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

作者：Jinfeng Li, Chen Bao, Zunyun Fu, Jingjing Mao, Lijun Liu, Xiaochen Chen, Mingyue Zheng, Chang‐Yun Wang, Chengyuan Wang, Yue‐Wei Guo, Baofu Xu · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-50209-z · 被引用次数：19 · 研究领域：Plant biochemistry and biosynthesis、Microbial Natural Products and Biosynthesis、Marine Sponges and Natural Products

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 2Z-geranylgeranyl diphosphate incubations and density functional theory-based Boltzmann population computations, reveale that a trans-fused bicycle with a 2Z-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.