医薬品生合成におけるスーパーオキシドの触媒作用の解明(Study Reveals Superoxide Catalytic Role in Biosynthesis of Medicinal Products)

2025-03-24 中国科学院(CAS)

<関連情報>

• https://english.cas.cn/newsroom/research_news/life/202503/t20250321_908532.shtml
• https://www.nature.com/articles/s41586-025-08670-3

チャノクラビン合成酵素はNADPH非依存的スーパーオキシド機構で作動する 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 & Shu-Shan Gao
Nature  Published:05 March 2025
DOI:https://doi.org/10.1038/s41586-025-08670-3

Abstract

More than ten ergot alkaloids comprising both natural and semi-synthetic products are used to treat various diseases^1,2. 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 disproportionation^5,6, EasC and its homologues represent a broader class of catalases that catalyse O₂-dependent radical reactions^4,7. 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.