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33  structures 13397  species 1  interaction 22011  sequences 25  architectures

Family: GSHPx (PF00255)

Summary: Glutathione peroxidase

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This is the Wikipedia entry entitled "Glutathione peroxidase". More...

Glutathione peroxidase Edit Wikipedia article

Glutathione peroxidase
Crystallographic structure of bovine glutathione peroxidase 1.[1]
EC number
CAS number 9013-66-5
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Glutathione peroxidase
Symbol GSHPx
Pfam PF00255
InterPro IPR000889
SCOP 1gp1

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. The biochemical function of glutathione peroxidase is to reduce lipid hydroperoxides to their corresponding alcohols and to reduce free hydrogen peroxide to water.


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.[2] 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 seleninic 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:[3]

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.[2] Gpx1 −/− mice showed up to 16 dB higher ABR thresholds than control mice. After 110 dB noise noise exposure for one hour, Gpx1 −/− mice had up to 15 dB greater noise-induced hearing loss compared with control mice.[4]"

Mice with knockouts for GPX3 (GPX3−/−) or GPX2 (GPX2−/−) also develop normally [5][6]

However, glutathione peroxidase 4 knockout mice die during early embryonic development.[2] Some evidence, though, indicates reduced levels of glutathione peroxidase 4 can increase life expectancy in mice.[7]

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


Glutathione peroxidase was discovered in 1957 by Gordon C. Mills.[8]

Clinical Significance

It has been shown that low levels of glutathione peroxidase as measured in the serum may be a contributing factor to vitiligo.[9] 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.[10] 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.[11] Glutathione peroxidase activity was found to be much lower in patients with relapsing-remitting multiple sclerosis.[12] One study has suggested that glutathione peroxidase and superoxide dismutase polymorphisms play a role in the development of celiac disease.[13]

Human proteins containing this domain



  1. ^ PDB 1GP1; Epp O, Ladenstein R, Wendel A (June 1983). "The refined structure of the selenoenzyme glutathione peroxidase at 0.2-nm resolution". Eur. J. Biochem. 133 (1): 51–69. doi:10.1111/j.1432-1033.1983.tb07429.x. PMID 6852035. 
  2. ^ a b c Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H (Aug 2007). "Trends in oxidative aging theories". Free Radical Biology & Medicine 43 (4): 477–503. doi:10.1016/j.freeradbiomed.2007.03.034. PMID 17640558. 
  3. ^ Bhabak KP, Mugesh G (Nov 2010). "Functional mimics of glutathione peroxidase: bioinspired synthetic antioxidants". Accounts of Chemical Research 43 (11): 1408–1419. doi:10.1021/ar100059g. PMID 20690615. 
  4. ^ Ohlemiller, KK; McFadden, SL; Ding, DL; Lear, PM; Ho, YS (2000). "Targeted mutation of the gene for cellular glutathione peroxidase (Gpx1) increases noise-induced hearing loss in mice". J Assoc Res Otolaryngol 1 (3): 243–54. doi:10.1007/s101620010043. 
  5. ^ Esworthy RS, Aranda R, Martín MG, Doroshow JH, Binder SW, Chu FF (Sep 2001). "Mice with combined disruption of Gpx1 and Gpx2 genes have colitis". American Journal of Physiology. Gastrointestinal and Liver Physiology 281 (3): G848–55. PMID 11518697. 
  6. ^ 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–F1253. doi:10.1152/ajprenal.00662.2009. PMID 20015939. 
  7. ^ Ran Q, Liang H, Ikeno Y, Qi W, Prolla TA, Roberts LJ et al. (Sep 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. 
  8. ^ Mills GC (Nov 1957). "Hemoglobin catabolism. I. Glutathione peroxidase, an erythrocyte enzyme which protects hemoglobin from oxidative breakdown". The Journal of Biological Chemistry 229 (1): 189–97. PMID 13491573. 
  9. ^ 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. doi:10.2310/7750.2014.14076. PMID 25775636. 
  10. ^ Sedighi O, Makhlough A, Shokrzadeh M, Hoorshad S (Sep 2014). "Association between plasma selenium and glutathione peroxidase levels and severity of diabetic nephropathy in patients with type two diabetes mellitus". Nephro-Urology Monthly 6 (5): e21355. doi:10.5812/numonthly.21355. PMC 4318010. PMID 25695036. 
  11. ^ Yang S, Jensen MK, Rimm EB, Willett W, Wu T (Nov 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. 
  12. ^ Socha K, Kochanowicz J, KarpiÅ„ska E, SoroczyÅ„ska J, Jakoniuk M, Mariak Z et al. (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. 
  13. ^ Katar M, Ozugurlu AF, Ozyurt H, Benli I (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. 

See also

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000889

Glutathione peroxidase (GSHPx) (EC) is an enzyme that catalyses the reduction of hydroxyperoxides by glutathione [PUBMED:, PUBMED:7565867]. Its main function is to protect against the damaging effect of endogenously formed hydroxyperoxides. 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 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 Escherichia coli protein btuE, a periplasmic protein involved in vitamin B12 transport, is evolutionarily related to GSHPxs, although the significance of this relationship is unclear. The structure of bovine seleno-glutathione peroxidase has been determined [PUBMED:6852035]. The protein belongs to the alpha-beta class, with a 3 layer(aba) sandwich architecture. The catalyic site of GSHPx contains a conserved residue which is either a cysteine or, in many eukaryotic GSHPx, a selenocysteine [PUBMED:2142875].

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan Thioredoxin (CL0172), which has the following description:

This clan contains families related to the thioredoxin family. Thioredoxins are small enzymes that are involved in redox reactions via the reversible oxidation of an active centre disulfide bond. The thioredoxin fold consists of a 3 layer alpha/beta/alpha sandwich and a central beta sheet.

The clan contains the following 52 members:

2Fe-2S_thioredx AhpC-TSA AhpC-TSA_2 Aminopep ArsC ArsD Calsequestrin DIM1 DSBA DUF1223 DUF1525 DUF1687 DUF2703 DUF2847 DUF4174 DUF836 DUF899 DUF953 ERp29_N Glutaredoxin GSHPx GST_N GST_N_2 GST_N_3 HyaE KaiB L51_S25_CI-B8 Metallopep MRP-S23 MRP-S25 Peptidase_M76 Phosducin Redoxin SCO1-SenC SelP_N Sep15_SelM SH3BGR T4_deiodinase Thioredox_DsbH Thioredoxin Thioredoxin_2 Thioredoxin_3 Thioredoxin_4 Thioredoxin_5 Thioredoxin_6 Thioredoxin_7 Thioredoxin_8 Thioredoxin_9 Tom37 TraF YtfJ_HI0045 Zincin_1


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Seed source: Prosite
Previous IDs: none
Type: Family
Author: Finn RD
Number in seed: 11
Number in full: 22011
Average length of the domain: 106.40 aa
Average identity of full alignment: 50 %
Average coverage of the sequence by the domain: 62.69 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 80369284 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.7 20.7
Trusted cut-off 20.7 20.7
Noise cut-off 20.6 20.6
Model length: 108
Family (HMM) version: 15
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Species distribution

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Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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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 33 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 seqence.

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