Summary: Glutathione peroxidase
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Glutathione peroxidase Edit Wikipedia article
| Glutathione peroxidase | |||||||||
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| Identifiers | |||||||||
| EC number | 1.11.1.9 | ||||||||
| CAS number | 9013-66-5 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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| Glutathione peroxidase | |||||||||||
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| Identifiers | |||||||||||
| Symbol | GSHPx | ||||||||||
| Pfam | PF00255 | ||||||||||
| InterPro | IPR000889 | ||||||||||
| PROSITE | PDOC00396 | ||||||||||
| SCOPe | 1gp1 / SUPFAM | ||||||||||
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Glutathione peroxidase (GPx) (EC 1.11.1.9) 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]
Contents
Isozymes
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) |
Reaction
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
- GS-SeR + GSH → GS-SG + RSeH
Glutathione reductase then reduces the oxidized glutathione to complete the cycle:
- GS–SG + NADPH + H+ → 2 GSH + NADP+.
Structure
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.
Discovery
Glutathione peroxidase was discovered in 1957 by Gordon C. Mills.[10]
Clinical significance
It has been shown that low levels of glutathione peroxidase as measured in the serum may be a contributing factor to vitiligo.[11] 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.[12] Glutathione peroxidase activity was found to be much lower in patients with relapsing-remitting multiple sclerosis.[13] One study has suggested that glutathione peroxidase and superoxide dismutase polymorphisms play a role in the development of celiac disease.[14]
See also
References
- ^ PDB: 1GP1; Epp O, Ladenstein R, Wendel A (Jun 1983). "The refined structure of the selenoenzyme glutathione peroxidase at 0.2-nm resolution". European Journal of Biochemistry / FEBS. 133 (1): 51–69. doi:10.1111/j.1432-1033.1983.tb07429.x. PMID 6852035.
- ^ Nachiappan, Vasanthi; Muthukumar, Kannan (December 2010). "Cadmium-induced oxidative stress in Saccharomyces cerevisiae". Indian Journal of Biochemistry and Biophysics. 47 (6). ISSN 0975-0959.
- ^ Muthukumar, Kannan; Rajakumar, Selvaraj; Sarkar, Mary Nirmala; Nachiappan, Vasanthi (2011-05-01). "Glutathione peroxidase3 of Saccharomyces cerevisiae protects phospholipids during cadmium-induced oxidative stress". Antonie van Leeuwenhoek. 99 (4): 761–771. doi:10.1007/s10482-011-9550-9. ISSN 1572-9699. PMID 21229313.
- ^ 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.
- ^ Bhabak KP, Mugesh G (Nov 2010). "Functional mimics of glutathione peroxidase: bioinspired synthetic antioxidants". Accounts of Chemical Research. 43 (11): 1408–19. doi:10.1021/ar100059g. PMID 20690615.
- ^ Ohlemiller KK, McFadden SL, Ding DL, Lear PM, Ho YS (Nov 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.
- ^ Esworthy RS, Aranda R, MartÃn 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. doi:10.1152/ajpgi.2001.281.3.G848. PMID 11518697.
- ^ Olson GE, Whitin JC, Hill KE, Winfrey VP, Motley AK, Austin LM, Deal J, Cohen HJ, Burk RF (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.
- ^ Ran Q, Liang H, Ikeno Y, Qi W, Prolla TA, Roberts LJ, Wolf N, Van Remmen H, VanRemmen H, Richardson A (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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Socha K, Kochanowicz J, Karpińska E, Soroczyńska J, Jakoniuk M, Mariak Z, Borawska MH (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.
- ^ 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.
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Internal database links
| SCOOP: | AhpC-TSA AhpC-TSA_2 Redoxin SCO1-SenC T4_deiodinase Thioredoxin Thioredoxin_2 Thioredoxin_7 Thioredoxin_8 TraF |
| Similarity to PfamA using HHSearch: | AhpC-TSA Redoxin |
External database links
| PROSITE: | PDOC00396 |
| SCOP: | 1gp1 |
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 ].
Gene Ontology
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
| Molecular function | glutathione peroxidase activity (GO:0004602) |
| Biological process | response to oxidative stress (GO:0006979) |
| oxidation-reduction process (GO:0055114) |
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 63 members:
2Fe-2S_thioredx AhpC-TSA AhpC-TSA_2 ArsC ArsD Calsequestrin DIM1 DSBA DUF1223 DUF1462 DUF1525 DUF1687 DUF2703 DUF2847 DUF4174 DUF6436 DUF899 DUF953 ERp29_N GILT Glrx-like Glutaredoxin GSHPx GST_N GST_N_2 GST_N_3 GST_N_4 GST_N_5 HyaE KaiB L51_S25_CI-B8 MRP-S23 MRP-S25 OST3_OST6 Phe_hydrox_dim Phosducin QSOX_Trx1 Rdx Redoxin SCO1-SenC SelP_N Sep15_SelM SH3BGR T4_deiodinase Thioredox_DsbH Thioredoxin Thioredoxin_11 Thioredoxin_12 Thioredoxin_13 Thioredoxin_14 Thioredoxin_15 Thioredoxin_16 Thioredoxin_2 Thioredoxin_3 Thioredoxin_4 Thioredoxin_5 Thioredoxin_6 Thioredoxin_7 Thioredoxin_8 Thioredoxin_9 Tom37 TraF YtfJ_HI0045Alignments
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Full (11537) |
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| RP15 (1673) |
RP35 (5233) |
RP55 (10761) |
RP75 (17586) |
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| PP/heatmap | 1 | ||||||
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| Seed (10) |
Full (11537) |
Representative proteomes | UniProt (40490) |
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| RP15 (1673) |
RP35 (5233) |
RP55 (10761) |
RP75 (17586) |
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| Raw Stockholm | |||||||
| Gzipped | |||||||
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
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Curation and family details
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Curation
| Seed source: | Prosite |
| Previous IDs: | none |
| Type: | Family |
| Sequence Ontology: | SO:0100021 |
| Author: |
Finn RD 
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| Number in seed: | 10 |
| Number in full: | 11537 |
| Average length of the domain: | 102.40 aa |
| Average identity of full alignment: | 42 % |
| Average coverage of the sequence by the domain: | 55.03 % |
HMM information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
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| Model details: |
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| Model length: | 108 | ||||||||||||
| Family (HMM) version: | 21 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
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Structures
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.
