Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Artículo científico |
| Language: | en |
| Published: |
Nature
2025
|
| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/40044871/ |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1868266234566410240 |
|---|---|
| author | Chen, Chun-Chi Yu, Zhi-Pu Liu, Ziwei Yao, Yongpeng Hagedoorn, Peter-Leon Schmitz, Rob Alexander Yang, Lujia Yu, Lu Liu, Aokun Sheng, Xiang Su, Hao Ma, Yaqing Wang, Te Huang, Jian-Wen Zhang, Lilan Yan, Juzhang Bao, Jinping Cui, Chengsen Li, Xian Shen, Panpan Zhang, Wuyuan Min, Jian Wang, Chang-Yun Guo, Rey-Ting Gao, Shu-Shan |
| author_facet | Chen, Chun-Chi Yu, Zhi-Pu Liu, Ziwei Yao, Yongpeng Hagedoorn, Peter-Leon Schmitz, Rob Alexander Yang, Lujia Yu, Lu Liu, Aokun Sheng, Xiang Su, Hao Ma, Yaqing Wang, Te Huang, Jian-Wen Zhang, Lilan Yan, Juzhang Bao, Jinping Cui, Chengsen Li, Xian Shen, Panpan Zhang, Wuyuan Min, Jian Wang, Chang-Yun Guo, Rey-Ting Gao, Shu-Shan Chen, Chun-Chi Yu, Zhi-Pu Liu, Ziwei Yao, Yongpeng Hagedoorn, Peter-Leon Schmitz, Rob Alexander Yang, Lujia Yu, Lu Liu, Aokun Sheng, Xiang Su, Hao Ma, Yaqing Wang, Te Huang, Jian-Wen Zhang, Lilan Yan, Juzhang Bao, Jinping Cui, Chengsen Li, Xian Shen, Panpan Zhang, Wuyuan Min, Jian Wang, Chang-Yun Guo, Rey-Ting Gao, Shu-Shan |
| collection | PubMed - marine biology |
| contents | Chanoclavine synthase operates by an NADPH-independent superoxide mechanism. Chen, Chun-Chi Yu, Zhi-Pu Liu, Ziwei Yao, Yongpeng Hagedoorn, Peter-Leon Schmitz, Rob Alexander Yang, Lujia Yu, Lu Liu, Aokun Sheng, Xiang Su, Hao Ma, Yaqing Wang, Te Huang, Jian-Wen Zhang, Lilan Yan, Juzhang Bao, Jinping Cui, Chengsen Li, Xian Shen, Panpan Zhang, Wuyuan Min, Jian Wang, Chang-Yun Guo, Rey-Ting Gao, Shu-Shan Binding Sites Biocatalysis Catalase Cryoelectron Microscopy Heme Models, Molecular NADP Superoxides Ergolines More than ten ergot alkaloids comprising both natural and semi-synthetic products are used to treat various diseases. The central C ring forms the core pharmacophore for ergot alkaloids, giving them structural similarity to neurotransmitters, thus enabling their modulation of neurotransmitter receptors. The haem catalase chanoclavine synthase (EasC) catalyses the construction of this ring through complex radical oxidative cyclization. Unlike canonical catalases, which catalyse HO disproportionation, EasC and its homologues represent a broader class of catalases that catalyse O-dependent radical reactions. 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), 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. |
| format | Artículo científico |
| id | pubmed_40044871 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Nature |
| record_format | pubmed |
| spellingShingle | Chanoclavine synthase operates by an NADPH-independent superoxide mechanism. Chen, Chun-Chi Yu, Zhi-Pu Liu, Ziwei Yao, Yongpeng Hagedoorn, Peter-Leon Schmitz, Rob Alexander Yang, Lujia Yu, Lu Liu, Aokun Sheng, Xiang Su, Hao Ma, Yaqing Wang, Te Huang, Jian-Wen Zhang, Lilan Yan, Juzhang Bao, Jinping Cui, Chengsen Li, Xian Shen, Panpan Zhang, Wuyuan Min, Jian Wang, Chang-Yun Guo, Rey-Ting Gao, Shu-Shan Binding Sites Biocatalysis Catalase Cryoelectron Microscopy Heme Models, Molecular NADP Superoxides Ergolines Chanoclavine synthase operates by an NADPH-independent superoxide mechanism. Chen, Chun-Chi Yu, Zhi-Pu Liu, Ziwei Yao, Yongpeng Hagedoorn, Peter-Leon Schmitz, Rob Alexander Yang, Lujia Yu, Lu Liu, Aokun Sheng, Xiang Su, Hao Ma, Yaqing Wang, Te Huang, Jian-Wen Zhang, Lilan Yan, Juzhang Bao, Jinping Cui, Chengsen Li, Xian Shen, Panpan Zhang, Wuyuan Min, Jian Wang, Chang-Yun Guo, Rey-Ting Gao, Shu-Shan Binding Sites Biocatalysis Catalase Cryoelectron Microscopy Heme Models, Molecular NADP Superoxides Ergolines More than ten ergot alkaloids comprising both natural and semi-synthetic products are used to treat various diseases. The central C ring forms the core pharmacophore for ergot alkaloids, giving them structural similarity to neurotransmitters, thus enabling their modulation of neurotransmitter receptors. The haem catalase chanoclavine synthase (EasC) catalyses the construction of this ring through complex radical oxidative cyclization. Unlike canonical catalases, which catalyse HO disproportionation, EasC and its homologues represent a broader class of catalases that catalyse O-dependent radical reactions. 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), 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. |
| title | Chanoclavine synthase operates by an NADPH-independent superoxide mechanism. |
| topic | Binding Sites Biocatalysis Catalase Cryoelectron Microscopy Heme Models, Molecular NADP Superoxides Ergolines |
| url | https://pubmed.ncbi.nlm.nih.gov/40044871/ |