Glutathione reductase (GSR) (GSR)

Glutathione reductase (GSR) is a central homodimeric flavoprotein that maintains the cellular pool of reduced glutathione (GSH) by catalyzing the NADPH-dependent reduction of glutathione disulfide (GSSG) (UniProt P00390). GSH is the most abundant non-protein thiol in cells and serves as a critical antioxidant, protecting DNA, proteins, and lipids from oxidative damage (PubMed: 15135301). In the context of pharmacology, GSR is often targeted alongside other nucleophilic proteins by electrophilic agents or specific inhibitors to compromise the antioxidant capacity of cancer cells, thereby enhancing the efficacy of pro-oxidant therapies (PubMed: 10657239). However, the non-specific nature of 'nucleophilic proteins' as a target category reflects the broad reactivity of certain drugs with various cellular thiols and amines. Inhibition of GSR can lead to severe oxidative stress and is a known mechanism for the cytotoxicity of certain chemotherapeutic agents like carmustine (DrugBank DB00499). This enzyme is also crucial in red blood cells, where its deficiency or inhibition can lead to hemolytic anemia due to the inability to neutralize reactive oxygen species. Therapeutic strategies targeting GSR often aim to sensitize tumors to radiation or other chemotherapies that generate oxidative stress.

Other names

GRGlutathione-disulfide reductaseGLURD1Nucleophilic proteins

Inhibition of glutathione reductase prevents the regeneration of reduced glutathione (GSH) from glutathione disulfide (GSSG), leading to an accumulation of reactive oxygen species and subsequent cellular damage or apoptosis (PubMed: 15135301).