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Discovery of non-squalene triterpenes

Hui Tao, Lukas Lauterbach, Guangkai Bian, Rong Chen, Anwei Hou, Takahiro Mori, Shu Cheng, Ben Hu, Li Lu, Xin Mu, Min Li, Naruhiko Adachi, Masato Kawasaki, Toshio Moriya, Toshiya Senda, Xinghuan Wang, Zixin Deng, Ikuro Abe (), Jeroen S. Dickschat () and Tiangang Liu ()
Additional contact information
Hui Tao: The University of Tokyo
Lukas Lauterbach: Kekulé-Institut für Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-Universität Bonn
Guangkai Bian: Wuhan University
Rong Chen: Zhongnan Hospital of Wuhan University
Anwei Hou: Kekulé-Institut für Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-Universität Bonn
Takahiro Mori: The University of Tokyo
Shu Cheng: Wuhan University
Ben Hu: Wuhan University
Li Lu: Wuhan University
Xin Mu: Wuhan University
Min Li: Wuhan University
Naruhiko Adachi: Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK)
Masato Kawasaki: Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK)
Toshio Moriya: Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK)
Toshiya Senda: Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK)
Xinghuan Wang: Zhongnan Hospital of Wuhan University
Zixin Deng: Wuhan University
Ikuro Abe: The University of Tokyo
Jeroen S. Dickschat: Kekulé-Institut für Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-Universität Bonn
Tiangang Liu: Wuhan University

Nature, 2022, vol. 606, issue 7913, 414-419

Abstract: Abstract All known triterpenes are generated by triterpene synthases (TrTSs) from squalene or oxidosqualene1. This approach is fundamentally different from the biosynthesis of short-chain (C10–C25) terpenes that are formed from polyisoprenyl diphosphates2–4. In this study, two fungal chimeric class I TrTSs, Talaromyces verruculosus talaropentaene synthase (TvTS) and Macrophomina phaseolina macrophomene synthase (MpMS), were characterized. Both enzymes use dimethylallyl diphosphate and isopentenyl diphosphate or hexaprenyl diphosphate as substrates, representing the first examples, to our knowledge, of non-squalene-dependent triterpene biosynthesis. The cyclization mechanisms of TvTS and MpMS and the absolute configurations of their products were investigated in isotopic labelling experiments. Structural analyses of the terpene cyclase domain of TvTS and full-length MpMS provide detailed insights into their catalytic mechanisms. An AlphaFold2-based screening platform was developed to mine a third TrTS, Colletotrichum gloeosporioides colleterpenol synthase (CgCS). Our findings identify a new enzymatic mechanism for the biosynthesis of triterpenes and enhance understanding of terpene biosynthesis in nature.

Date: 2022
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DOI: 10.1038/s41586-022-04773-3

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