Enediyne Polyketide Synthases Stereoselectively Reduce the β‑Ketoacyl Intermediates to β‑d‑Hydroxyacyl Intermediates in Enediyne Core Biosynthesis

Abstract

PKSE biosynthesizes an enediyne core precursor from decarboxylative condensation of eight malonyl-CoAs. The KR domain of PKSE is responsible for iterative β-ketoreduction in each round of polyketide chain elongation. KRs from selected PKSEs were investigated in vitro with β-ketoacyl-SNACs as substrate mimics. Each of the KRs reduced the β-ketoacyl-SNACs stereoselectively, all affording the corresponding β-d-hydroxyacyl-SNACs, and the catalytic efficiencies (<i>k</i>_cat/<i>K</i>_M) of the KRs increased significantly as the chain length of the β-ketoacyl-SNAC substrate increases