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Glutathione reductase

February 04, 2023

Glutathione reductase (GR) also known as glutathione-disulfide reductase (GSR) is an enzyme that in humans is encoded by the GSR gene. Glutathione reductase (EC 1.8.1.7) catalyzes the reduction of glutathione disulfide (GSSG) to the sulfhydryl form glutathione (GSH), which is a critical molecule in resisting oxidative stress and maintaining the reducing environment of the cell.[5][6][7] Glutathione reductase functions as dimeric disulfide oxidoreductase and utilizes an FAD prosthetic group and NADPH to reduce one molar equivalent of GSSG to two molar equivalents of GSH:

GSR
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGSR, HEL-75, HEL-S-122m, glutathione reductase, glutathione-disulfide reductase, GR, GSRD
External IDsOMIM: 138300 MGI: 95804 HomoloGene: 531 GeneCards: GSR
Orthologs
SpeciesHumanMouse
Entrez

2936

14782

Ensembl

ENSG00000104687

ENSMUSG00000031584

UniProt

P00390

P47791

RefSeq (mRNA)

NM_001195104
NM_000637
NM_001195102
NM_001195103

NM_010344

RefSeq (protein)

NP_000628
NP_001182031
NP_001182032
NP_001182033

NP_034474

Location (UCSC)Chr 8: 30.68 – 30.73 MbChr 8: 34.14 – 34.19 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
General reaction catalyzed by glutathione reductase

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.[8] In these organisms, glutathione reduction is performed by either the thioredoxin or the trypanothione system, respectively.[8][9]

Function

glutathione-disulfide reductase
 
Human GSR with bound glutathione and FADH
Identifiers
EC no.1.8.1.7
CAS no.9001-48-3
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

Glutathione plays a key role in maintaining proper function and preventing oxidative stress in human cells. It can act as a scavenger for hydroxyl radicals, singlet oxygen, and various electrophiles. Reduced glutathione reduces the oxidized form of the enzyme glutathione peroxidase, which in turn reduces hydrogen peroxide (H2O2), a dangerously reactive species within the cell. [In the following illustration of redox reeactions, the rightmost arrow is reversed; it should be pointing up not down.] In addition, it plays a key role in the metabolism and clearance of xenobiotics, acts as a cofactor in certain detoxifying enzymes, participates in transport, and regenerates antioxidants such and Vitamins E and C to their reactive forms. The ratio of GSSG/GSH present in the cell is a key factor in properly maintaining the oxidative balance of the cell, that is, it is critical that the cell maintains high levels of the reduced glutathione and a low level of the oxidized glutathione disulfide. This narrow balance is maintained by glutathione reductase, which catalyzes the reduction of GSSG to GSH.[5]

 
Reduced glutathione reductase, glutathione peroxidase and glutathione interact to reduce hydrogen peroxide to water, in order to protect the cell from oxidative damage.

Structure

Glutathione reductase from human erythrocytes is a homodimer consisting of 52Kd monomers, each containing 3 domains. GR exhibits single sheet, double layered topology where an anti-parallel beta-sheet is largely exposed to the solvent on one face while being covered by random coils on the other face.[10] This includes and NADPH-binding Domain, FAD-binding domain(s) and a dimerization domain. Each monomer contains 478 residues and one FAD molecule. GR is a thermostable protein, retaining function up to 65 °C.[11][12]

Reaction mechanism

 
Graphical representation of overall reaction catalyzed by GR
 
GR catalytic cycle

Steps:

1 NADPH binding to the oxidized enzyme
2 Reduction of FAD to FADH− anion by NADPH
3 Reduced FADH− anion collapses into a charge relay complex and reduces Cys58-Cys63 disulfide
4 Oxidized Glutathione disulfide binds to the reduced enzyme and forms a mixed disulfide with Cys58 and releases one reduced glutathione
5 Cys63 attacks the mixed disulfide on Cys58 to release a reduced glutathione and reform the redox active disulfide

Reductive half

The action of GR proceeds through two distinct half reactions, a reductive half mechanism followed by an oxidative half. In the first half, NADPH reduces FAD present in GSR to produce a transient FADH− anion. This anion then quickly breaks a disulfide bond of Cys58 - Cys63, forming a short lived covalent bond a stable charge-transfer complex between the flavin and Cys63. The now oxidized NADP+ is released and is subsequently replaced by a new molecule of NADPH. This is the end of the so-called reductive half of the mechanism.

Oxidative half

In the oxidative half of the mechanism, Cys63 nucleophilically attacks 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 release the first molecule of 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.[13]

Inhibition

In vitro, glutathione reductase is inhibited by low concentrations of sodium arsenite and methylated arsenate metabolites, but in vivo, significant Glutathione Reductase inhibition by sodium arsenate has only been at 10 mg/kg/day.[14] Glutathione reductase is also inhibited by some flavanoids, a class of pigments produced by plants.[15]

Clinical significance

GSH is a key cellular antioxidant and plays a major role in the phase 2 metabolic clearance of electrophilic xenobiotics. The importance of the GSH pathway and enzymes that affect this delicate balance is gaining an increased level of attention in recent years. Although glutathione reductase has been an attractive target for many pharmaceuticals, there have been no successful glutathione reductase related therapeutic compounds created to date. In particular, glutathione reductase appears to be a good target for anti-malarials, as the glutathione reductase of the malaria parasite Plasmodium falciparum has a significantly different protein fold than that of mammalian glutathione reductase.[16] By designing drugs specific to p. falciparum it may be possible to selectively induce oxidative stress in the parasite, while not affecting the host.

