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Hybrid Type I and II Polyketide Synthases Yield Distinct Aromatic Polyketides

Authors :
Zhao, Li Ya
Shi, Jing
Xu, Zhao Yang
Sun, Jia Lin
Yan, Zhang Yuan
Tong, Zhi Wu
Tan, Ren Xiang
Jiao, Rui Hua
Ge, Hui Ming
Source :
Journal of the American Chemical Society; 20240101, Issue: Preprints
Publication Year :
2024

Abstract

Bacterial 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 hybrid type I and type II PKSs are extremely rare. Here, we report the discovery of a gene cluster encoding both modular type I and type II PKSs as well as KAS III through extensive bioinformatics analysis, leading to the characterization of the hybrid polyketide, spirocycline A. The structure of spirocycline A is rare among all aromatic polyketides, featuring a unique starter unit and 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 two trans-acting ketoreductase (KR) and enoylreductase (ER). It is then transferred by KAS III to the type II PKS system, which synthesizes the tricyclic aromatic polyketide backbone. The subsequent formation of the spirocycle and dimerization are 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.

Details

Language :
English
ISSN :
00027863 and 15205126
Issue :
Preprints
Database :
Supplemental Index
Journal :
Journal of the American Chemical Society
Publication Type :
Periodical
Accession number :
ejs67699941
Full Text :
https://doi.org/10.1021/jacs.4c08803