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42  structures 5798  species 0  interactions 12301  sequences 99  architectures

Family: GSHPx (PF00255)

Summary: Glutathione peroxidase

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Glutathione peroxidase Edit Wikipedia article

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

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

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

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][15]

The activity of this enzyme has been reported to be decreased in case of copper deficiency in the liver and plasma.[16]

Clinical significance

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]

See also


  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.
  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, Aleksey V.; Baziyan, Elena V.; Polyanskikh, Lyudmila S.; Petrosyan, Mariya A. (17 June 2021). "Experience of measuring glutathione peroxidase activity in surgically induced endometrial-like lesions in rats". Journal of Obstetrics and Women's Diseases. 70 (2): 55–61. doi:10.17816/JOWD52877.
  15. ^ 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.
  16. ^ 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.
  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.

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This tab holds annotation information from the InterPro database.

InterPro entry IPR000889

Glutathione peroxidase (GSHPx) ( EC ) is an enzyme that catalyses the reduction of hydroperoxides by glutathione [ PUBMED:7565867 ]. Its main function is to protect against the damaging effect of endogenously formed hydroperoxides. In higher vertebrates, several forms of GSHPx are known, including a ubiquitous cytosolic form (GSHPx-1), a gastrointestinal cytosolic form (GSHPx-GI), a plasma secreted form (GSHPx-P), and an epididymal secretory form (GSHPx-EP). In mammals there are eight GPx, divided in two clusters, the classical GPx (GPx1, GPx2, GPx3, GPx5 and GPx6) and phospholipid hydroperoxide GPx (GPx4, GPx7 and GPx8). The classical GPx is multimeric (commonly tetrameric) and soluble, while the phospholipid hydroperoxide (PHGPx) is monomeric and often membrane-associated [ PUBMED:23567855 ]. In addition to these characterised forms, the sequence of a protein of unknown function [ PUBMED:2771650 ] has been shown to be evolutionary related to those of GSHPx's.

In filarial nematode parasites, the major soluble cuticular protein (gp29) is a secreted GSHPx, which may provide a mechanism of resistance to the immune reaction of the mammalian host by neutralising the products of the oxidative burst of leukocytes [ PUBMED:1631065 ]. The structure of bovine seleno-glutathione peroxidase has been determined [ PUBMED:6852035 ]. The protein belongs to the alpha-beta class, with a three layer(aba) sandwich architecture. The catalytic site of GSHPx contains a conserved residue which is either a cysteine or, in many eukaryotic GSHPx, a selenocysteine [ PUBMED:2142875 ].

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Seed source: Prosite
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: Finn RD
Number in seed: 10
Number in full: 12301
Average length of the domain: 103.40 aa
Average identity of full alignment: 42 %
Average coverage of the sequence by the domain: 54.94 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.0 27.0
Trusted cut-off 27.0 27.0
Noise cut-off 26.9 26.9
Model length: 108
Family (HMM) version: 22
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the GSHPx domain has been found. There are 42 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A0G2KAD1 View 3D Structure Click here
A0A0P0WGL5 View 3D Structure Click here
A0A0R0GIC5 View 3D Structure Click here
A0A1D6K2D3 View 3D Structure Click here
A0A1D6K2F9 View 3D Structure Click here
A0A1D8PPH4 View 3D Structure Click here
A0A2R8RWH8 View 3D Structure Click here
A4I211 View 3D Structure Click here
A4I212 View 3D Structure Click here
A4ID89 View 3D Structure Click here
A6QLY2 View 3D Structure Click here
A8WFK6 View 3D Structure Click here
B4FRF0 View 3D Structure Click here
B6T5N2 View 3D Structure Click here
B7FAE9 View 3D Structure Click here
C0P3R8 View 3D Structure Click here
C6SZX7 View 3D Structure Click here
C6T020 View 3D Structure Click here
C6T333 View 3D Structure Click here
C6T3V3 View 3D Structure Click here
D3ZPW7 View 3D Structure Click here
D3ZQI1 View 3D Structure Click here
F1QTD7 View 3D Structure Click here
F1R5F7 View 3D Structure Click here
F6NSX3 View 3D Structure Click here
F6NYT7 View 3D Structure Click here
F8W4K8 View 3D Structure Click here
H2KYJ6 View 3D Structure Click here
I1JNS2 View 3D Structure Click here
I1K5J0 View 3D Structure Click here
I1K6J6 View 3D Structure Click here
I1KP94 View 3D Structure Click here
I1KP95 View 3D Structure Click here
I1L819 View 3D Structure Click here
I1LGG2 View 3D Structure Click here
I1MX60 View 3D Structure Click here
I1N9F3 View 3D Structure Click here
K7KS34 View 3D Structure Click here
O02621 View 3D Structure Click here
O04922 View 3D Structure Click here