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Phylogeny-directed discovery and mutagenesis of a tricyclic gersemiane synthase

文献类型：期刊论文

作者Chen, Xiaochen3; Chen, Bao2; Xu, Baofu1,2,3
刊名ORGANIC & BIOMOLECULAR CHEMISTRY
出版日期2025-10-29
卷号23期号:42页码:9635-9643
ISSN号1477-0520
DOI10.1039/d5ob01208b
通讯作者Xu, Baofu(bfxu@simm.ac.cn)
英文摘要Eunicellane diterpenoids, characterized by a 6,10-bicyclic core, are prone to undergo further cyclization into gersemiane diterpenoids via acid- or epoxidation-mediated protonation. However, it remains unclear whether classical type I terpene synthases (TSs), phylogenetically related to reported eunicellane synthases, can catalyze this protonation reaction, a process typically driven by type II TSs. To address this question, we employed a phylogeny-directed discovery approach starting from the eunicellane synthase MicA. This led to the discovery of SsFitTS, a tricyclic gersemiane synthase capable of catalyzing the protonation of a natural eunicellane intermediate within its classical type I TS active pocket. Through mutagenesis and molecular docking studies, we elucidated the mechanistic basis for this type I TS's ability to mediate a typically type II-like reaction while retaining its canonical type I fold. Our study not only demonstrated that the phylogeny-based genome mining method can unveil cryptic TSs but also facilitated the decoding of the structural basis underlying the determination of terpene scaffolds.
资助项目National Key Research and Development Program of China[2022YFC2804100] ; National Key Research and Development Program of China[tsqn20230623] ; Taishan Scholars Program[SYS202205] ; Shandong Laboratory Program[23PJ1415300] ; Shanghai Pujiang Program[ZR2024QB357] ; Shandong Provincial Natural Science Foundation[2024CXPT029] ; Key R&D Program of Shandong Province, China[22407117] ; National Natural Science Foundation of China
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001589867900001
出版者ROYAL SOC CHEMISTRY
源URL[http://119.78.100.183/handle/2S10ELR8/321690]  
专题中国科学院上海药物研究所
通讯作者Xu, Baofu
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
3.Shandong First Med Univ & Shandong Acad Med Sci, Jinan 250117, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Xiaochen,Chen, Bao,Xu, Baofu. Phylogeny-directed discovery and mutagenesis of a tricyclic gersemiane synthase[J]. ORGANIC & BIOMOLECULAR CHEMISTRY,2025,23(42):9635-9643.
APA Chen, Xiaochen,Chen, Bao,&Xu, Baofu.(2025).Phylogeny-directed discovery and mutagenesis of a tricyclic gersemiane synthase.ORGANIC & BIOMOLECULAR CHEMISTRY,23(42),9635-9643.
MLA Chen, Xiaochen,et al."Phylogeny-directed discovery and mutagenesis of a tricyclic gersemiane synthase".ORGANIC & BIOMOLECULAR CHEMISTRY 23.42(2025):9635-9643.

入库方式： OAI收割

来源：上海药物研究所

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