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

Jinfeng Li, Bao Chen, Zunyun Fu, Jingjing Mao, Lijun Liu, Xiaochen Chen, Mingyue Zheng, Chang-Yun Wang (), Chengyuan Wang (), Yue-Wei Guo () and Baofu Xu ()
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Jinfeng Li: Bohai Rim Advanced Research Institute for Drug Discovery
Bao Chen: Bohai Rim Advanced Research Institute for Drug Discovery
Zunyun Fu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhangjiang Hi-Tech Park
Jingjing Mao: Shanghai Institute of Immunity and Infection
Lijun Liu: Bohai Rim Advanced Research Institute for Drug Discovery
Xiaochen Chen: Bohai Rim Advanced Research Institute for Drug Discovery
Mingyue Zheng: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhangjiang Hi-Tech Park
Chang-Yun Wang: Ocean University of China
Chengyuan Wang: Shanghai Institute of Immunity and Infection
Yue-Wei Guo: Bohai Rim Advanced Research Institute for Drug Discovery
Baofu Xu: Bohai Rim Advanced Research Institute for Drug Discovery

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-50209-z

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