Structural Enzymology of Polyketide Synthase: The Structure–Sequence–Function Correlation

Abstract

Polyketides are a large class of structurally diverse, acetate derived natural products that exhibit a wide range of bioactivities. The biosynthesis of polyketides from acyl-CoA thioesters is catalyzed by polyketide synthase (PKS), a multi-enzyme complex that is highly homologous to fatty acid synthase (FAS). This chapter will focus on the structural enzymology of the Type II PKS enzymes that are responsible for the synthesis of aromatic polyketides such as actinorhodin, tetracycline, and tetracenomycin. Structures of initiation and condensation domains provide valuable insights into the molecular factors governing starter unit selectivity and chain-length control. Similarly, recently solved structures of polyketide modifying enzymes show how these enzymes govern reduction and cyclization patterns that further add to the diversity of polyketide products. The role protein-protein interactions in mediating the activity of the individual domains will also be discussed. A detailed understanding of the structural features controlling polyketide biosynthesis and modification offers a powerful tool for the controlled and rational design of novel polyketides through enzyme engineering.