There are two main classes of GR targeting compounds:[17][18][19][20]

  1. Inhibitors of GSSG binding, or dimerization: Reactive electrophiles such as gold compounds, and fluoronaphthoquinones.
  2. Drugs which use glutathione reductase to regenerate, such as redox cyclers. Two examples of these types of compounds are Methylene blue and Naphthoquinone.

Clinical trials performed in Burkina Faso have revealed mixed results when treating malaria with Naphthoquinones

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.[21]

Lupus is an autoimmune disorder in which patients produce an elevated quantity of antibodies that attack DNA and other cell components. In a recent study, a single nucleotide polymorphism (SNP) in the Glutathione Reductase gene was found to be highly associated with lupus in African Americans in the study.[22] African Americans with lupus have also been shown to express less reduced glutathione in their T cells.[23] The study's authors believe that reduced glutathione reductase activity may contribute to the increased production of reactive oxygen in African Americans with lupus.[22]

In mice, glutathione reductase has been implicated in the oxidative burst, a component of the immune response.[24] The oxidative burst is a defense mechanism in which neutrophils produce and release reactive oxidative species in the vicinity of bacteria or fungi to destroy the foreign cells. Glutathione Reductase deficient neutrophils were shown to produce a more transient oxidative burst in response to bacteria than neutrophils that express GR at ordinary levels.[24] The mechanism of Glutathione Reductase in sustaining the oxidative burst is still unknown.[24]

Deficiency

Glutathione reductase deficiency is a rare disorder in which the glutathione reductase activity is absent from erythrocytes, leukocytes or both. In one study this disorder was observed in only two cases in 15,000 tests for glutathione reductase deficiency performed over the course of 30 years.[25] In the same study, glutathione reductase deficiency was associated with cataracts and favism in one patient and their family, and with severe unconjugated hyperbilirubinemia in another patient.[25] It has been proposed that the glutathione redox system (of which glutathione reductase is a part) is almost exclusively responsible for the protecting of eye lens cells from hydrogen peroxide because these cells are deficient in catalase, an enzyme which catalyzes the breakdown of hydrogen peroxide, and the high rate of cataract incidence in glutathione reductase deficient individuals.[26]

Some patients exhibit deficient levels of glutathione activity as a result of not consuming enough riboflavin in their diets. Riboflavin is a precursor for FAD, whose reduced form donates two electron to the disulfide bond which is present in the oxidized form of glutathione reductase in order to begin the enzyme's catalytic cycle. In 1999, a study found that 17.8% of males and 22.4% of females examined in Saudi Arabia suffered from low glutathione reductase activity due to riboflavin deficiency.[27]

Connection to favism

In favism, patients lack glucose-6-phosphate dehydrogenase, an enzyme in their pentose phosphate pathway that reduces NADP+ to NADPH while catalyzing the conversion of glucose-6-phosphate to 6-phosphoglucono-δ-lactone. Glucose-6-phosphate dehydrogenase deficient individuals have less NADPH available for the reduction of oxidized glutathione via glutathione reductase. Thus their basal ratio of oxidized to reduced glutathione is significantly higher than that of patients who express glucose-6-phosphate dehydrogenase, normally, making them unable to effectively respond to high levels of reactive oxygen species, which causes cell lysis.[28]

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.[29] Alternatively the activity can be measured using roGFP (redox-sensitive Green Fluorescent Protein).[30]

In plants

As it does in human cells, glutathione reductase helps to protect plant cells from reactive oxygen species. In plants, reduced glutathione participates in the glutathione-ascorbate cycle in which reduced glutathione reduces dehydroascorbate, a reactive byproduct of the reduction of hydrogen peroxide. In particular, glutathione reductase contributes to plants' response to abiotic stress.[31] The enzyme's activity has been shown to be modulated in response to metals, metalloids, salinity, drought, UV radiation and heat induced stress.[31]

History

Glutathione reductase was first purified in 1955 at Yale University by P. Janmeda.[32] Janmeda also identified NADPH as the primary electron donor for the enzyme. Later groups confirmed the presence of FAD and the thiol group, and an initial mechanism was suggested for the mechanism in 1965.[33][34] The initial (low resolution) structure of glutathione reductase was solved in 1977. This was quickly followed by a 3Å structure by Shulze et al. in 1978.[35] Glutathione reductase has been studied exhaustively since these early experiments, and is subsequently one of the most well characterized enzymes to date.

