Glutathione reductase

Glutathione reductase, also known as GSR, is a human gene.cite web | title = Entrez Gene: GSR glutathione reductase| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2936| accessdate = ]

The protein encoded by this gene is an enzyme (EC number|1.8.1.7) which reduces glutathione disulfide (GSSG) to the sulfhydryl form GSH, which is an important cellular antioxidant.cite journal | author = Meister A | title = Glutathione metabolism and its selective modification | journal = J. Biol. Chem. | volume = 263 | issue = 33 | pages = 17205–8 | year = 1988 | pmid = 3053703 | doi = | issn = | url = http://www.jbc.org/cgi/reprint/263/33/17205 ] cite journal | author = Mannervik B | title = The enzymes of glutathione metabolism: an overview | journal = Biochem. Soc. Trans. | volume = 15 | issue = 4 | pages = 717–8 | year = 1987 | pmid = 3315772 | doi = | issn = ]

For every mole of oxidized glutathione (GSSG) one mole of NADPH is required to reduce GSSG to GSH. NADPH reduces FAD present in GSR to produces a transient FADH^- anion. This anion then quickly breaks a disulfide bond (Cys₅₈ - Cys₆₃) and leads to Cys₆₃ nucleophilically attacking the nearest sulfide unit in the GSSG molecule (promoted by His₄₆₇) which creates a mixed disulfide bond (GS-Cys₅₈) and a GS^- anion. His₄₆₇ of GSR then protonates the GS^- anion to form the first GSH. Next, Cys₆₃ nucleophilically attacks the sulfide of Cys₅₈ releasing a GS^- anion which in turn picks up a solvent proton and is released from the enzyme, thereby creating the second GSH. So, for every GSSG and NADPH you gain two reduced GSH molecules that can again act as antioxidants scavanging reactive oxygen species in the cell.

In cells exposed to high levels of oxidative stress, like red blood cells, up to 10% of the glucose consumption may be directed to the pentose phosphate pathway (PPP) for production of the NADPH needed for this reaction. In the case of erythrocytes, if the PPP is non-functional then the oxidative stress in the cell will lead to cell lysis and anemia. [Champe, et al. Biochemistry, Fourth Edition. Lippincott Williams and Wilkins. 2008]

