Glutathione peroxidase

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Glutathione peroxidase
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MetaCycmetabolic pathway
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Glutathione peroxidase
Identifiers
SymbolGSHPx
SCOP2
1gp1 / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB2f8aB:14-128 1gp1A:19-133

Glutathione peroxidase (GPx) (

hydroperoxides to their corresponding alcohols and to reduce free hydrogen peroxide to water.[3]

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

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

kDa
.

Discovery

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]

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

It has been shown that low levels of glutathione peroxidase as measured in the

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

References

  1. PMID 6852035
    .
  2. PMID 21355423
    .
  3. S2CID 21850794
    .
  4. ^
    PMID 17640558
    .
  5. PMID 20690615
    .
  6. PMID 11545230
    .
  7. S2CID 21615743
    .
  8. PMID 20015939
    .
  9. PMID 17895430
    .
  10. PMID 13491573
    .
  11. PMID 6066618
    .
  12. PMID 727443
    .
  13. PMID 2434712
    .
  14. S2CID 52038817
    .
  15. S2CID 236219189
    .
  16. ISSN 0003-2697
    .
  17. S2CID 32708904
    .
  18. PMID 25156995
    .
  19. PMID 24943732
    .
  20. PMID 24634124
    .
  21. PMID 24748564
    .
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