Interactive pathway map

Interactive pathway can be found here: pathway map

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000104687 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031584 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b Deponte M (May 2013). "Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes". Biochim. Biophys. Acta. 1830 (5): 3217–66. doi:10.1016/j.bbagen.2012.09.018. PMID 23036594.
  6. ^ Meister A (November 1988). "Glutathione metabolism and its selective modification". J. Biol. Chem. 263 (33): 17205–8. doi:10.1016/S0021-9258(19)77815-6. PMID 3053703.
  7. ^ Mannervik B (August 1987). "The enzymes of glutathione metabolism: an overview". Biochem. Soc. Trans. 15 (4): 717–8. doi:10.1042/bst0150717. PMID 3315772.
  8. ^ a b 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. Bibcode:2001Sci...291..643K. doi:10.1126/science.291.5504.643. PMID 11158675.
  9. ^ 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.
  10. ^ Grisham, Reginald H. Garrett,... Charles M. (2005). Biochemistry (3rd ed.). Belmont, CA: Thomson Brooks/Cole. ISBN 0534490336.
  11. ^ Masella R, Di Benedetto R, Varì R, Filesi C, Giovannini C (October 2005). "Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes". J. Nutr. Biochem. 16 (10): 577–86. doi:10.1016/j.jnutbio.2005.05.013. PMID 16111877.
  12. ^ Dym O, Eisenberg D (September 2001). "Sequence-structure analysis of FAD-containing proteins". Protein Sci. 10 (9): 1712–28. doi:10.1110/ps.12801. PMC 2253189. PMID 11514662.
  13. ^ Berkholz DS, Faber HR, Savvides SN, Karplus PA (October 2008). "Catalytic cycle of human glutathione reductase near 1 A resolution". J. Mol. Biol. 382 (2): 371–84. doi:10.1016/j.jmb.2008.06.083. PMC 2593804. PMID 18638483.
  14. ^ Rodríguez VM, Del Razo LM, Limón-Pacheco JH, Giordano M, Sánchez-Peña LC, Uribe-Querol E, Gutiérrez-Ospina G, Gonsebatt ME (March 2005). "Glutathione reductase inhibition and methylated arsenic distribution in Cd1 mice brain and liver". Toxicol. Sci. 84 (1): 157–66. doi:10.1093/toxsci/kfi057. PMID 15601678.
  15. ^ Elliott AJ, Scheiber SA, Thomas C, Pardini RS (October 1992). "Inhibition of glutathione reductase by flavonoids. A structure-activity study". Biochem. Pharmacol. 44 (8): 1603–8. doi:10.1016/0006-2952(92)90478-2. PMID 1329770.
  16. ^ Sarma GN, Savvides SN, Becker K, Schirmer M, Schirmer RH, Karplus PA (May 2003). "Glutathione reductase of the malarial parasite Plasmodium falciparum: crystal structure and inhibitor development". J. Mol. Biol. 328 (4): 893–907. doi:10.1016/s0022-2836(03)00347-4. PMID 12729762.
  17. ^ Buchholz K, Schirmer RH, Eubel JK, Akoachere MB, Dandekar T, Becker K, Gromer S (January 2008). "Interactions of methylene blue with human disulfide reductases and their orthologues from Plasmodium falciparum". Antimicrob. Agents Chemother. 52 (1): 183–91. doi:10.1128/AAC.00773-07. PMC 2223905. PMID 17967916.
  18. ^ Müller T, Johann L, Jannack B, Brückner M, Lanfranchi DA, Bauer H, Sanchez C, Yardley V, Deregnaucourt C, Schrével J, Lanzer M, Schirmer RH, Davioud-Charvet E (August 2011). "Glutathione reductase-catalyzed cascade of redox reactions to bioactivate potent antimalarial 1,4-naphthoquinones--a new strategy to combat malarial parasites" (PDF). J. Am. Chem. Soc. 133 (30): 11557–71. doi:10.1021/ja201729z. PMID 21682307.
  19. ^ Deponte M, Urig S, Arscott LD, Fritz-Wolf K, Réau R, Herold-Mende C, Koncarevic S, Meyer M, Davioud-Charvet E, Ballou DP, Williams CH, Becker K (May 2005). "Mechanistic studies on a novel, highly potent gold-phosphole inhibitor of human glutathione reductase". J. Biol. Chem. 280 (21): 20628–37. doi:10.1074/jbc.M412519200. PMID 15792952.
