Mechanistic Insight into Peptidyl‐Cysteine Oxidation by the Copper‐Dependent Formylglycine‐Generating Enzyme
Yao Wu, Cong Zhao, Yanzhuang Su, Sason Shaik, Wenzhen Lai
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 O 2 , which will be useful for future experimental work.