Citation: Pan Luo, Jian-Ming Lv, Hong-Ting Zhen, Ying-Qi Zhao, Jing-Yuan Liu, Jin-Yu Hong, Shao-Yang Li, Gao-Qian Wang, Guo-Dong Chen, Shui-Xing Zhang, Dan Hu, Hao Gao. Identification of two novel sesterterpene skeletons offers the first experimental evidence for the cyclization mechanism of mangicdiene synthase[J]. Chinese Chemical Letters, ;2026, 37(1): 111042. doi: 10.1016/j.cclet.2025.111042 shu

Identification of two novel sesterterpene skeletons offers the first experimental evidence for the cyclization mechanism of mangicdiene synthase

Pan Luo ^{a, b, c, 1} ,
Jian-Ming Lv ^{b, 1} ,
Hong-Ting Zhen ^{b, 1} ,
Ying-Qi Zhao ^b ,
Jing-Yuan Liu ^b ,
Jin-Yu Hong ^b ,
Shao-Yang Li ^b ,
Gao-Qian Wang ^b ,
Guo-Dong Chen ^{b, c} ,
Shui-Xing Zhang ^{a, *,} ,
Dan Hu ^{b, *,} ,
Hao Gao ^{a, b, *,}

a.
First Affiliated Hospital of Jinan University, Guangzhou 510630, China
b.
Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy/State Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China
c.
School of Pharmacy and Food Engineering, Wuyi University, Jiangmen 529020, China

shui7515@126.com

thudan@jnu.edu.cn

tghao@jnu.edu.cn

Received Date: 19 December 2024
Revised Date: 3 March 2025
Accepted Date: 5 March 2025
Available Online: 7 March 2025

Figures(4)

Mangicol-type sesterterpenoids possess potent anti-inflammatory activity, characterized by a 5–5–6–5 tetracyclic carbon skeleton formed by mangicdiene synthase FgMS. Two proposed mechanisms for mangicdiene formation involve either C6-C10 cyclization (path a) or C2-C10 cyclization (path b) after the C10 carbocation formation, but neither has been experimentally validated. Here, we have identified a second mangicdiene synthase ManD, which is derived from Fusarium sp. JNU-XJ070152–01 and shares high amino acid sequence identity with FgMS. Through heterologous expression of manD in Aspergillus oryzae NSAR1, we observed production not only of mangicdiene (1) and variecoltetraene (2), previously identified by expression of FgMS in Escherichia coli, but also two novel sesterterpene skeletons fusadiene (3) and fusatriene (4). The identification of fusadiene and fusatriene supports the occurrence of two key carbocation intermediates in path b, thus experimentally confirming that mangicdiene is built via path b for the first time, consistent with previous density functional theory (DFT) calculation results.
- Mangicol-type sesterterpenoid,
- Terpene cyclase,
- Heterologous expression,
- Aspergillus oryzae,
- Cyclization mechanism
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