Chanoclavine synthase operates by an NADPH-independent superoxide mechanism
More than ten ergot alkaloids comprising both natural and semi-synthetic products are used to treat various diseases<sup>1,2</sup>. The central C ring forms the core pharmacophore for ergot alkaloids, giving them structural similarity to neurotransmitters, thus enabling their modulation of neurotransmitter receptors<sup>3</sup>. The haem catalase chanoclavine synthase (EasC) catalyses the construction of this ring through complex radical oxidative cyclization<sup>4</sup>. Unlike canonical catalases, which catalyse H<sub>2</sub>O<sub>2</sub> disproportionation<sup>5,6</sup>, EasC and its homologues represent a broader class of catalases that catalyse O<sub>2</sub>-dependent radical reactions<sup>4,7</sup>. 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)<sup>8,9</sup>, 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.
Authors
- Juzhang Yan
- Hao Su (ORCID: https://orcid.org/0000-0002-0178-6610)
- Peter‐Leon Hagedoorn (ORCID: https://orcid.org/0000-0001-6342-2022)
- Zhi‐Pu Yu
- Te Wang (ORCID: https://orcid.org/0000-0002-8688-7479)
- Xian Li (ORCID: https://orcid.org/0000-0002-4095-2554)
- Yaqing Ma (ORCID: https://orcid.org/0009-0001-4766-2592)
- Rey‐Ting Guo (ORCID: https://orcid.org/0000-0003-2942-7246)
- Lujia Yang
- Xiang Sheng (ORCID: https://orcid.org/0000-0002-6542-6649)
- Shu‐Shan Gao (ORCID: https://orcid.org/0000-0001-6335-2052)
- Wuyuan Zhang (ORCID: https://orcid.org/0000-0002-3182-5107)
- Jian Min (ORCID: https://orcid.org/0000-0002-6341-2462)
- Chengsen Cui (ORCID: https://orcid.org/0000-0002-6867-1826)
- Yongpeng Yao (ORCID: https://orcid.org/0000-0002-6084-1683)
- Rob A. Schmitz (ORCID: https://orcid.org/0000-0001-5145-991X)
- Pan‐Pan Shen (ORCID: https://orcid.org/0000-0002-5504-2799)
- Aokun Liu (ORCID: https://orcid.org/0009-0001-0630-2734)
- Chang‐Yun Wang (ORCID: https://orcid.org/0000-0002-0236-1606)
- Chun‐Chi Chen (ORCID: https://orcid.org/0000-0002-7459-5591)
- Lu Yu (ORCID: https://orcid.org/0000-0003-4852-0008)
- Jian‐Wen Huang (ORCID: https://orcid.org/0000-0001-8098-0245)
- Lilan Zhang (ORCID: https://orcid.org/0000-0003-0475-3408)
- Jinping Bao
- Ziwei Liu (ORCID: https://orcid.org/0009-0005-4275-4710)
Institutions
- University of Science and Technology of China (CN)
- Hangzhou Normal University (CN)
- Chinese Academy of Sciences (CN)
- Hefei Institutes of Physical Science (CN)
- High Magnetic Field Laboratory (CN)
- Intelligent Synthetic Biology Center (KR)
- Qingdao National Laboratory for Marine Science and Technology (CN)
- Institute of Microbiology (CN)
- Tianjin Institute of Industrial Biotechnology (CN)
- Ocean University of China (CN)
- Hubei University (CN)
- Delft University of Technology (NL)
Publication Details
- Journal
- Nature
- Published
- 2025-03-05
- DOI
- https://doi.org/10.1038/s41586-025-08670-3
- Citations
- 12
- Primary Topic
- Metal-Catalyzed Oxygenation Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 6.45