Glutathione peroxidase

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Glutathione peroxidase
Crystallographic structure of bovine glutathione peroxidase 1.[1]
EC no.
CAS no.9013-66-5
IntEnzIntEnz view
ExPASyNiceZyme view
MetaCycmetabolic pathway
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Glutathione peroxidase
Available protein structures:
Pfam  structures / ECOD  
PDBsumstructure summary
PDB2f8aB:14-128 1gp1A:19-133

Glutathione peroxidase (GPx) (EC is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage.[2] The biochemical function of glutathione peroxidase is to reduce lipid hydroperoxides to their corresponding alcohols and to reduce free hydrogen peroxide to water.[3]


Several isozymes are encoded by different genes, which vary in cellular location and substrate specificity. Glutathione peroxidase 1 (GPx1) is the most abundant version, found in the cytoplasm of nearly all mammalian tissues, whose preferred substrate is hydrogen peroxide. Glutathione peroxidase 4 (GPx4) has a high preference for lipid hydroperoxides; it is expressed in nearly every mammalian cell, though at much lower levels. Glutathione peroxidase 2 is an intestinal and extracellular enzyme, while glutathione peroxidase 3 is extracellular, especially abundant in plasma.[4] So far, eight different isoforms of glutathione peroxidase (GPx1-8) have been identified in humans.

Gene Locus Enzyme
GPX1 Chr. 3 p21.3 glutathione peroxidase 1
GPX2 Chr. 14 q24.1 glutathione peroxidase 2 (gastrointestinal)
GPX3 Chr. 5 q23 glutathione peroxidase 3 (plasma)
GPX4 Chr. 19 p13.3 glutathione peroxidase 4 (phospholipid hydroperoxidase)
GPX5 Chr. 6 p21.32 glutathione peroxidase 5 (epididymal androgen-related protein)
GPX6 Chr. 6 p21 glutathione peroxidase 6 (olfactory)
GPX7 Chr. 1 p32 glutathione peroxidase 7
GPX8 Chr. 5 q11.2 glutathione peroxidase 8 (putative)


The main reaction that glutathione peroxidase catalyzes is:

2GSH + H2O2 → GS–SG + 2H2O

where GSH represents reduced monomeric glutathione, and GS–SG represents glutathione disulfide. The mechanism involves oxidation of the selenol of a selenocysteine residue by hydrogen peroxide. This process gives the derivative with a selenenic acid (RSeOH) group. The selenenic acid is then converted back to the selenol by a two step process that begins with reaction with GSH to form the GS-SeR and water. A second GSH molecule reduces the GS-SeR intermediate back to the selenol, releasing GS-SG as the by-product. A simplified representation is shown below:[5]

RSeH + H2O2 → RSeOH + H2O
RSeOH + GSH → GS-SeR + H2O

Glutathione reductase then reduces the oxidized glutathione to complete the cycle:

GS–SG + NADPH + H+ → 2 GSH + NADP+.


Mammalian GPx1, GPx2, GPx3, and GPx4 have been shown to be selenium-containing enzymes, whereas GPx6 is a selenoprotein in humans with cysteine-containing homologues in rodents. GPx1, GPx2, and GPx3 are homotetrameric proteins, whereas GPx4 has a monomeric structure. As the integrity of the cellular and subcellular membranes depends heavily on glutathione peroxidase, its antioxidative protective system itself depends heavily on the presence of selenium.

Animal models[edit]

Mice genetically engineered to lack glutathione peroxidase 1 (Gpx1−/− mice) are grossly phenotypically normal and have normal lifespans, indicating this enzyme is not critical for life. However, Gpx1−/− mice develop cataracts at an early age and exhibit defects in muscle satellite cell proliferation.[4] Gpx1 −/− mice showed up to 16 dB higher auditory brainstem response (ABR) thresholds than control mice. After 110 dB noise exposure for one hour, Gpx1 −/− mice had up to 15 dB greater noise-induced hearing loss compared with control mice.[6]"

Mice with knockouts for GPX3 (GPX3−/−) or GPX2 (GPX2−/−) also develop normally [7][8]

However, glutathione peroxidase 4 knockout mice die during early embryonic development.[4] Some evidence, though, indicates reduced levels of glutathione peroxidase 4 can increase life expectancy in mice.[9]

The bovine erythrocyte enzyme has a molecular weight of 84 kDa.