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Sinet PM, Bresson JL, Couturier J, "et al." |title= [Possible localization of the glutathione reductase (EC 1.6.4.2) on the 8p21 band] |journal=Ann. Genet. |volume=20 |issue= 1 |pages= 13–7 |year= 1977 |pmid= 302667 |doi=
*cite journal | author=Krohne-Ehrich G, Schirmer RH, Untucht-Grau R |title=Glutathione reductase from human erythrocytes. Isolation of the enzyme and sequence analysis of the redox-active peptide. |journal=Eur. J. Biochem. |volume=80 |issue= 1 |pages= 65–71 |year= 1978 |pmid= 923580 |doi=
*cite journal | author=Loos H, Roos D, Weening R, Houwerzijl J |title=Familial deficiency of glutathione reductase in human blood cells. |journal=Blood |volume=48 |issue= 1 |pages= 53–62 |year= 1976 |pmid= 947404 |doi=
*cite journal | author=Tutic M, Lu XA, Schirmer RH, Werner D |title=Cloning and sequencing of mammalian glutathione reductase cDNA. |journal=Eur. J. Biochem. |volume=188 |issue= 3 |pages= 523–8 |year= 1990 |pmid= 2185014 |doi=
*cite journal | author=Palmer EJ, MacManus JP, Mutus B |title=Inhibition of glutathione reductase by oncomodulin. |journal=Arch. Biochem. Biophys. |volume=277 |issue= 1 |pages= 149–54 |year= 1990 |pmid= 2306116 |doi=
*cite journal | author=Arnold HH, Heinze H |title=Treatment of human peripheral lymphocytes with concanavalin A activates expression of glutathione reductase. |journal=FEBS Lett. |volume=267 |issue= 2 |pages= 189–92 |year= 1990 |pmid= 2379581 |doi=
*cite journal | author=Karplus PA, Schulz GE |title=Refined structure of glutathione reductase at 1.54 A resolution. |journal=J. Mol. Biol. |volume=195 |issue= 3 |pages= 701–29 |year= 1987 |pmid= 3656429 |doi=
*cite journal | author=Pai EF, Schulz GE |title=The catalytic mechanism of glutathione reductase as derived from x-ray diffraction analyses of reaction intermediates. |journal=J. Biol. Chem. |volume=258 |issue= 3 |pages= 1752–7 |year= 1983 |pmid= 6822532 |doi=
*cite journal | author=Krauth-Siegel RL, Blatterspiel R, Saleh M, "et al." |title=Glutathione reductase from human erythrocytes. The sequences of the NADPH domain and of the interface domain. |journal=Eur. J. Biochem. |volume=121 |issue= 2 |pages= 259–67 |year= 1982 |pmid= 7060551 |doi=
*cite journal | author=Thieme R, Pai EF, Schirmer RH, Schulz GE |title=Three-dimensional structure of glutathione reductase at 2 A resolution. |journal=J. Mol. Biol. |volume=152 |issue= 4 |pages= 763–82 |year= 1982 |pmid= 7334521 |doi=
*cite journal | author=Huang J, Philbert MA |title=Distribution of glutathione and glutathione-related enzyme systems in mitochondria and cytosol of cultured cerebellar astrocytes and granule cells. |journal=Brain Res. |volume=680 |issue= 1-2 |pages= 16–22 |year= 1995 |pmid= 7663973 |doi=
*cite journal | author=Savvides SN, Karplus PA |title=Kinetics and crystallographic analysis of human glutathione reductase in complex with a xanthene inhibitor. |journal=J. Biol. Chem. |volume=271 |issue= 14 |pages= 8101–7 |year= 1996 |pmid= 8626496 |doi=
*cite journal | author=Nordhoff A, Tziatzios C, van den Broek JA, "et al." |title=Denaturation and reactivation of dimeric human glutathione reductase--an assay for folding inhibitors. |journal=Eur. J. Biochem. |volume=245 |issue= 2 |pages= 273–82 |year= 1997 |pmid= 9151953 |doi=
*cite journal | author=Stoll VS, Simpson SJ, Krauth-Siegel RL, "et al." |title=Glutathione reductase turned into trypanothione reductase: structural analysis of an engineered change in substrate specificity. |journal=Biochemistry |volume=36 |issue= 21 |pages= 6437–47 |year= 1997 |pmid= 9174360 |doi= 10.1021/bi963074p
*cite journal | author=Becker K, Savvides SN, Keese M, "et al." |title=Enzyme inactivation through sulfhydryl oxidation by physiologic NO-carriers. |journal=Nat. Struct. Biol. |volume=5 |issue= 4 |pages= 267–71 |year= 1998 |pmid= 9546215 |doi=
*cite journal | author=Kelner MJ, Montoya MA |title=Structural organization of the human glutathione reductase gene: determination of correct cDNA sequence and identification of a mitochondrial leader sequence. |journal=Biochem. Biophys. Res. Commun. |volume=269 |issue= 2 |pages= 366–8 |year= 2000 |pmid= 10708558 |doi= 10.1006/bbrc.2000.2267
*cite journal | author=Qanungo S, Mukherjea M |title=Ontogenic profile of some antioxidants and lipid peroxidation in human placental and fetal tissues. |journal=Mol. Cell. Biochem. |volume=215 |issue= 1-2 |pages= 11–9 |year= 2001 |pmid= 11204445 |doi=
*cite journal | author=Berry Y, Truscott RJ |title=The presence of a human UV filter within the lens represents an oxidative stress. |journal=Exp. Eye Res. |volume=72 |issue= 4 |pages= 411–21 |year= 2001 |pmid= 11273669 |doi= 10.1006/exer.2000.0970
*cite journal | author=Rhie G, Shin MH, Seo JY, "et al." |title=Aging- and photoaging-dependent changes of enzymic and nonenzymic antioxidants in the epidermis and dermis of human skin in vivo. |journal=J. Invest. Dermatol. |volume=117 |issue= 5 |pages= 1212–7 |year= 2001 |pmid= 11710935 |doi= 10.1046/j.0022-202x.2001.01469.x
*cite journal | author=Zatorska A, Józwiak Z |title=Involvement of glutathione and glutathione-related enzymes in the protection of normal and trisomic human fibroblasts against daunorubicin. |journal=Cell Biol. Int. |volume=26 |issue= 5 |pages= 383–91 |year= 2003 |pmid= 12095224 |doi=

1.8-enzyme-stub

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