Engineering of Acyltransferase Domains in Polyketide Synthases

Abstract

Polyketides are among the most abundant secondary metabolites and widely distributed in bacteria, fungi, and plants. Polyketides that are produced by Type I modular polyketide synthases (PKSs) have a variety of pharmacological and agricultural applications. Type I modular PKSs are multi-domain enzymes that produce unique and diverse molecular structures by combining particular types of catalytic domains in a specific order where a module is defined as a set of catalytic domains that are required for a single round of polyketide chain elongation and modification reactions. An acyltransferase (AT) domain in each PKS module determines a specific extender substrate incorporated into the growing polyketide chain and is therefore often the primary target of PKS engineering efforts. More than, 20 different extender substrates have been proposed to be directly incorporated into naturally occurring polyketides by AT domains. In this review, we will describe three different approaches to change substrates in a given PKS module by AT domain engineering and attempt to summarize the opportunities and challenges for each strategy.