Endowing homodimeric carbamoyltransferase GdmN with iterative functions through structural characterization and mechanistic studies

Jianhua Wei, Xuan Zhang, Yucong Zhou, Xingnuo Cheng, Zhi Lin, Mancheng Tang, Jianting Zheng, Binju Wang, Qianjin Kang () and Linquan Bai ()
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Jianhua Wei: Shanghai Jiao Tong University
Xuan Zhang: Xiamen University
Yucong Zhou: Shanghai Jiao Tong University
Xingnuo Cheng: Shanghai Jiao Tong University
Zhi Lin: Shanghai Jiao Tong University
Mancheng Tang: Shanghai Jiao Tong University
Jianting Zheng: Shanghai Jiao Tong University
Binju Wang: Xiamen University
Qianjin Kang: Shanghai Jiao Tong University
Linquan Bai: Shanghai Jiao Tong University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Iterative enzymes, which catalyze sequential reactions, have the potential to improve the atom economy and diversity of industrial enzymatic processes. Redesigning one-step enzymes to be iterative biocatalysts could further enhance these processes. Carbamoyltransferases (CTases) catalyze carbamoylation, an important modification for the bioactivity of many secondary metabolites with pharmaceutical applications. To generate an iterative CTase, we determine the X-ray structure of GdmN, a one-step CTase involved in ansamycin biosynthesis. GdmN forms a face-to-face homodimer through unusual C-terminal domains, a previously unknown functional form for CTases. Structural determination of GdmN complexed with multiple intermediates elucidates the carbamoylation process and identifies key binding residues within a spacious substrate-binding pocket. Further structural and computational analyses enable multi-site enzyme engineering, resulting in an iterative CTase with the capacity for successive 7-O and 3-O carbamoylations. Our findings reveal a subclade of the CTase family and exemplify the potential of protein engineering for generating iterative enzymes.

Date: 2022
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DOI: 10.1038/s41467-022-34387-2

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