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Information on EC 1.11.1.12 - phospholipid-hydroperoxide glutathione peroxidase and Organism(s) Mus musculus and UniProt Accession O70325

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IUBMB Comments
A protein containing a selenocysteine residue. The products of action of EC 1.13.11.12 lipoxygenase on phospholipids can act as acceptors; H2O2 can also act, but much more slowly (cf. EC 1.11.1.9 glutathione peroxidase).
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This record set is specific for:
Mus musculus
UNIPROT: O70325
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The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
Synonyms
selenoprotein p, phgpx, glutathione peroxidase 4, phospholipid hydroperoxide glutathione peroxidase, gpx-4, glutathione peroxidase-4, npgpx, selenoperoxidase, gpx4b, gpx4a, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glutathione peroxidase 4
-
-
hydroperoxide glutathione peroxidase
-
-
-
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nPHGPx
-
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peroxidation-inhibiting protein
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-
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peroxidation-inhibiting protein: peroxidase, glutathione (phospholipid hydroperoxide-reducing)
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-
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PHGPX
phospholipid hydroperoxide glutathione peroxidase
sperm nucleus-specific glutathione peroxidase
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-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
redox reaction
-
-
-
-
oxidation
reduction
PATHWAY SOURCE
PATHWAYS
-
-, -, -, -, -, -, -, -, -, -, -
SYSTEMATIC NAME
IUBMB Comments
glutathione:lipid-hydroperoxide oxidoreductase
A protein containing a selenocysteine residue. The products of action of EC 1.13.11.12 lipoxygenase on phospholipids can act as acceptors; H2O2 can also act, but much more slowly (cf. EC 1.11.1.9 glutathione peroxidase).
CAS REGISTRY NUMBER
COMMENTARY hide
97089-70-8
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
2 glutathione + a hydroperoxy-fatty-acyl-[lipid]
glutathione disulfide + a hydroxy-fatty-acyl-[lipid] + H2O
show the reaction diagram
-
-
-
?
glutathione + a lipid hydroperoxide
glutathione disulfide + lipid + H2O
show the reaction diagram
-
-
-
-
?
glutathione + L-alpha-phosphatidylcholine hydroperoxide
?
show the reaction diagram
L-alpha-phosphatidylcholine hydroperoxide is a specific substrate of GPx4
-
-
?
glutathione + lipid hydroperoxide
glutathione disulfide + lipid + H2O
show the reaction diagram
-
-
-
-
?
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
2 glutathione + a hydroperoxy-fatty-acyl-[lipid]
glutathione disulfide + a hydroxy-fatty-acyl-[lipid] + H2O
show the reaction diagram
-
-
-
?
glutathione + a lipid hydroperoxide
glutathione disulfide + lipid + H2O
show the reaction diagram
-
-
-
-
?
additional information
?
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-
PHGPx-/- mice are embryonically lethal at gestation day 7.5. PHGPx+/- mice cells show decreased life span after exposure to irradiation and increased susceptibility to oxidative and genotoxic stress
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-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
glutathione
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-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
selenium
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-
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(1S,3R)-RSL3
disrupts mitochondrial morphology and provokes strong mitochondrial impairment
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RSL3
a selective GPx4 inhibitor, mediates concentration-dependent inhibition of GPX4, lipid peroxidation, enhanced mitochondrial fragmentation, loss of mitochondrial membrane potential, and reduced mitochondrial respiration. Ferroptosis inhibitors, such as deferoxamine, ferrostatin-1 and liproxstatin-1, but also CRISPR/Cas9 Bid knockout and the BID inhibitor BI-6c9 protect against RSL3 toxicity. Cell toxicity of the different RSL3 isomers in HT22 wild-type cells, overview
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
mouse embryonic fibroblasts
Manually annotated by BRENDA team
PHGPx expression is tightly regulated in pachytene spermatocytes, with any spatial-temporal increase in PHGPx expression resulting in damage to spermatogenesis and eventual loss of haploid cells
Manually annotated by BRENDA team
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smooth muscle cells
Manually annotated by BRENDA team
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-
Manually annotated by BRENDA team
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white matter
Manually annotated by BRENDA team
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keratinized surface epithelium