Glutathione peroxidase was discovered in 1957 by Gordon C. Mills.[10]

Methods for determining glutathione peroxidase activity[edit]

Activity of glutathione peroxidase is measured spectrophotometrically using several methods. A direct assay by linking the peroxidase reaction with glutathione reductase with measurement of the conversion of NADPH to NADP is widely used.[11] The other approach is measuring residual GSH in the reaction with Ellman's reagent. Based on this, several procedures for measuring glutathione peroxidase activity were developed using various hydroperoxides as substrates for reduction, e.g. cumene hydroperoxide,[12] tert-butyl hydroperoxide [13] and hydrogen peroxide.[14]

The other methods include the use of CUPRAC reagent with spectrophotometric detection of the reaction product[15] or o-phtalaldehyde as a fluorescent reagent.[16]

Clinical significance[edit]

It has been shown that low levels of glutathione peroxidase as measured in the serum may be a contributing factor to vitiligo.[17] Lower plasma glutathione peroxide levels were also observed in patients with type 2 diabetes with macroalbuminuria and this was correlated to the stage of diabetic nephropathy.[citation needed] In one study, the activity of glutathione peroxidase along with other antioxidant enzymes such as superoxide dismutase and catalase was not associated with coronary heart disease risk in women.[18] Glutathione peroxidase activity was found to be much lower in patients with relapsing-remitting multiple sclerosis.[19] One study has suggested that glutathione peroxidase and superoxide dismutase polymorphisms play a role in the development of celiac disease.[20]

The activity of this enzyme has been reported to be decreased in case of copper deficiency in the liver and plasma.[21]

See also[edit]


