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非鲨烯三萜的发现。

Discovery of non-squalene triterpenes.

机构信息

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

Kekulé-Institut für Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.

出版信息

Nature. 2022 Jun;606(7913):414-419. doi: 10.1038/s41586-022-04773-3. Epub 2022 Jun 1.

DOI:10.1038/s41586-022-04773-3
PMID:35650436
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9177416/
Abstract

All known triterpenes are generated by triterpene synthases (TrTSs) from squalene or oxidosqualene. This approach is fundamentally different from the biosynthesis of short-chain (C-C) terpenes that are formed from polyisoprenyl diphosphates. 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.

摘要

所有已知的三萜类化合物都是由鲨烯或氧化鲨烯通过三萜合成酶 (TrTSs) 生成的。这种方法从根本上不同于短链 (C-C) 萜类化合物的生物合成，后者是由聚异戊二烯二磷酸形成的。在这项研究中，两种真菌嵌合 I 类 TrTSs，即 Talaromyces verruculosus talaropentaene synthase (TvTS) 和 Macrophomina phaseolina macrophomene synthase (MpMS)，得到了表征。这两种酶都使用二甲基丙烯基二磷酸和异戊烯基二磷酸或六聚异戊二烯二磷酸作为底物，据我们所知，这是首次证明非鲨烯依赖的三萜类化合物生物合成。在同位素标记实验中研究了 TvTS 和 MpMS 的环化机制及其产物的绝对构型。TvTS 的萜烯环化酶结构域和全长 MpMS 的结构分析提供了对其催化机制的详细了解。开发了一个基于 AlphaFold2 的筛选平台来挖掘第三种 TrTS，即 Colletotrichum gloeosporioides colleterpenol synthase (CgCS)。我们的发现确定了三萜类化合物生物合成的新酶促机制，并增强了对自然界中萜类化合物生物合成的理解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a06b/9177416/40b1c657e7e2/41586_2022_4773_Fig11_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a06b/9177416/7740f39447be/41586_2022_4773_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a06b/9177416/3431c27e86ea/41586_2022_4773_Fig5_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a06b/9177416/90dd9330c5af/41586_2022_4773_Fig6_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a06b/9177416/5c7d57f69c68/41586_2022_4773_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a06b/9177416/c33ba084a241/41586_2022_4773_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a06b/9177416/f97b821d0d87/41586_2022_4773_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a06b/9177416/c7f9f0723c05/41586_2022_4773_Fig10_ESM.jpg
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