persulfidation

Persulfidation, also known as S-sulfhydration, is a post-translational modification in which a reactive cysteine thiol (-SH) in a protein is converted to a persulfide (-SSH). This adds a sulfur atom to the cysteine, forming a sulfur-containing linkage. It is a reversible, redox-based signaling modification that can alter protein function, interactions, and localization. Hydrogen sulfide (H2S) is the primary biological donor.

Within cells, persulfidation arises from enzymatic production of H2S by enzymes such as cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase, as well as non-enzymatic reactions. The reactive thiolate form of cysteine (Cys-S−) is targeted, and persulfide formation can be favored by oxidative conditions and the presence of metal centers or reductants. Persulfidation is generally considered reversible, with cellular thiol-redox systems able to remove the extra sulfur.

Functionally, persulfidation modulates diverse biological processes, including metabolism, stress responses, mitochondrial function, and signaling pathways. It can either activate or inhibit enzyme activity, alter protein stability, or change interactions with partners. In many organisms, persulfidation is proposed to contribute to cytoprotection against oxidative stress and to mediate hydrogen sulfide signaling.

Detection and study of persulfidation rely on chemical labeling and proteomic approaches, such as modified thiol-switch assays and mass spectrometry. However, sample handling can introduce artifacts, so rigorous controls are essential. Ongoing work seeks to map the persulfidome and to clarify the conditions under which persulfidation is physiologically relevant.

Persulfidation is an area of active research in both animal and plant biology, with implications for aging, disease, and stress adaptation. It is considered part of a broader family of redox-based post-translational modifications that regulate protein function through reversible covalent modification of cysteine residues.