A Hybrid Type I and II Polyketide Synthases Yields Distinct Aromatic Polyketides

Abstract

ABSTRACTBacterial aromatic polyketides are compounds with multiple aromatic rings synthesized by bacterial type II polyketide synthases (PKSs), some of which have been developed into clinical drugs. Compounds containing aromatic polyketides synthesized by a hybrid type I and type II PKSs are extremely rare. Here, we report the discovery of a gene cluster encoding both modular type I PKS, type II PKS and KAS III through extensive bioinformatics analysis, leading to the characterization of the hybrid polyketide, spirocycline A. The structure of spirocycline A is unprecedented among all aromatic polyketides, featuring a unique starter unit, four spirocycles, and forming a dimer. Biosynthetic studies indicate that the starter unit of this molecule is synthesized by type I PKS in collaboration with twotrans-acting ketoreductase (KR) and enoylreductase (ER). It is then transferred by KAS III to the type II PKS system, which then synthesizes the tricyclic aromatic polyketide backbone. The subsequent formation of the spirocycle and dimerization is carried out by four redox enzymes encoded in the gene cluster. Overall, the discovery of spirocycline A provides a new approach for identifying novel aromatic polyketides and offers potential enzymatic tools for the bioengineering of these hybrid polyketides.Table of Contents