Glutathione reductase

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Glutathione reductase

PDB rendering based on 1GRE.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsGSR; MGC78522
External IDsOMIM: 138300 MGI: 95804 HomoloGene: 531 ChEMBL: 2755 GeneCards: GSR Gene
EC number1.8.1.7
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez293614782
EnsemblENSG00000104687ENSMUSG00000031584
UniProtP00390P47791
RefSeq (mRNA)NM_000637NM_010344
RefSeq (protein)NP_000628NP_034474
Location (UCSC)Chr 8:
30.54 – 30.59 Mb		Chr 8:
33.65 – 33.7 Mb
PubMed search
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Glutathione reductase, also known as GSR or GR, is an enzyme (EC 1.8.1.7) that reduces glutathione disulfide (GSSG) to the sulfhydryl form GSH, which is an important cellular antioxidant.[1][2]

For every mole of oxidized glutathione (GSSG), one mole of NADPH is required to reduce GSSG to GSH. The enzyme forms a FAD-bound homodimer. The glutathione reductase is conserved between all kingdoms. In bacteria, yeasts, and animals, one glutathione reductase gene is found; however, in plant genomes, two GR genes are encoded. Drosophila and Trypanosomes do not have any GR at all.[3] In these organisms, glutathione reduction is performed by either the thioredoxin or the trypanothione system, respectively.[3][4]

Reaction mechanism of human glutathione reductase

NADPH reduces FAD present in GSR to produce a transient FADH- anion. This anion then quickly breaks a disulfide bond (Cys58 - Cys63) and leads to Cys63's 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, two reduced GSH molecules are gained, which can again act as antioxidants scavenging reactive oxygen species in the cell.

Glutathione reductase in human cells

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.[5]

Monitoring glutathione reductase activity

The activity of glutathione reductase is used as indicator for oxidative stress. The activity can be monitored by the NADPH consumption, with absorbance at 340 nm, or the formed GSH can be visualized by Ellman's reagent.[6] Alternatively the activity can be measured using roGFP (redox-sensitive Green Fluorescent Protein).[7]

References

  1. ↑ Meister A (1988). "Glutathione metabolism and its selective modification". J. Biol. Chem. 263 (33): 17205–8. PMID 3053703. 
  2. ↑ Mannervik B (1987). "The enzymes of glutathione metabolism: an overview". Biochem. Soc. Trans. 15 (4): 717–8. PMID 3315772. 
  3. ↑ 3.0 3.1 Kanzok SM, Fechner A, Bauer H, Ulschmid JK, Müller HM, Botella-Munoz J, Schneuwly S, Schirmer R, Becker K (2001). "Substitution of the thioredoxin system for glutathione reductase in Drosophila melanogaster". Science 291 (5504): 643–6. doi:10.1126/science.291.5504.643. PMID 11158675. 
  4. ↑ Krauth-Siegel RL, Comini MA (2008). "Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism". Biochim Biophys Acta 1780 (11): 1236–48. doi:10.1016/j.bbagen.2008.03.006. PMID 18395526. 
  5. ↑ Champe, et al. Biochemistry, Fourth Edition. Lippincott Williams and Wilkins. 2008
  6. ↑ Smith IK, Vierheller TL, Thorne CA (1988). "RAssay of glutathione reductase in crude tissue homogenates using 5,5'-dithiobis(2-nitrobenzoic acid)". Anal Biochem 175 (2): 408–13. doi:10.1016/0003-2697(88)90564-7. PMID 3239770. 
  7. ↑ Marty L, Siala W, Schwarzländer M, Fricker MD, Wirtz M, Sweetlove LJ, Meyer Y, Meyer AJ, Reichheld JP, Hell R. (2009). "The NADPH-dependent thioredoxin system constitutes a functional backup for cytosolic glutathione reductase in Arabidopsis". Proc Natl Acad Sci U S A 106 (22): 9109–14. doi:10.1073/pnas.0900206106. PMC 2690020. PMID 19451637. 

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. doi:10.1111/j.1432-1033.1977.tb11856.x. 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. doi:10.1111/j.1432-1033.1990.tb15431.x. PMID 2185014. 
  • Palmer EJ, MacManus JP, Mutus B (1990). "Inhibition of glutathione reductase by oncomodulin". Arch. Biochem. Biophys. 277 (1): 149–54. doi:10.1016/0003-9861(90)90563-E. 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. doi:10.1016/0014-5793(90)80922-6. PMID 2379581. 
  • Karplus PA, Schulz GE (1987). "Refined structure of glutathione reductase at 1.54 A resolution". J. Mol. Biol. 195 (3): 701–29. doi:10.1016/0022-2836(87)90191-4. 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. doi:10.1111/j.1432-1033.1982.tb05780.x. 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. doi:10.1016/0022-2836(81)90126-1. 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. doi:10.1016/0006-8993(95)00209-9. 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. doi:10.1074/jbc.271.14.8101. 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. doi:10.1111/j.1432-1033.1997.00273.x. 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. doi:10.1038/nsb0498-267. 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. doi:10.1023/A:1026511420505. 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. doi:10.1006/cbir.2002.0861. PMID 12095224. 
Oxidoreductases: sulfur oxidoreductases (EC 1.8)
1.8.1: NAD or NADP
1.8.2: cytochrome
1.8.3: oxygen
1.8.4: disulfide
  • Glutathione-homocystine transhydrogenase
1.8.5: quinone
1.8.98: Other, known
  • CoB-CoM heterodisulfide reductase
1.8.99: Other
  • B
  • enzm
  • 1.1
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      • 2.7.10
      • 11-12
    • 8
  • 3.1
      • 3.1.3.48
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      • 3.4.21
      • 22
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  • 4.1
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    • 99
  • 6.1-3
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    • 5-6
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