| Glutathione reductase (GR, EC 1.6.4.2) is an ubiquitous enzyme which catalyzes the reduction of oxidized glutathione (GSSG) to glutathione (GSH). Glutathione reductase is essential for the glutathione redox cycle that maintains adequate levels of reduced cellular GSH. GSH serves as an antioxidant, reacting with free radicals and organic peroxides, in amino acid transport, and as a substrate for the glutathione peroxidases and glutathione S-transferases in the detoxification of organic peroxides and metabolism of xenobiotics, respectively (Dolphin, 1989).
This homodimeric enzyme is a member of the family of flavoprotein disulfide oxidoreductases. Each subunit has four domains; beginning at the N-terminus: an FAD-binding domain, an NADPH-binding domain, a central domain and an interface domain. The active sites of GR are at the dimeric interface. Since the GSSG binding site is composed of residues from both subunits, only the dimeric form is active (Bashir, 1995).
Oxidized glutathione is reduced by a multi-step reaction in which GR is initially reduced by NADPH forming a semiquinone of FAD, a sulfur radical and a thiol. The reduced GR (GRred) reacts with a molecule of GSSG resulting in a disulfide interchange which produces a molecule of GSH and the GRred-SG complex. An electron rearrangement in GRred-SG results in a second disulfide interchange, splitting off the second molecule of GSH and restoring the GR to the oxidized form (Massey, 1965).
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