic engineering of these PKSs has emerged as a powerful method for rationally modifying the structures of these natural products. In order to modify the extender units used by individual PKS modules, our lab has explored the feasibility of using a discrete acyl transferase (AT) to complement a mutant PKS in which one AT domain has been inactivated by mutagenesis (Kumar et al, JACS 125, 14307, 2003). In this presentation we will describe our efforts to enhance efficiency of this biosynthetic engineering strategy. Specifically, we have screened a number of discrete AT proteins to identify one with strong complementation activity in a variety of contexts. The structure, mechanism and biosynthetic potential of this AT protein have been analyzed in further detail.