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 () and Jingdan Liang ()
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Jialiang Wang: Shanghai Jiao Tong University
Xiaojie Wang: Shanghai Jiao Tong University
Xixi Li: Shanghai Jiao Tong University
LiangLiang Kong: Chinese Academy of Sciences
Zeqian Du: Shanghai Jiao Tong University
Dandan Li: Shanghai Jiao Tong University
Lixia Gou: North China University of Science and Technology
Hao Wu: Shanghai Jiao Tong University
Wei Cao: Shanghai Jiao Tong University
Xiaozheng Wang: Shanghai Jiao Tong University
Shuangjun Lin: Shanghai Jiao Tong University
Ting Shi: Shanghai Jiao Tong University
Zixin Deng: Shanghai Jiao Tong University
Zhijun Wang: Shanghai Jiao Tong University
Jingdan Liang: Shanghai Jiao Tong University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36989-w

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