  20. ^ Deponte M (May 2013). "Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes". Biochim. Biophys. Acta. 1830 (5): 3217–66. doi:10.1016/j.bbagen.2012.09.018. PMID 23036594.
  21. ^ Champe PC, Harvey RA, Ferrier DR (2008). Biochemistry (fourth ed.). Lippincott Williams and Wilkins. ISBN 978-0-7817-6960-0.
  22. ^ a b Ramos PS, Oates JC, Kamen DL, Williams AH, Gaffney PM, Kelly JA, Kaufman KM, Kimberly RP, Niewold TB, Jacob CO, Tsao BP, Alarcón GS, Brown EE, Edberg JC, Petri MA, Ramsey-Goldman R, Reveille JD, Vilá LM, James JA, Guthridge JM, Merrill JT, Boackle SA, Freedman BI, Scofield RH, Stevens AM, Vyse TJ, Criswell LA, Moser KL, Alarcón-Riquelme ME, Langefeld CD, Harley JB, Gilkeson GS (June 2013). "Variable association of reactive intermediate genes with systemic lupus erythematosus in populations with different African ancestry". J. Rheumatol. 40 (6): 842–9. doi:10.3899/jrheum.120989. PMC 3735344. PMID 23637325.
  23. ^ Gergely P, Grossman C, Niland B, Puskas F, Neupane H, Allam F, Banki K, Phillips PE, Perl A (January 2002). "Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus". Arthritis Rheum. 46 (1): 175–90. doi:10.1002/1529-0131(200201)46:1<175::AID-ART10015>3.0.CO;2-H. PMC 4020417. PMID 11817589.
  24. ^ a b c Yan J, Meng X, Wancket LM, Lintner K, Nelin LD, Chen B, Francis KP, Smith CV, Rogers LK, Liu Y (March 2012). "Glutathione reductase facilitates host defense by sustaining phagocytic oxidative burst and promoting the development of neutrophil extracellular traps". J. Immunol. 188 (5): 2316–27. doi:10.4049/jimmunol.1102683. PMC 3480216. PMID 22279102.
  25. ^ a b Kamerbeek NM, Zwieten R, Boer M, Morren G, Vuil H, Bannink N, Lincke C, Dolman KM, Becker K, Schirmer RH, Gromer S, Roos D (2007). "Molecular basis of glutathione reductase deficiency in human blood cells". Blood. 109 (8): 3560–3566. doi:10.1182/blood-2006-08-042531. PMID 17185460.
  26. ^ Roos D, Weening RS, Voetman AA, van Schaik ML, Bot AA, Meerhof LJ, Loos JA (May 1979). "Protection of phagocytic leukocytes by endogenous glutathione: studies in a family with glutathione reductase deficiency". Blood. 53 (5): 851–66. doi:10.1182/blood.V53.5.851.851. PMID 435643.
  27. ^ Warsy AS, el-Hazmi MA (November 1999). "Glutathione reductase deficiency in Saudi Arabia". East. Mediterr. Health J. 5 (6): 1208–12. doi:10.26719/1999.5.6.1208. PMID 11924113.
  28. ^ Cappellini MD, Fiorelli G (January 2008). "Glucose-6-phosphate dehydrogenase deficiency". Lancet. 371 (9606): 64–74. doi:10.1016/S0140-6736(08)60073-2. PMID 18177777. S2CID 29165746.
  29. ^ 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.
  30. ^ 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. Bibcode:2009PNAS..106.9109M. doi:10.1073/pnas.0900206106. PMC 2690020. PMID 19451637.
  31. ^ a b Gill SS, Anjum NA, Hasanuzzaman M, Gill R, Trivedi DK, Ahmad I, Pereira E, Tuteja N (September 2013). "Glutathione and glutathione reductase: a boon in disguise for plant abiotic stress defense operations". Plant Physiol. Biochem. 70: 204–12. doi:10.1016/j.plaphy.2013.05.032. PMID 23792825.
  32. ^ Racker E (December 1955). "Glutathione reductase from bakers' yeast and beef liver". J. Biol. Chem. 217 (2): 855–65. doi:10.1016/S0021-9258(18)65950-2. PMID 13271446.
  33. ^ Massey V, Williams CH (November 1965). "On the reaction mechanism of yeast glutathione reductase". J. Biol. Chem. 240 (11): 4470–80. doi:10.1016/S0021-9258(18)97085-7. PMID 4378936.
  34. ^ Mapson LW, Isherwood FA (January 1963). "Glutathione reductase from germinated peas". Biochem. J. 86: 173–91. doi:10.1042/bj0860173. PMC 1201730. PMID 13932735.
  35. ^ Schulz GE, Schirmer RH, Sachsenheimer W, Pai EF (May 1978). "The structure of the flavoenzyme glutathione reductase". Nature. 273 (5658): 120–4. Bibcode:1978Natur.273..120S. doi:10.1038/273120a0. PMID 25387. S2CID 4153363.

