Mechanism of the Glutathione Persulfide Oxidation Process Catalyzed by Ethylmalonic Encephalopathy Protein 1

Ethylmalonic encephalopathy protein 1 (ETHE1) is a β-lactamase fold-containing protein, which is related to the increased cellular levels of hydrogen sulfide. ETHE1 is essential for the survival of a range of organisms and catalyzes the oxidation of glutathione persulfide (GSSH). Currently, the catalytic mechanism of ETHE1 still remains unclear, despite a catalytic cycle that has been suggested from the crystal structure and a proposal for the mechanistically related cysteine dioxygenase (CDO). In this Article, we performed a series of quantum mechanical/molecular mechanical (QM/MM) calculations on the substrate GSSH oxidation by human ETHE1. Our calculation results reveal that the ground state of the iron(II)-superoxo reactant is quintet, which can be described as GSS+•–Fe(II)–O2•, and the most feasible reaction channel was found to start from the cleavage of dioxygen and a concerted attack of distal oxygen on the sulfur atom of the substrate, forming the metal-bound activated oxygen and a sulfite interm...