Glutathione reductase

From Wikipedia, the free encyclopedia

PDB rendering based on 1GRE.

Available structures: 1bwc, 1dnc, 1gra, 1grb, 1gre, 1grf, 1grg, 1grt, 1gsn, 1k4q, 1xan, 2aaq, 2gh5, 2grt, 3grs, 3grt, 4gr1, 4grt, 5grt

Identifiers

Symbol(s)

GSR; MGC78522

External IDs

OMIM: 138300 MGI: 95804 HomoloGene: 531

EC number

1.8.1.7

Gene ontology
Molecular Function:	• glutathione-disulfide reductase activity • disulfide oxidoreductase activity • FAD binding • NADP binding
Cellular Component:	• cytoplasm • mitochondrion
Biological Process:	• electron transport • glutathione metabolic process • cell redox homeostasis

RNA expression pattern

More reference expression data

Orthologs

Human

Mouse

n/a

n/a

Refseq

NM_000637 (mRNA)
NP_000628 (protein)

NM_010344 (mRNA)
NP_034474 (protein)

Location

Chr 8: 30.66 - 30.7 Mb

n/a

Pubmed search

[1]

[2]

Glutathione reductase, also known as GSR, is a human gene.^[1]

The protein encoded by this gene is an enzyme (EC 1.8.1.7) which reduces glutathione disulfide (GSSG) to the sulfhydryl form GSH, which is an important cellular antioxidant.^[2]^[3]

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 in non-functional then the oxidative stress in the cell will lead to cell lysis and anemia. ^[4]

[edit] References

^ Entrez Gene: GSR glutathione reductase.
^ Meister A (1988). "Glutathione metabolism and its selective modification". J. Biol. Chem. 263 (33): 17205–8. PMID 3053703.
^ Mannervik B (1987). "The enzymes of glutathione metabolism: an overview". Biochem. Soc. Trans. 15 (4): 717–8. PMID 3315772.
^ Champe, et al. Biochemistry, Fourth Edition. Lippincott Williams and Wilkins. 2008

[edit] Further reading

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