Further reading

  • Sinet PM, Bresson JL, Couturier J, Laurent C, Prieur M, Rethoré MO, Taillemite JL, Toudic D, Jérome H, Lejeune J (1977). "[Possible localization of the glutathione reductase (EC 1.6.4.2) on the 8p21 band]". Ann. Genet. (in French). 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. doi:10.1182/blood.V48.1.53.53. 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. S2CID 40084640.
  • 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. doi:10.1016/S0021-9258(18)33050-3. PMID 6822532.
  • Krauth-Siegel RL, Blatterspiel R, Saleh M, Schiltz E, Schirmer RH, Untucht-Grau R (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. S2CID 39710661.
  • 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, Schott MK, Kalbitzer HR, Becker K, Schubert D, Schirmer RH (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, Walsh CT, Pai E (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, Schirmer RH, Karplus PA (1998). "Enzyme inactivation through sulfhydryl oxidation by physiologic NO-carriers". Nat. Struct. Biol. 5 (4): 267–71. doi:10.1038/nsb0498-267. PMID 9546215. S2CID 20607289.
  • 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. S2CID 22048227.
  • 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, Choi WW, Cho KH, Kim KH, Park KC, Eun HC, Chung JH (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. S2CID 31321422.

February 04, 2023
glutathione, reductase, also, known, glutathione, disulfide, reductase, enzyme, that, humans, encoded, gene, catalyzes, reduction, glutathione, disulfide, gssg, sulfhydryl, form, glutathione, which, critical, molecule, resisting, oxidative, stress, maintaining. Glutathione reductase GR also known as glutathione disulfide reductase GSR is an enzyme that in humans is encoded by the GSR gene Glutathione reductase EC 1 8 1 7 catalyzes the reduction of glutathione disulfide GSSG to the sulfhydryl form glutathione GSH which is a critical molecule in resisting oxidative stress and maintaining the reducing environment of the cell 5 6 7 Glutathione reductase functions as dimeric disulfide oxidoreductase and utilizes an FAD prosthetic group and NADPH to reduce one molar equivalent of GSSG to two molar equivalents of GSH GSRAvailable structuresPDBOrtholog search PDBe RCSBList of PDB id codes1BWC 1DNC 1GRA 1GRB 1GRE 1GRF 1GRG 1GRH 1GRT 1GSN 1K4Q 1XAN 2AAQ 2GH5 2GRT 3DJG 3DJJ 3DK4 3DK8 3DK9 3GRS 3GRT 4GR1 4GRT 5GRT 1ALG 3SQPIdentifiersAliasesGSR HEL 75 HEL S 122m glutathione reductase glutathione disulfide reductase GR GSRDExternal IDsOMIM 138300 MGI 95804 HomoloGene 531 GeneCards GSRGene location Human Chr Chromosome 8 human 1 Band8p12Start30 678 066 bp 1 End30 727 846 bp 1 Gene location Mouse Chr Chromosome 8 mouse 2 Band8 A4 8 20 69 cMStart34 142 551 bp 2 End34 188 191 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inpylorusislet of Langerhansrenal medullaseminal vesicularectumduodenumpalpebral conjunctivacardiamonocytejejunal mucosaTop expressed incumulus cellmucous cell of stomachmolarproximal tubuleEpithelium of stomachpyloric antrumascending aortaduodenumkidneyaortic valveMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functionflavin adenine dinucleotide binding glutathione disulfide reductase NADPH activity NADP binding oxidoreductase activity oxidoreductase activity acting on a sulfur group of donors NAD P as acceptor electron transfer activityCellular componentcytoplasm cytosol mitochondrial matrix mitochondrion extracellular exosome external side of plasma membraneBiological processnucleobase containing small molecule interconversion glutathione metabolic process cell redox homeostasis cellular oxidant detoxification cellular response to oxidative stress electron transport chainSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez293614782EnsemblENSG00000104687ENSMUSG00000031584UniProtP00390P47791RefSeq mRNA NM 001195104NM 000637NM 001195102NM 001195103NM 010344RefSeq protein NP 000628NP 001182031NP 001182032NP 001182033NP 034474Location UCSC Chr 8 30 68 30 73 MbChr 8 34 14 34 19 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse General reaction catalyzed by glutathione reductase 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 8 In these organisms glutathione reduction is performed by either the thioredoxin or the trypanothione system respectively 8 9 Contents 1 Function 2 Structure 3 Reaction mechanism 3 1 Reductive half 3 2 Oxidative half 4 Inhibition 5 Clinical significance 5 1 Deficiency 5 2 Connection to favism 6 Monitoring glutathione reductase activity 7 In plants 8 History 9 Interactive pathway map 10 References 11 Further readingFunction Editglutathione disulfide reductase Human GSR with bound glutathione and FADHIdentifiersEC no 1 8 1 7CAS no 9001 48 3DatabasesIntEnzIntEnz viewBRENDABRENDA entryExPASyNiceZyme viewKEGGKEGG entryMetaCycmetabolic pathwayPRIAMprofilePDB structuresRCSB PDB PDBe PDBsumGene OntologyAmiGO QuickGOSearchPMCarticlesPubMedarticlesNCBIproteinsGlutathione plays a key role in maintaining proper function and preventing oxidative stress in human cells It can act as a scavenger for hydroxyl radicals singlet oxygen and various electrophiles Reduced glutathione reduces the oxidized form of the enzyme glutathione peroxidase which in turn reduces hydrogen peroxide H2O2 a dangerously reactive species within the cell In the following illustration of redox reeactions the rightmost arrow is reversed it should be pointing up not down In addition it plays a key role in the metabolism and clearance of xenobiotics acts as a cofactor in certain detoxifying enzymes participates in transport and regenerates antioxidants such and Vitamins E and C to their reactive forms The ratio of GSSG