Glutathione peroxidase

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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[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.[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]

Human proteins containing this domain[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". 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 (August 2007). "Trends in oxidative aging theories". Free Radic. Biol. Med. 43 (4): 477–503. doi:10.1016/j.freeradbiomed.2007.03.034. PMID 17640558. 
  3. ^ Krishna P. Bhabak, Govindasamy Mugesh "Functional Mimics of Glutathione Peroxidase: Bioinspired Synthetic Antioxidants" Acc. Chem. Res., 2010, 43 (11), pp 1408–1419. doi:10.1021/ar100059g
  4. ^ Ohlemiller KK1, McFadden SL, Ding DL, Lear PM, Ho YS. Targeted mutation of the gene for cellular glutathione peroxidase (Gpx1) increases noise-induced hearing loss in mice. J Assoc Res Otolaryngol. 2000 Nov;1(3):243-54.
  5. ^ Esworthy, RS; Aranda, R; Martin, MG; Doroshow, JH; Binder, SW; Chu, FF (2001). "Mice with combined disruption of Gpx1 and Gpx2 genes have colitis.". American Journal of Physiology 281 (3): G848–55. PMID 11518697. 
  6. ^ Olson, GE; Whitin, JC; Hill, KE; et al. (2010). "Extracellular glutathione peroxidase (Gpx3) binds specifically to basement membranes of mouse renal cortex tubule cells". American Journal of Physiology 298 (5): F1244–F1253. doi:10.1152/ajprenal.00662.2009. 
  7. ^ Ran Q, Liang H, Ikeno Y (2007). "Reduction in glutathione peroxidase 4 increases life span through increased sensitivity to apoptosis". J. Gerontol. A Biol. Sci. Med. Sci. 62 (9): 932–42. doi:10.1093/gerona/62.9.932. PMID 17895430. 
  8. ^ MILLS GC (November 1957). "Hemoglobin catabolism. I. Glutathione peroxidase, an erythrocyte enzyme which protects hemoglobin from oxidative breakdown". J. Biol. Chem. 229 (1): 189–97. PMID 13491573. 

See also[edit]