C-N bond formation by a polyketide synthase

Jialiang Wang; Xiaojie Wang; Xixi Li; LiangLiang Kong; Zeqian Du; Dandan Li; Lixia Gou; Hao Wu; Wei Cao; Xiaozheng Wang; Shuangjun Lin; Ting Shi; Zixin Deng; Zhijun Wang; Jingdan Liang

doi:10.1038/s41467-023-36989-w

C-N bond formation by a polyketide synthase

Nat Commun. 2023 Mar 10;14(1):1319. doi: 10.1038/s41467-023-36989-w.

Authors

Jialiang Wang^#¹, Xiaojie Wang^#^{1

2}, Xixi Li^#¹, LiangLiang Kong^#³, Zeqian Du^#¹, Dandan Li^#¹, Lixia Gou⁴, Hao Wu¹, Wei Cao¹, Xiaozheng Wang¹, Shuangjun Lin⁵, Ting Shi⁶, Zixin Deng⁷, Zhijun Wang⁸, Jingdan Liang⁹

Affiliations

¹ State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
² Department of Molecular Biology, Shanghai Jikaixing Biotech Inc., Shanghai, 200131, China.
³ National Facility for Protein Science in Shanghai, Chinese Academy of Sciences, Shanghai, 201204, China.
⁴ School of Life Science, North China University of Science and Technology, Tangshan, Hebei, China.
⁵ State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. linsj@sjtu.edu.cn.
⁶ State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. tshi@sjtu.edu.cn.
⁷ State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. zxdeng@sjtu.edu.cn.
⁸ State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. wangzhijun@sjtu.edu.cn.
⁹ State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. jdliang@sjtu.edu.cn.

^# Contributed equally.

Abstract

Assembly-line polyketide synthases (PKSs) are molecular factories that produce diverse metabolites with wide-ranging biological activities. PKSs usually work by constructing and modifying the polyketide backbone successively. Here, we present the cryo-EM structure of CalA3, a chain release PKS module without an ACP domain, and its structures with amidation or hydrolysis products. The domain organization reveals a unique "∞"-shaped dimeric architecture with five connected domains. The catalytic region tightly contacts the structural region, resulting in two stabilized chambers with nearly perfect symmetry while the N-terminal docking domain is flexible. The structures of the ketosynthase (KS) domain illustrate how the conserved key residues that canonically catalyze C-C bond formation can be tweaked to mediate C-N bond formation, revealing the engineering adaptability of assembly-line polyketide synthases for the production of novel pharmaceutical agents.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Catalytic Domain
Polyketide Synthases* / metabolism

Substances

Polyketide Synthases