Chanoclavine synthase operates by an NADPH-independent superoxide mechanism
Chun Chi Chen (Chinese Academy of Sciences, Hubei University, Hangzhou Normal University)
Zhi Pu Yu (Ocean University of China, Chinese Academy of Sciences)
Ziwei Liu (Hubei University, Hangzhou Normal University)
Peter Leon Hagedoorn (TU Delft - BT/Biocatalysis)
Rob Alexander Schmitz (TU Delft - BT/Biocatalysis)
Aokun Liu (University of Science and Technology of China, Chinese Academy of Science)
Jian Wen Huang (Hangzhou Normal University, Hubei University)
Rey Ting Guo (Hangzhou Normal University, Hubei University)
Shu Shan Gao (National Center of Technology Innovation for Synthetic Biology, Tianjin, Chinese Academy of Sciences)
undefined More Authors (External organisation)
More Info
expand_more
Other than for strictly personal use, it is not permitted to download, forward or distribute the text or part of it, without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license such as Creative Commons.
Abstract
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 H2O2 disproportionation, EasC and its homologues represent a broader class of catalases that catalyse O2-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.
help_outline