GSH present in the cell is a key factor in properly maintaining the oxidative balance of the cell that is it is critical that the cell maintains high levels of the reduced glutathione and a low level of the oxidized glutathione disulfide This narrow balance is maintained by glutathione reductase which catalyzes the reduction of GSSG to GSH 5 Reduced glutathione reductase glutathione peroxidase and glutathione interact to reduce hydrogen peroxide to water in order to protect the cell from oxidative damage Structure EditGlutathione reductase from human erythrocytes is a homodimer consisting of 52Kd monomers each containing 3 domains GR exhibits single sheet double layered topology where an anti parallel beta sheet is largely exposed to the solvent on one face while being covered by random coils on the other face 10 This includes and NADPH binding Domain FAD binding domain s and a dimerization domain Each monomer contains 478 residues and one FAD molecule GR is a thermostable protein retaining function up to 65 C 11 12 Reaction mechanism Edit Graphical representation of overall reaction catalyzed by GR GR catalytic cycle Steps 1 NADPH binding to the oxidized enzyme2 Reduction of FAD to FADH anion by NADPH3 Reduced FADH anion collapses into a charge relay complex and reduces Cys58 Cys63 disulfide4 Oxidized Glutathione disulfide binds to the reduced enzyme and forms a mixed disulfide with Cys58 and releases one reduced glutathione5 Cys63 attacks the mixed disulfide on Cys58 to release a reduced glutathione and reform the redox active disulfide Reductive half Edit The action of GR proceeds through two distinct half reactions a reductive half mechanism followed by an oxidative half In the first half NADPH reduces FAD present in GSR to produce a transient FADH anion This anion then quickly breaks a disulfide bond of Cys58 Cys63 forming a short lived covalent bond a stable charge transfer complex between the flavin and Cys63 The now oxidized NADP is released and is subsequently replaced by a new molecule of NADPH This is the end of the so called reductive half of the mechanism Oxidative half Edit In the oxidative half of the mechanism Cys63 nucleophilically attacks 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 release the first molecule of 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 13 Inhibition EditIn vitro glutathione reductase is inhibited by low concentrations of sodium arsenite and methylated arsenate metabolites but in vivo significant Glutathione Reductase inhibition by sodium arsenate has only been at 10 mg kg day 14 Glutathione reductase is also inhibited by some flavanoids a class of pigments produced by plants 15 Clinical significance EditGSH is a key cellular antioxidant and plays a major role in the phase 2 metabolic clearance of electrophilic xenobiotics The importance of the GSH pathway and enzymes that affect this delicate balance is gaining an increased level of attention in recent years Although glutathione reductase has been an attractive target for many pharmaceuticals there have been no successful glutathione reductase related therapeutic compounds created to date In particular glutathione reductase appears to be a good target for anti malarials as the glutathione reductase of the malaria parasite Plasmodium falciparum has a significantly different protein fold than that of mammalian glutathione reductase 16 By designing drugs specific to p falciparum it may be possible to selectively induce oxidative stress in the parasite while not affecting the host There are two main classes of GR targeting compounds 17 18 19 20 Inhibitors of GSSG binding or dimerization Reactive electrophiles such as gold compounds and fluoronaphthoquinones Drugs which use glutathione reductase to regenerate such as redox cyclers Two examples of these types of compounds are Methylene blue and Naphthoquinone Clinical trials performed in Burkina Faso have revealed mixed results when treating malaria with NaphthoquinonesIn 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 21 Lupus is an autoimmune disorder in which patients produce an elevated quantity of antibodies that attack DNA and other cell components In a recent study a single nucleotide polymorphism SNP in the Glutathione Reductase gene was found to be highly associated with lupus in African Americans in the study 22 African Americans with lupus have also been shown to express less reduced glutathione in their T cells 23 The study s authors believe that reduced glutathione reductase activity may contribute to the increased production of reactive oxygen in African Americans with lupus 22 In mice glutathione reductase has been implicated in the oxidative burst a component of the immune response 24 The oxidative burst is a defense mechanism in which neutrophils produce and release reactive oxidative species in the vicinity of bacteria or fungi to destroy the foreign cells Glutathione Reductase deficient neutrophils were shown to produce a more transient oxidative burst in response to bacteria than neutrophils that express GR at ordinary levels 24 The mechanism of Glutathione Reductase in sustaining the oxidative burst is still unknown 24 Deficiency Edit Glutathione reductase deficiency is a rare disorder in which the glutathione reductase activity is absent from erythrocytes leukocytes or both In one study this disorder was observed in only two cases in 15 000 tests for glutathione reductase deficiency performed over the course of 30 years 25 In the same study glutathione reductase deficiency was associated with cataracts and favism in one patient and their family and with severe unconjugated hyperbilirubinemia in another patient 25 