Aminoacyl chain translocation catalysed by a type II thioesterase domain in an unusual non-ribosomal peptide synthetase

Shan Wang, William D. G. Brittain, Qian Zhang, Zhou Lu, Ming Him Tong, Kewen Wu, Kwaku Kyeremeh, Matthew Jenner (), Yi Yu (), Steven L. Cobb () and Hai Deng ()
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Shan Wang: University of Aberdeen
William D. G. Brittain: Durham University, Science Site
Qian Zhang: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Centre for Fluorinated Pharmaceuticals, School of Pharmaceutical Sciences, Wuhan University
Zhou Lu: University of Aberdeen
Ming Him Tong: University of Aberdeen
Kewen Wu: University of Aberdeen
Kwaku Kyeremeh: University of Ghana
Matthew Jenner: University of Warwick
Yi Yu: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Centre for Fluorinated Pharmaceuticals, School of Pharmaceutical Sciences, Wuhan University
Steven L. Cobb: Durham University, Science Site
Hai Deng: University of Aberdeen

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Non-Ribosomal Peptide Synthetases (NRPSs) assemble a diverse range of natural products with important applications in both medicine and agriculture. They consist of several multienzyme subunits that must interact with each other in a highly controlled manner to facilitate efficient chain transfer, thus ensuring biosynthetic fidelity. Several mechanisms for chain transfer are known for NRPSs, promoting structural diversity. Herein, we report the first biochemically characterized example of a type II thioesterase (TEII) domain capable of catalysing aminoacyl chain transfer between thiolation (T) domains on two separate NRPS subunits responsible for installation of a dehydrobutyrine moiety. Biochemical dissection of this process reveals the central role of the TEII-catalysed chain translocation event and expands the enzymatic scope of TEII domains beyond canonical (amino)acyl chain hydrolysis. The apparent co-evolution of the TEII domain with the NRPS subunits highlights a unique feature of this enzymatic cassette, which will undoubtedly find utility in biosynthetic engineering efforts.

Date: 2022
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DOI: 10.1038/s41467-021-27512-0

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