Chanoclavine synthase operates by an NADPH-independent superoxide mechanism

Chun-Chi Chen, Zhi-Pu Yu, Ziwei Liu, Yongpeng Yao, Peter-Leon Hagedoorn, Rob Alexander Schmitz, Lujia Yang, Lu Yu, Aokun Liu, Xiang Sheng, Hao Su, Yaqing Ma, Te Wang, Jian-Wen Huang, Lilan Zhang, Juzhang Yan, Jinping Bao, Chengsen Cui, Xian Li, Panpan Shen, Wuyuan Zhang, Jian Min, Chang-Yun Wang, Rey-Ting Guo () and Shu-Shan Gao ()
Additional contact information
Chun-Chi Chen: Hangzhou Normal University
Zhi-Pu Yu: Chinese Academy of Sciences
Ziwei Liu: Hangzhou Normal University
Yongpeng Yao: Chinese Academy of Sciences
Peter-Leon Hagedoorn: Delft University of Technology
Rob Alexander Schmitz: Delft University of Technology
Lujia Yang: Chinese Academy of Sciences
Lu Yu: University of Science and Technology of China
Aokun Liu: University of Science and Technology of China
Xiang Sheng: Chinese Academy of Sciences
Hao Su: Chinese Academy of Sciences
Yaqing Ma: Chinese Academy of Sciences
Te Wang: Hubei University
Jian-Wen Huang: Hangzhou Normal University
Lilan Zhang: Hubei University
Juzhang Yan: Chinese Academy of Sciences
Jinping Bao: Chinese Academy of Sciences
Chengsen Cui: Chinese Academy of Sciences
Xian Li: Hangzhou Normal University
Panpan Shen: Hangzhou Normal University
Wuyuan Zhang: Chinese Academy of Sciences
Jian Min: Hubei University
Chang-Yun Wang: Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center
Rey-Ting Guo: Hangzhou Normal University
Shu-Shan Gao: Chinese Academy of Sciences

Nature, 2025, vol. 640, issue 8059, 840-846

Abstract: Abstract More than ten ergot alkaloids comprising both natural and semi-synthetic products are used to treat various diseases1,2. The central C ring forms the core pharmacophore for ergot alkaloids, giving them structural similarity to neurotransmitters, thus enabling their modulation of neurotransmitter receptors3. The haem catalase chanoclavine synthase (EasC) catalyses the construction of this ring through complex radical oxidative cyclization4. Unlike canonical catalases, which catalyse H2O2 disproportionation5,6, EasC and its homologues represent a broader class of catalases that catalyse O2-dependent radical reactions4,7. We have elucidated the structure of EasC by cryo-electron microscopy, revealing a nicotinamide adenine dinucleotide phosphate (reduced) (NADPH)-binding pocket and a haem pocket common to all haem catalases, with a unique homodimeric architecture that is, to our knowledge, previously unobserved. The substrate prechanoclavine unprecedentedly binds in the NADPH-binding pocket, instead of the previously suspected haem-binding pocket, and two pockets were connected by a slender tunnel. Contrary to the established mechanisms, EasC uses superoxide rather than the more generally used transient haem iron–oxygen complexes (such as compounds I, II and III)8,9, to mediate substrate transformation through superoxide-mediated cooperative catalysis of the two distant pockets. We propose that this reactive oxygen species mechanism could be widespread in metalloenzyme-catalysed reactions.

Date: 2025
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DOI: 10.1038/s41586-025-08670-3

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