It has been proposed that the glutathione redox system of which glutathione reductase is a part is almost exclusively responsible for the protecting of eye lens cells from hydrogen peroxide because these cells are deficient in catalase an enzyme which catalyzes the breakdown of hydrogen peroxide and the high rate of cataract incidence in glutathione reductase deficient individuals 26 Some patients exhibit deficient levels of glutathione activity as a result of not consuming enough riboflavin in their diets Riboflavin is a precursor for FAD whose reduced form donates two electron to the disulfide bond which is present in the oxidized form of glutathione reductase in order to begin the enzyme s catalytic cycle In 1999 a study found that 17 8 of males and 22 4 of females examined in Saudi Arabia suffered from low glutathione reductase activity due to riboflavin deficiency 27 Connection to favism Edit In favism patients lack glucose 6 phosphate dehydrogenase an enzyme in their pentose phosphate pathway that reduces NADP to NADPH while catalyzing the conversion of glucose 6 phosphate to 6 phosphoglucono d lactone Glucose 6 phosphate dehydrogenase deficient individuals have less NADPH available for the reduction of oxidized glutathione via glutathione reductase Thus their basal ratio of oxidized to reduced glutathione is significantly higher than that of patients who express glucose 6 phosphate dehydrogenase normally making them unable to effectively respond to high levels of reactive oxygen species which causes cell lysis 28 Monitoring glutathione reductase activity EditThe 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 29 Alternatively the activity can be measured using roGFP redox sensitive Green Fluorescent Protein 30 In plants EditAs it does in human cells glutathione reductase helps to protect plant cells from reactive oxygen species In plants reduced glutathione participates in the glutathione ascorbate cycle in which reduced glutathione reduces dehydroascorbate a reactive byproduct of the reduction of hydrogen peroxide In particular glutathione reductase contributes to plants response to abiotic stress 31 The enzyme s activity has been shown to be modulated in response to metals metalloids salinity drought UV radiation and heat induced stress 31 History EditGlutathione reductase was first purified in 1955 at Yale University by P Janmeda 32 Janmeda also identified NADPH as the primary electron donor for the enzyme Later groups confirmed the presence of FAD and the thiol group and an initial mechanism was suggested for the mechanism in 1965 33 34 The initial low resolution structure of glutathione reductase was solved in 1977 This was quickly followed by a 3A structure by Shulze et al in 1978 35 Glutathione reductase has been studied exhaustively since these early experiments and is subsequently one of the most well characterized enzymes to date Interactive pathway map EditInteractive pathway can be found here pathway mapReferences Edit a b c GRCh38 Ensembl release 89 ENSG00000104687 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000031584 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine a b Deponte M May 2013 Glutathione catalysis and the reaction mechanisms of glutathione dependent enzymes Biochim Biophys Acta 1830 5 3217 66 doi 10 1016 j bbagen 2012 09 018 PMID 23036594 Meister A November 1988 Glutathione metabolism and its selective modification J Biol Chem 263 33 17205 8 doi 10 1016 S0021 9258 19 77815 6 PMID 3053703 Mannervik B August 1987 The enzymes of glutathione metabolism an overview Biochem Soc Trans 15 4 717 8 doi 10 1042 bst0150717 PMID 3315772 a b Kanzok SM Fechner A Bauer H Ulschmid JK Muller 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 Bibcode 2001Sci 291 643K doi 10 1126 science 291 5504 643 PMID 11158675 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 Grisham Reginald H Garrett Charles M 2005 Biochemistry 3rd ed Belmont CA Thomson Brooks Cole ISBN 0534490336 Masella R Di Benedetto R Vari R Filesi C Giovannini C October 2005 Novel mechanisms of natural antioxidant compounds in biological systems involvement of glutathione and glutathione related enzymes J Nutr Biochem 16 10 577 86 doi 10 1016 j jnutbio 2005 05 013 PMID 16111877 Dym O Eisenberg D September 2001 Sequence structure analysis of FAD containing proteins Protein Sci 10 9 1712 28 doi 10 1110 ps 12801 PMC 2253189 PMID 11514662 Berkholz DS Faber HR Savvides SN Karplus PA October 2008 Catalytic cycle of human glutathione reductase near 1 A resolution J Mol Biol 382 2 371 84 doi 10 1016 j jmb 2008 06 083 PMC 2593804 PMID 18638483 Rodriguez VM Del Razo LM Limon Pacheco JH Giordano M Sanchez Pena LC Uribe Querol E Gutierrez Ospina G Gonsebatt ME March 2005 Glutathione reductase inhibition and methylated arsenic distribution in Cd1 mice brain and liver Toxicol Sci 84 1 157 66 doi 10 1093 toxsci kfi057 PMID 15601678 Elliott AJ Scheiber SA Thomas C Pardini RS October 1992 Inhibition of glutathione reductase by flavonoids A structure activity study Biochem Pharmacol 44 8 1603 8 doi 10 1016 0006 2952 92 90478 2 PMID 1329770 Sarma GN Savvides SN Becker K Schirmer M Schirmer RH Karplus PA May 2003 Glutathione reductase of the malarial parasite Plasmodium falciparum crystal structure and inhibitor development J Mol Biol 328 4 893 907 doi 10 1016 s0022 2836 03 00347 4 PMID 12729762 Buchholz K Schirmer RH Eubel JK Akoachere MB Dandekar T Becker K Gromer S January 2008 Interactions of methylene blue with human disulfide reductases and their orthologues from Plasmodium falciparum Antimicrob Agents Chemother 52 1 183 91 doi 10 1128 AAC 00773 07 PMC 2223905 PMID 17967916 Muller T Johann L Jannack B