Mechanistic Insight into Peptidyl‐Cysteine Oxidation by the Copper‐Dependent Formylglycine‐Generating Enzyme

Autor: Yao Wu, Cong Zhao, Yanzhuang Su, Sason Shaik, Wenzhen Lai
Rok vydání: 2023
Předmět:
Zdroj: Angewandte Chemie International Edition. 62
ISSN: 1521-3773
1433-7851
DOI: 10.1002/anie.202212053
Popis: The copper-dependent formylglycine-generating enzyme (FGE) catalyzes the oxygen-dependent oxidation of specific peptidyl-cysteine residues to formylglycine. Our QM/MM calculations provide a very likely mechanism for this transformation. The reaction starts with dioxygen binding to the tris-thiolate Cu(I) center to form a triplet Cu(II)-superoxide complex. The rate-determining hydrogen atom abstraction involves a triplet-singlet crossing to form a Cu(II)-OOH species that couples with the substrate radical, leading to a Cu(I)-alkylperoxo intermediate. This is accompanied by proton transfer from the hydroperoxide to the S atom of the substrate via a nearby water molecule. The subsequent O-O bond cleavage is coupled with the C-S bond breaking that generates the formylglycine and a Cu(II)-oxyl complex. Moreover, our results suggest that the aldehyde oxygen of the final product originates from O2, which will be useful for future experimental work.
Databáze: OpenAIRE
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