| Glutathione (GSH) is a low-molecular-weight tripeptide thiol antioxidant composed of glutamate, cysteine, and glycine, synthesized via two sequential ATP-dependent steps catalyzed by glutamate-cysteine ligase and glutathione synthetase. It primarily exists in reduced (GSH) and oxidized disulfide (GSSG) forms, which interconvert to regulate cellular redox balance. GSH features a unique γ-glutamyl peptide bond between glutamate’s γ-carboxyl and cysteine’s amino group, imparting resistance to degradation by γ-glutamyl cyclotransferase and most peptidases; the cysteine thiol (-SH) acts as the nucleophilic center for redox chemistry, while glycine stabilizes the C-terminus. GSH directly scavenges reactive oxygen and nitrogen species (ROS/RNS) via thiol-disulfide exchange, serves as an essential reductant for glutathione peroxidases (GPx) that detoxify peroxides (with GSSG reduced back to GSH by glutathione reductase using NADPH), and conjugates electrophilic xenobiotics, heavy metals, and endogenous toxins through glutathione S-transferases (GSTs) for phase II detoxification and mercapturic acid export. These processes maintain protein sulfhydryl homeostasis, support Nrf2-driven antioxidant gene expression, facilitate iron-sulfur cluster assembly and metal trafficking, and modulate signaling pathways such as NF-κB. GSH depletion is implicated in oxidative stress-related diseases, including Parkinson’s disease, liver cirrhosis, cancer, diabetes, and premature aging. |