  1. ^ PDB: 1GP1​; Epp O, Ladenstein R, Wendel A (June 1983). "The refined structure of the selenoenzyme glutathione peroxidase at 0.2-nm resolution". European Journal of Biochemistry. 133 (1): 51–69. doi:10.1111/j.1432-1033.1983.tb07429.x. PMID 6852035.
  2. ^ Muthukumar K, Nachiappan V (December 2010). "Cadmium-induced oxidative stress in Saccharomyces cerevisiae". Indian Journal of Biochemistry & Biophysics. 47 (6): 383–7. PMID 21355423.
  3. ^ Muthukumar K, Rajakumar S, Sarkar MN, Nachiappan V (May 2011). "Glutathione peroxidase3 of Saccharomyces cerevisiae protects phospholipids during cadmium-induced oxidative stress". Antonie van Leeuwenhoek. 99 (4): 761–71. doi:10.1007/s10482-011-9550-9. PMID 21229313. S2CID 21850794.
  4. ^ a b c Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H (August 2007). "Trends in oxidative aging theories". Free Radical Biology & Medicine. 43 (4): 477–503. doi:10.1016/j.freeradbiomed.2007.03.034. PMID 17640558.
  5. ^ Bhabak KP, Mugesh G (November 2010). "Functional mimics of glutathione peroxidase: bioinspired synthetic antioxidants". Accounts of Chemical Research. 43 (11): 1408–19. doi:10.1021/ar100059g. PMID 20690615.
  6. ^ Ohlemiller KK, McFadden SL, Ding DL, Lear PM, Ho YS (November 2000). "Targeted mutation of the gene for cellular glutathione peroxidase (Gpx1) increases noise-induced hearing loss in mice". Journal of the Association for Research in Otolaryngology. 1 (3): 243–54. doi:10.1007/s101620010043. PMC 2504546. PMID 11545230.
  7. ^ Esworthy RS, Aranda R, Martín MG, Doroshow JH, Binder SW, Chu FF (September 2001). "Mice with combined disruption of Gpx1 and Gpx2 genes have colitis". American Journal of Physiology. Gastrointestinal and Liver Physiology. 281 (3): G848-55. doi:10.1152/ajpgi.2001.281.3.G848. PMID 11518697. S2CID 21615743.
  8. ^ Olson GE, Whitin JC, Hill KE, Winfrey VP, Motley AK, Austin LM, et al. (May 2010). "Extracellular glutathione peroxidase (Gpx3) binds specifically to basement membranes of mouse renal cortex tubule cells". American Journal of Physiology. Renal Physiology. 298 (5): F1244-53. doi:10.1152/ajprenal.00662.2009. PMC 2867408. PMID 20015939.
  9. ^ Ran Q, Liang H, Ikeno Y, Qi W, Prolla TA, Roberts LJ, et al. (September 2007). "Reduction in glutathione peroxidase 4 increases life span through increased sensitivity to apoptosis". The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 62 (9): 932–42. doi:10.1093/gerona/62.9.932. PMID 17895430.
  10. ^ Mills GC (November 1957). "Hemoglobin catabolism. I. Glutathione peroxidase, an erythrocyte enzyme which protects hemoglobin from oxidative breakdown". The Journal of Biological Chemistry. 229 (1): 189–97. doi:10.1016/S0021-9258(18)70608-X. PMID 13491573.
  11. ^ Paglia DE, Valentine WN (July 1967). "Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase". The Journal of Laboratory and Clinical Medicine. 70 (1): 158–69. PMID 6066618.
  12. ^ Zakowski JJ, Tappel AL (September 1978). "A semiautomated system for measurement of glutathione in the assay of glutathione peroxidase". Analytical Biochemistry. 89 (2): 430–6. doi:10.1016/0003-2697(78)90372-X. PMID 727443.
  13. ^ Moin VM (1986). "[A simple and specific method for determining glutathione peroxidase activity in erythrocytes]". Laboratornoe Delo. 12 (12): 724–7. PMID 2434712.
  14. ^ Razygraev AV, Yushina AD, Titovich IA (August 2018). "Correction to: A Method of Measuring Glutathione Peroxidase Activity in Murine Brain: Application in Pharmacological Experiment". Bulletin of Experimental Biology and Medicine. 165 (4): 589–592. doi:10.1007/s10517-018-4219-2. PMID 30121905. S2CID 52038817.
  15. ^ Ahmed, A. Y.; Aowda, S. A.; Hadwan, M. H. (2021). "A validated method to assess glutathione peroxidase enzyme activity". Chemical Papers. 75 (12): 6625–6637. doi:10.1007/s11696-021-01826-1. ISSN 2585-7290. S2CID 236219189.
  16. ^ Ramos Martinez, J. I.; Launay, J.-M.; Dreux, C. (1979). "A sensitive fluorimetric microassay for the determination of glutathione peroxidase activity. Application to human blood platelets". Analytical Biochemistry. 98 (1): 154–159. doi:10.1016/0003-2697(79)90720-6. ISSN 0003-2697.
  17. ^ Zedan H, Abdel-Motaleb AA, Kassem NM, Hafeez HA, Hussein MR (Mar 2015). "Low glutathione peroxidase activity levels in patients with vitiligo". Journal of Cutaneous Medicine and Surgery. 19 (2): 144–8. doi:10.2310/7750.2014.14076. PMID 25775636. S2CID 32708904.
  18. ^ Yang S, Jensen MK, Rimm EB, Willett W, Wu T (November 2014). "Erythrocyte superoxide dismutase, glutathione peroxidase, and catalase activities and risk of coronary heart disease in generally healthy women: a prospective study". American Journal of Epidemiology. 180 (9): 901–8. doi:10.1093/aje/kwu195. PMC 4207716. PMID 25156995.
  19. ^ Socha K, Kochanowicz J, Karpińska E, Soroczyńska J, Jakoniuk M, Mariak Z, Borawska MH (June 2014). "Dietary habits and selenium, glutathione peroxidase and total antioxidant status in the serum of patients with relapsing-remitting multiple sclerosis". Nutrition Journal. 13: 62. doi:10.1186/1475-2891-13-62. PMC 4080729. PMID 24943732.
  20. ^ Katar M, Ozugurlu AF, Ozyurt H, Benli I (February 2014). "Evaluation of glutathione peroxidase and superoxide dismutase enzyme polymorphisms in celiac disease patients". Genetics and Molecular Research. 13 (1): 1030–7. doi:10.4238/2014.February.20.4. PMID 24634124.
  21. ^ Hordyjewska, Anna; Popiołek, Łukasz; Kocot, Joanna (2014). "The many 'faces' of copper in medicine and treatment". Biometals. 27 (4): 611–621. doi:10.1007/s10534-014-9736-5. PMC 4113679. PMID 24748564.