Mechanistic Insight into Peptidyl-Cysteine Oxidation by the Copper-Dependent Formylglycine-Generating Enzyme |
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| Authors: | Yao Wu Cong Zhao Yanzhuang Su Prof Dr Sason Shaik Prof Dr Wenzhen Lai |
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| Institution: | 1. Key Laboratory of Advanced Light Conversion Materials and Biophotonics, Department of Chemistry, Renmin University of China, Beijing, 100872 China;2. Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904 Israel |
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| 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 CuI center to form a triplet CuII-superoxide complex. The rate-determining hydrogen atom abstraction involves a triplet-singlet crossing to form a CuII−OOH species that couples with the substrate radical, leading to a CuI-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 CuII-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. |
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| Keywords: | C−H Activation C−S Cleavage Copper Dioxygen Activation O−O Cleavage |
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