Glutathione biosynthetic pathway and redox metabolism (GSH pathway) (GSH pathway)

The cellular glutathione biosynthetic pathway and redox pool represent the central mechanism for maintaining intracellular redox homeostasis and protecting cells from oxidative damage. Glutathione (GSH) is a tripeptide synthesized from glutamate, cysteine, and glycine through the sequential action of glutamate-cysteine ligase (GCL) and glutathione synthetase (GSS) (Lu, 2013, Biochimica et Biophysica Acta). The redox pool is regulated by the balance between GSH and its oxidized form (GSSG), a process facilitated by enzymes such as glutathione reductase and glutathione peroxidase (Deponte, 2013, Biochimica et Biophysica Acta). This system plays a pivotal role in detoxifying reactive oxygen species (ROS) and electrophilic xenobiotics, as well as regulating ferroptosis, a form of regulated cell death (Dixon et al., 2012, Cell). In many cancers, the GSH pathway is upregulated to confer resistance to oxidative stress and chemotherapy, leading to the development of inhibitors like buthionine sulfoximine to sensitize tumors (Traverso et al., 2013, Oxidative Medicine and Cellular Longevity). Conversely, in conditions like neurodegeneration or acetaminophen toxicity, therapeutic strategies aim to replenish the GSH pool using precursors like N-acetylcysteine to prevent cell death (Rushworth & Megson, 2014, Free Radical Biology and Medicine).

Other names

Glutathione metabolismGSH redox cycleGamma-glutamyl cycleGlutathione homeostasisGSH/GSSG redox couple

Modulation of glutathione levels through inhibition of rate-limiting enzymes like glutamate-cysteine ligase, inhibition of the cystine/glutamate antiporter (System Xc-), or provision of biosynthetic precursors like N-acetylcysteine to alter the cellular redox state.