Mechanistic Insight into Peptidyl‐Cysteine Oxidation by the Copper‐Dependent Formylglycine‐Generating Enzyme. (12th January 2023)

• Record Type: Journal Article
• Authors: Wu, Yao; Zhao, Cong; Su, Yanzhuang; Shaik, Sason; Lai, Wenzhen
• Is Part Of: Angewandte Chemie. Volume 135:Number 7(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-01-12
• Subjects: C−H Activation -- C−S Cleavage -- Copper -- Dioxygen Activation -- O−O Cleavage; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202212053
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: 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. Abstract : QM/MM calculations reveal the reaction mechanism of the FGE‐catalyzed oxidative conversion of peptidyl‐cysteines into formylglycine. Triplet‐singlet crossing initiates the rate‐limiting hydrogen atom abstraction from substrate to generate a Cu II −OOH species. A nearby water molecule plays a vital role in the formation of the Cu I ‐alkylperoxo intermediate, which is the key species that can undergo O−O bond cleavage to give formylglycine.