Manually annotated by BRENDA team
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pituicytes
Manually annotated by BRENDA team
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-
Manually annotated by BRENDA team
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of arteries
Manually annotated by BRENDA team
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parafollicular cells and follicular basement membrane
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
transgenic mice in which PHGPx is overexpressed solely in the mitochondrion. Mitochondria-specific GPx4 overexpression protects cardiac contractile function and preserves electron transport chain complex activities following ischemia/reperfusion
Manually annotated by BRENDA team
additional information
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
ferroptosis is an oxidative form of regulated necrotic cell death featuring glutathione (GSH) depletion, disrupted glutathione peroxidase-4 (GPX4) redox defense and detrimental lipid reactive oxygen species (ROS) formation. Mitochondrial damage in models of oxidative glutamate toxicity, glutathione peroxidase depletion, and ferroptosis. (1S,3R)-RSL3, a selective GPx4 inhibitor, mediates concentration-dependent inhibition of GPX4, lipid peroxidation, enhanced mitochondrial fragmentation, loss of mitochondrial membrane potential, and reduced mitochondrial respiration. Ferroptosis inhibitors, such as deferoxamine, ferrostatin-1 and liproxstatin-1, but also CRISPR/Cas9 Bid knockout and the BID inhibitor BI-6c9 protect against RSL3 toxicity. The mitochondria-targeted ROS scavenger mitoquinone (MitoQ) preserves mitochondrial integrity and function, and cell viability despite significant loss of GPX4 expression and associated increases in general lipid peroxidation after exposure to RSL3. BID inhibitor BI-6c9 and ferroptosis inhibitors abrogate 1S, 3R-RSL3 induced cell death, phenotypes, overview
metabolism
mitochondrial rescue prevents glutathione peroxidase-dependent ferroptosis
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
GPX4_MOUSE
197
0
22229
Swiss-Prot
Secretory Pathway (Reliability: 4)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
20000
-
-
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
1 * 20000, calculated, GPx4 is monomeric in solution under reducing conditions, small-angle X-ray scattering
monomer
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structure of the selenocysteine 46 to cysteine mutant, residues Met1 to Leu170, to 1.8 A resolution
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
U46C
selenocysteine 46 to cysteine mutant, crystallization data
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
production of a transgenic mouse line overexpressing mPHGPx in the testis during the prophase of the first meiotic division, when the endogenous mPHGPx level is markedly lower than in the postmeiotic phase. Such mPHGPx overexpression is associated with male germ apoptosis, seminiferous tubule disorganization and reduced fertility
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
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MPHGPx transgenic mice made diabetic by multiple low-dose streptozotocin injections show decreased ejection fraction and fractional shortening in diabetic hearts that is reversed with hydroperoxide glutathione peroxidase mPHDPx4 overexpression. MPHGPx overexpression increases electron transport chain function while attenuating hydrogen peroxide production and lipid peroxidation in diabetic mPHGPx interfibrillar mitochondria. mPHGPx overexpression lessens proteomic loss observed in diabetic interfibrillar mitochondria. Posttranslational modifications, including oxidations and deamidations, are attenuated with mPHGPx overexpression. Mitochondrial protein import dysfunction in diabetic interfibrillar mitochondria is reversed with mPHGPx overexpression correlating with protein import constituent preservation. Oxidative phosphorylation, tricarboxylic acid cycle, and fatty acid oxidation processes most influenced in diabetic interfibrillar mitochondria are preserved by mPHGPx overexpression
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Schneider, M.; Vogt Weisenhorn, D.M.; Seiler, A.; Bornkamm, G.W.; Brielmeier, M.; Conrad, M.
Embryonic expression profile of phospholipid hydroperoxide glutathione peroxidase
Gene Expr. Patterns
6
489-494
2006
Mus musculus
Manually annotated by BRENDA team
Imai, H.; Saito, M.; Kirai, N.; Hasegawa, J.; Konishi, K.; Hattori, H.; Nishimura, M.; Naito, S.; Nakagawa, Y.
Identification of the positive regulatory and distinct core regions of promoters, and transcriptional regulation in three types of mouse phospholipid hydroperoxide glutathione peroxidase
J. Biochem.
140
573-590
2006
Mus musculus
Manually annotated by BRENDA team
Borchert, A.; Wang, C.C.; Ufer, C.; Schiebel, H.; Savaskan, N.E.; Kuhn, H.
