GSR encodes glutathione reductase, an enzyme involved in maintaining the redox balance in the cell by catalyzing the reduction of glutathione disulphide (GSSG) to glutathione (GSH). Expression of GSR is regulated in part by the KEAP1-NFE2L2 pathway, and NFE2L2 binds to the anti-oxidant response (ARE) elements in the GSR promoter as demonstrated by chromatin immunoprecipitation (ChIP) studies in mouse (Harvey et al, 2009; Thimmulappa et al, 2002; reviewed in Baird and Yamamoto, 2020).

Glutathione reductase (GSR) contributes to the redox balance in a cell by catalyzing the reduction of glutathione disulphide (GSSG) to glutathione (GSH). Expression of GSR is regulated in part by the KEAP1:NFE2L2 pathway through anti-oxidant response elements (AREs) in the promoter (Harvey et al, 2009; Thimmulappa et al, 2002; reviewed in Baird and Yamamoto, 2020).

Glutathione reductase (GSR) homodimer is involved in the reduction of selenodiglutathione (GSSeSG) into gluthathioselenol (GSSeH) and reduced glutathione (GSH). This reaction is inferred from the event in rat (Bjornstedt et al. 1992).

Glutathione reductase (GSR) in the mitochondrial matrix regenerates reduced glutathione from oxidized glutathione and NADPH (Berkholz et al. 2008).

Glutathione S-Transferases (GSTs; EC 2.5.1.18) are another major set of phase II conjugation enzymes. They can be found in the cytosol as well as being microsomal membrane-bound. Cytosolic GSTs are encoded by at least 5 gene families (alpha, mu, pi, theta and zeta GST) whereas membrane-bound enzymes are encoded by single genes. Soluble GSTs are homo- or hetero-dimeric enzymes (approximately 25KDa subunits) which can act on a wide range of endogenous and exogenous electrophiles. GSTs mediate conjugation using glutathione (GSH), a tripeptide synthesized from its precursor amino acids gamma-glutamate, cysteine and glycine. A generalized reaction is

RX + GSH -> HX + GSR

Glutathione conjugates are excreted in bile and converted to cysteine and mercapturic acid conjugates in the intestine and kidneys. GSH is the major, low molecular weight, non-protein thiol synthesized de novo in mammalian cells. As well as taking part in conjugation reactions, GSH also has antioxidant ability and can metabolize endogenous and exogenous compounds. The nucleophilic GSH attacks the electrophilic substrate forming a thioether bond between the cysteine residue of GSH and the electrophile. The result is generally a less reactive and more water-soluble conjugate that can be easily excreted. In some cases, GSTs can activate compounds to reactive species such as certain haloalkanes and haloalkenes. Substrates for GSTs include epoxides, alkenes and compounds with electrophilic carbon, sulfur or nitrogen centres. There are two types of conjugation reaction with glutathione: displacement reactions where glutathione displaces an electron-withdrawing group and addition reactions where glutathione is added to activated double bond structures or strained ring systems.