Noncanonical Functions of Ketosynthase Domains in Type I Polyketide Synthases

Abstract Modular type I polyketide synthases (PKSs) are remarkable molecular machines that can synthesize structurally complex polyketide natural products with a wide range of biological activities. In these molecular machines, ketosynthase (KS) domains play a central role, typically by catalyzing decarboxylative Claisen condensation for polyketide chain extension. Noncanonical KS domains with catalytic functions rather than Claisen condensation have increasingly been evidenced, further demonstrating the capability of type I PKSs for structural diversity. This review provides an overview of the reactions involving unusual KS activities, including PKS priming, acyl transfer, Dieckmann condensation, Michael addition, aldol‐lactonization bicyclization, C−N bond formation and decarbonylation. Insights into these reactions can deepen the understanding of PKS‐based assembly line chemistry and guide the efforts for rational engineering of polyketide‐related molecules.