Journal Article

Discovery of a terpene synthase synthesizing a nearly non-flexible eunicellane reveals the basis of flexibility

Wang, Chang-Yun, Xu, Baofu, Li, Jinfeng, Guo, Yue-Wei, Wang, Chengyuan, Chen, Bao, Mao, Jingjing, Chen, Xiaochen, Liu, Lijun, Fu, Zunyun, Zheng, Mingyue

2024

Overview

Eunicellane diterpenoids, containing a typical 6,10-bicycle, are bioactive compounds widely present in marine corals, but rarely found in bacteria and plants. The intrinsic macrocycle exhibits innate structural flexibility resulting in dynamic conformational changes. However, the mechanisms controlling flexibility remain unknown. The discovery of a terpene synthase, MicA, that is responsible for the biosynthesis of a nearly non-flexible eunicellane skeleton, enable us to propose a feasible theory about the flexibility in eunicellane structures. Parallel studies of all eunicellane synthases in nature discovered to date, including 2 Z -geranylgeranyl diphosphate incubations and density functional theory-based Boltzmann population computations, reveale that a trans -fused bicycle with a 2 Z -configuration alkene restricts conformational flexibility resulting in a nearly non-flexible eunicellane skeleton. The catalytic route and the enzymatic mechanism of MicA are also elucidated by labeling experiments, density functional theory calculations, structural analysis of the artificial intelligence-based MicA model, and mutational studies. Eunicellane diterpenoids are bioactive compounds with a typical 6,10-bicycle, and their scaffolds exhibit innate structural flexibility, but the mechanistic basis for controlling flexibility was unknown. Here, the authors report a genome mining-based discovery of a terpene synthase, MicA, that synthesizes a nearly non-flexible eunicellane skeleton, and propose that configurations of bridging carbons and their adjacent double bond govern flexibility in eunicellane structures.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 119/118 / 140/131 / 140/58 / 38/23 / 631/45/173 / 639/638/45/607 / 639/638/92/349/977 / 82/80 / 82/83 / Alkyl and Aryl Transferases - chemistry / Alkyl and Aryl Transferases - genetics / Alkyl and Aryl Transferases - metabolism / Artificial intelligence / Bicycles / Bioactive compounds / Bioinformatics / Biological activity / Biosynthesis / Configurations / Corals / Density functional theory / Diterpenes / Diterpenes - chemistry / Diterpenes - metabolism / Flexibility / Genomics / Humanities and Social Sciences / Mica / Models, Molecular / multidisciplinary / Polyisoprenyl Phosphates - chemistry / Polyisoprenyl Phosphates - metabolism / Science / Science (multidisciplinary) / Structural analysis / Structure-function relationships / Terpene synthase