The role of phospholipid hydroperoxide glutathione peroxidase isoforms in murine embryogenesis
J. Biol. Chem.
281
19655-19664
2006
Mus musculus
Manually annotated by BRENDA team
Conrad, M.; Moreno, S.G.; Sinowatz, F.; Ursini, F.; Koelle, S.; Roveri, A.; Brielmeier, M.; Wurst, W.; Maiorino, M.; Bornkamm, G.W.
The nuclear form of phospholipid hydroperoxide glutathione peroxidase is a protein thiol peroxidase contributing to sperm chromatin stability
Mol. Cell. Biol.
25
7637-7644
2005
Mus musculus
Manually annotated by BRENDA team
Conrad, M.; Schneider, M.; Seiler, A.; Bornkamm, G.W.
Physiological role of phospholipid hydroperoxide glutathione peroxidase in mammals
Biol. Chem.
388
1019-1025
2007
Homo sapiens, Mus musculus, Rattus norvegicus, Sus scrofa
Manually annotated by BRENDA team
Puglisi, R.; Bevilacqua, A.; Carlomagno, G.; Lenzi, A.; Gandini, L.; Stefanini, M.; Mangia, F.; Boitani, C.
Mice overexpressing the mitochondrial phospholipid hydroperoxide glutathione peroxidase in male germ cells show abnormal spermatogenesis and reduced fertility
Endocrinology
148
4302-4309
2007
Mus musculus (O70325), Mus musculus
Manually annotated by BRENDA team
Dabkowski, E.R.; Williamson, C.L.; Hollander, J.M.
Mitochondria-specific transgenic overexpression of phospholipid hydroperoxide glutathione peroxidase (GPx4) attenuates ischemia/reperfusion-associated cardiac dysfunction
Free Radic. Biol. Med.
45
855-865
2008
Mus musculus, Mus musculus (O70325)
Manually annotated by BRENDA team
Baek, I.J.; Seo, D.S.; Yon, J.M.; Lee, S.R.; Jin, Y.; Nahm, S.S.; Jeong, J.H.; Choo, Y.K.; Kang, J.K.; Lee, B.J.; Yun, Y.W.; Nam, S.Y.
Tissue expression and cellular localization of phospholipid hydroperoxide glutathione peroxidase (PHGPx) mRNA in male mice
J. Mol. Histol.
38
237-244
2007
Mus musculus
Manually annotated by BRENDA team
Conrad, M.
Transgenic mouse models for the vital selenoenzymes cytosolic thioredoxin reductase, mitochondrial thioredoxin reductase and glutathione peroxidase 4
Biochim. Biophys. Acta
1790
1575-1585
2009
Mus musculus
Manually annotated by BRENDA team
Baseler, W.A.; Dabkowski, E.R.; Jagannathan, R.; Thapa, D.; Nichols, C.E.; Shepherd, D.L.; Croston, T.L.; Powell, M.; Razunguzwa, T.T.; Lewis, S.E.; Schnell, D.M.; Hollander, J.M.
Reversal of mitochondrial proteomic loss in Type 1 diabetic heart with overexpression of phospholipid hydroperoxide glutathione peroxidase
Am. J. Physiol. Regul. Integr. Comp. Physiol.
304
R553-R565
2013
Mus musculus
Manually annotated by BRENDA team
Janowski, R.; Scanu, S.; Niessing, D.; Madl, T.
Crystal and solution structural studies of mouse phospholipid hydroperoxide glutathione peroxidase 4
Acta Crystallogr. Sect. F
72
743-749
2016
Mus musculus (O70325), Mus musculus
Manually annotated by BRENDA team
Jelinek, A.; Heyder, L.; Daude, M.; Plessner, M.; Krippner, S.; Grosse, R.; Diederich, W.E.; Culmsee, C.
Mitochondrial rescue prevents glutathione peroxidase-dependent ferroptosis
Free Radic. Biol. Med.
117
45-57
2018
Mus musculus (O70325), Mus musculus
Manually annotated by BRENDA team