Sglutathionylation

S-glutathionylation is a reversible post-translational modification in which a glutathione molecule is covalently attached to a cysteine thiol in a protein, forming a mixed disulfide (protein-SSG). This modification commonly arises under oxidative or nitrosative stress when the cellular redox balance shifts toward oxidized glutathione (GSSG) or through transnitrosation pathways, and it can also occur as part of normal redox signaling.

Mechanistically, a cysteine thiol can attack a disulfide bond involving glutathione, yielding protein-SSG. The modification can occur spontaneously but is often facilitated by enzymes such as glutaredoxins. Reversal, or deglutathionylation, is primarily carried out by glutaredoxins and related thiol-disulfide systems, restoring the free thiol and regenerating reduced glutathione.

Functional consequences of S-glutathionylation are diverse. It can modulate enzyme activity, alter protein conformation, affect protein–protein interactions, and influence cellular localization, thereby acting as a reversible redox switch. In addition to regulating signaling pathways, S-glutathionylation can protect sensitive cysteine residues from irreversible oxidation and may serve as a sensor of cellular redox state.

Detection and study of S-glutathionylation rely on redox proteomics and targeted assays. Mass spectrometry identifies modified cysteines, while techniques such as the biotin-switch approach and specific antibodies aid in profiling glutathionylated proteins. The modification is relevant in physiology and in various diseases where oxidative stress is a feature, including aging, cardiovascular disorders, neurodegeneration, and cancer.