S-desulfurization: A different covalent modification mechanism from persulfidation by GSH

Abstract

Post-translational transformation of cysteine residues to persulfides, known as protein S-sulfhydration or persulfidation, is a beneficial H2S signaling mechanism. In this paper, we found that GSH is bound to active cysteine sites of protein by S-desulfurization, which is a new covalent modification mechanism of protein, thus regulating catalytic activity. Here, we provide direct evidence that GSH modifies the reactive cysteine residues of four enzymes (alliinase/D-LDH/ADH/G6PD) and generates protein-SG or protein-SSG derivatives by S-desulfurization. S-desulfurization, α-carbon nucleophilic substitution or thiol-disulfide exchange occurs and H2S is released as a by-product. S-desulfurization is the opposite of persulfidation in terms of H2S production/consumption and enzyme inhibition/mitigation. Here, we elucidated the GSH mechanisms and H2S mechanisms in the enzyme-metabolite system and the beneficial roles of persulfidation and S-desulfurization. These theoretical findings are now shedding light on understanding GSH and H2S molecular functions and providing new theoretical basis for them in cell signaling pathways.