Sandbox 181: Difference between revisions

GSH reductase has a central five-stranded parallel beta-sheet (β1, β2, β3, β7 and β8) <ref name="Dym">PMID:11514662</ref>. This central β-sheet is surrounded by α-helices 1 and 2 with a crossover connection of a three-stranded antiparallel β-sheet (β4-6).

The action of glutathione reductase proceeds through a cyclic series of structures in differing redox states . NADPH binds causing a transient reduction of flavin and this reduced flavin consequently reduces Cys58-Cys63 disulfide bond, forming a short lived covalent intermediate with Cys63. Following this, a stable charge-transfer complex between flavin and the Cys63 thiolate forms. After formation the NADP+ dissociates and is replaced by another NADPH. This is the end of the reductive first half of the mechanism and the oxidative half is initiated upon the binding of GSSG. The Cys58 in glutathione reductase attacks CysI of the GSSG to form a mixed disulfide between the first GS and Cys58. The second GSH is the free to leave and the disulfide bond is reformed between Cys58 and Cys63 of glutathione reductase. Finally, the first molecule of GSH is released. The glutathione reductase is then able to be recycled to allow for the binding of NADPH once again<ref name="main"/>.

For proper functioning and prevention of damage to a cell, GSH plays an essential role in preventing oxidative stress in human cells. GSH directly scavenges hydroxyl radicals and singlet oxygens, plays a role as a cofactor in several detoxifying enzymes, participates in amino acid transport through the plasma membrane, and can regenerate important antioxidants such as Vitamins E and C to their reactive forms <ref>PMID:16111877</ref>. The antioxidant capacity of glutathione is linked to the redox state of GSSG/2GSH inside the cell<ref>PMID: 12809732 </ref>. The function of GSH reductase is to maintain this narrow redox state of  high reduced to oxidized ratio of GSH in the cell<ref>PMID: 16111877 </ref>.

Heredity deficiency of GSH reductase is rare<ref name="Kamerbeek">PMID: 17185460 </ref>. A deficiency is most often due a genetic mutation and in two related case studies a deletion of the Asp385-Arg478 segment was found <ref name="Kamerbeek"/>. This shorted the protein to 43.8 kDA and once expressed, was likely degraded due to misfolding, leading to a deficiency of GSH reductase<ref name="Kamerbeek"/>. The symptoms and consequences in these genetically related cases were favism, cataracts, and a reduced lifespan of red blood cells<ref name="Kamerbeek"/>. The formation of cataracts in these patients was likely due to UV-induced oxidative damage to the lens of the eye<ref name="Kamerbeek"/>.

A second mutation in the GSH reductase gene truncated GSH reductase at Trp287 by changing the TGG codon for Trp287 into a premature TGA stop codon <ref name="Kamerbeek"/>. The folding-initiating helix 11 of residues 439 to 454 is then missing causing the improper folding and an inactive enzyme <ref name="Kamerbeek"/>. Additionally, Gly330 is exchanged for a GCG codon for alanine <ref name="Kamerbeek"/>. The exchange of glycine to alanine affects catalysis and stability of GSH reductase by disrupting the proper FAD binding necessitating the presence of higher concentrations of FAD to saturate the apoenzyme <ref name="Kamerbeek"/>.

In addition to mutation, an insufficient intake to riboflavin (Vitamin B12) through the diet results in the GSH reductase remaining as an inactive apoenzyme <ref name="Kamerbeek"/>. A deficiency in FAD is usually only found in malnourished populations and these populations make up the more common occurrence of a GSH reductase deficiency<ref name="Kamerbeek"/>. The clinical symptoms of cataracts, favism and reduced lifespans of red blood cells are also seen in dietary deficiency of RSH reductase.