Bruckner M Lanfranchi DA Bauer H Sanchez C Yardley V Deregnaucourt C Schrevel J Lanzer M Schirmer RH Davioud Charvet E August 2011 Glutathione reductase catalyzed cascade of redox reactions to bioactivate potent antimalarial 1 4 naphthoquinones a new strategy to combat malarial parasites PDF J Am Chem Soc 133 30 11557 71 doi 10 1021 ja201729z PMID 21682307 Deponte M Urig S Arscott LD Fritz Wolf K Reau R Herold Mende C Koncarevic S Meyer M Davioud Charvet E Ballou DP Williams CH Becker K May 2005 Mechanistic studies on a novel highly potent gold phosphole inhibitor of human glutathione reductase J Biol Chem 280 21 20628 37 doi 10 1074 jbc M412519200 PMID 15792952 Deponte M May 2013 Glutathione catalysis and the reaction mechanisms of glutathione dependent enzymes Biochim Biophys Acta 1830 5 3217 66 doi 10 1016 j bbagen 2012 09 018 PMID 23036594 Champe PC Harvey RA Ferrier DR 2008 Biochemistry fourth ed Lippincott Williams and Wilkins ISBN 978 0 7817 6960 0 a b Ramos PS Oates JC Kamen DL Williams AH Gaffney PM Kelly JA Kaufman KM Kimberly RP Niewold TB Jacob CO Tsao BP Alarcon GS Brown EE Edberg JC Petri MA Ramsey Goldman R Reveille JD Vila LM James JA Guthridge JM Merrill JT Boackle SA Freedman BI Scofield RH Stevens AM Vyse TJ Criswell LA Moser KL Alarcon Riquelme ME Langefeld CD Harley JB Gilkeson GS June 2013 Variable association of reactive intermediate genes with systemic lupus erythematosus in populations with different African ancestry J Rheumatol 40 6 842 9 doi 10 3899 jrheum 120989 PMC 3735344 PMID 23637325 Gergely P Grossman C Niland B Puskas F Neupane H Allam F Banki K Phillips PE Perl A January 2002 Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus Arthritis Rheum 46 1 175 90 doi 10 1002 1529 0131 200201 46 1 lt 175 AID ART10015 gt 3 0 CO 2 H PMC 4020417 PMID 11817589 a b c Yan J Meng X Wancket LM Lintner K Nelin LD Chen B Francis KP Smith CV Rogers LK Liu Y March 2012 Glutathione reductase facilitates host defense by sustaining phagocytic oxidative burst and promoting the development of neutrophil extracellular traps J Immunol 188 5 2316 27 doi 10 4049 jimmunol 1102683 PMC 3480216 PMID 22279102 a b Kamerbeek NM Zwieten R Boer M Morren G Vuil H Bannink N Lincke C Dolman KM Becker K Schirmer RH Gromer S Roos D 2007 Molecular basis of glutathione reductase deficiency in human blood cells Blood 109 8 3560 3566 doi 10 1182 blood 2006 08 042531 PMID 17185460 Roos D Weening RS Voetman AA van Schaik ML Bot AA Meerhof LJ Loos JA May 1979 Protection of phagocytic leukocytes by endogenous glutathione studies in a family with glutathione reductase deficiency Blood 53 5 851 66 doi 10 1182 blood V53 5 851 851 PMID 435643 Warsy AS el Hazmi MA November 1999 Glutathione reductase deficiency in Saudi Arabia East Mediterr Health J 5 6 1208 12 doi 10 26719 1999 5 6 1208 PMID 11924113 Cappellini MD Fiorelli G January 2008 Glucose 6 phosphate dehydrogenase deficiency Lancet 371 9606 64 74 doi 10 1016 S0140 6736 08 60073 2 PMID 18177777 S2CID 29165746 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 Marty L Siala W Schwarzlander 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 Bibcode 2009PNAS 106 9109M doi 10 1073 pnas 0900206106 PMC 2690020 PMID 19451637 a b Gill SS Anjum NA Hasanuzzaman M Gill R Trivedi DK Ahmad I Pereira E Tuteja N September 2013 Glutathione and glutathione reductase a boon in disguise for plant abiotic stress defense operations Plant Physiol Biochem 70 204 12 doi 10 1016 j plaphy 2013 05 032 PMID 23792825 Racker E December 1955 Glutathione reductase from bakers yeast and beef liver J Biol Chem 217 2 855 65 doi 10 1016 S0021 9258 18 65950 2 PMID 13271446 Massey V Williams CH November 1965 On the reaction mechanism of yeast glutathione reductase J Biol Chem 240 11 4470 80 doi 10 1016 S0021 9258 18 97085 7 PMID 4378936 Mapson LW Isherwood FA January 1963 Glutathione reductase from germinated peas Biochem J 86 173 91 doi 10 1042 bj0860173 PMC 1201730 PMID 13932735 Schulz GE Schirmer RH Sachsenheimer W Pai EF May 1978 The structure of the flavoenzyme glutathione reductase Nature 273 5658 120 4 Bibcode 1978Natur 273 120S doi 10 1038 273120a0 PMID 25387 S2CID 4153363 Further reading EditSinet PM Bresson JL Couturier J Laurent C Prieur M Rethore MO Taillemite JL Toudic D Jerome H Lejeune J 1977 Possible localization of the glutathione reductase EC 1 6 4 2 on the 8p21 band Ann Genet in French 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 doi 10 1182 blood V48 1 53 53 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 S2CID 40084640 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 doi 10 1016 S0021 9258 18 33050 3 PMID 6822532 Krauth Siegel RL Blatterspiel R Saleh M Schiltz E Schirmer RH Untucht Grau R 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 S2CID 39710661 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 Schott MK Kalbitzer HR Becker K Schubert D Schirmer RH 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 Walsh CT Pai E 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 Schirmer RH Karplus PA 1998 Enzyme inactivation through sulfhydryl oxidation by physiologic NO carriers Nat Struct Biol 5 4 267 71 doi 10 1038 nsb0498 267 PMID 9546215 S2CID 20607289 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 S2CID 22048227 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 Choi WW Cho KH Kim KH Park KC Eun HC Chung JH 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 Jozwiak 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 S2CID 31321422 Retrieved from https en wikipedia org w index php title Glutathione reductase amp oldid 1136268051, wikipedia, wiki, book, books, library,

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