Glutathione-disulfide reductase (GSR) (GSR)

Glutathione-disulfide reductase (GSR) is a critical homodimeric flavoprotein enzyme that maintains the intracellular pool of reduced glutathione (GSH) by catalyzing the NADPH-dependent reduction of glutathione disulfide (GSSG) (UniProt: P00390). This process is essential for protecting cells against oxidative damage caused by reactive oxygen species and for maintaining a reduced environment necessary for protein function and DNA synthesis (PubMed: 15135301). In the context of oncology, GSR is a significant target for nitrosourea drugs like carmustine and lomustine, which inhibit the enzyme through carbamoylation of its active site by isocyanate metabolites (DrugBank: DB00571). This inhibition leads to the depletion of GSH and an accumulation of GSSG, thereby increasing oxidative stress and sensitizing tumor cells to the cytotoxic effects of DNA-alkylating agents (PubMed: 3065444). The phrase 'and other cellular proteins' in the target name reflects the broad carbamoylating activity of these drugs, which also affects DNA repair enzymes and RNA processing factors, contributing to their overall therapeutic efficacy and toxicity (PubMed: 6323055). Dysregulation or deficiency of GSR is associated with various pathologies, including hemolytic anemia and increased susceptibility to oxidative stress-induced cell death (OMIM: 138300).

Other names

Glutathione reductaseGRGRDGSRDGlutathione-disulfide reductase, mitochondrial

Inhibition of glutathione-disulfide reductase prevents the regeneration of reduced glutathione (GSH) from its oxidized form (GSSG), leading to a depletion of the cellular antioxidant pool, increased oxidative stress, and potentiation of DNA damage.