GST_N family, Class Mu subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. The class Mu subfamily is composed of eukaryotic GSTs. In rats, at least six distinct class Mu subunits have been identified, with homologous genes in humans for five of these subunits. Class Mu GSTs can form homodimers and heterodimers, giving a large number of possible isoenzymes that can be formed, all with overlapping activities but different substrate specificities. They are the most abundant GSTs in human liver, skeletal muscle and brain, and are believed to provide protection against diseases including cancer and neurodegenerative disorders. Some isoenzymes have additional specific functions. Human GST M1-1 acts as an endogenous inhibitor of ASK1 (apoptosis signal-regulating kinase 1), thereby suppressing ASK1-mediated cell death. Human GSTM2-2 and 3-3 have been identified as prostaglandin E2 synthases in the brain and may play crucial roles in temperature and sleep-wake regulation.
Feature 1:GSH binding site (G-site) [chemical binding site]
Evidence:
Structure:1XW5; Human GST M2-2 with bound GSH; contacts at 3.5A
Structure:1FHE; Fasciola hepatica GST with bound GSH; contacts at 3.5A
Structure:1UA5; Schistosoma japonicum GST with bound GSH; contacts at 3.5A
Comment:The GST active site is composed of a GSH binding site (G-site), common to all GSTs, and a xenobiotic binding site (H-site), which varies between different classes and isotypes. Residues from the N-terminal TRX-fold domain form the G-site while the H-site is comprised mainly of residues from the C-terminal alpha helical domain.
Comment:The N-terminal tyrosine is essential for activating the thiol group of GSH by stabilizing the thiolate anion form.
Jiyao W et al.(2023). "The conserved domain database in 2023.",