deglutathionylation

Deglutathionylation is the process of removing a glutathione moiety from a protein cysteine that has been modified by S-glutathionylation. S-glutathionylation, a reversible post-translational modification, occurs when the thiol group of a cysteine forms a mixed disulfide with glutathione (protein-SSG). Deglutathionylation restores the free thiol, reversing the modification and enabling redox-regulated changes in protein activity in response to cellular redox state.

Glutaredoxins are the primary deglutathionylating enzymes. They catalyze the removal of protein-SSG using reduced glutathione (GSH) as an electron donor, yielding the reduced cysteine and oxidized glutathione (GSSG). The reaction is part of a catalytic cycle sustained by glutathione reductase, which regenerates GSH from GSSG using NADPH. In addition to glutaredoxins, the thioredoxin system can contribute to deglutathionylation under certain conditions, and non-enzymatic exchange with GSH can occur in highly reducing environments.

Deglutathionylation has broad biological significance as a dynamic redox switch that modulates enzyme activity, protein–protein interactions, and signaling pathways. By removing glutathione adducts, it also helps protect sensitive cysteines from irreversible oxidation during oxidative or nitrosative stress.

Dysregulated deglutathionylation is linked to various diseases characterized by oxidative stress, including aging-related disorders, cardiovascular disease, and neurodegeneration. Research methods to study it include detection of protein-SSG by specific antibodies, mass spectrometry, and assays of GLRX activity.