GPX4_PIG
ID GPX4_PIG Reviewed; 197 AA.
AC P36968;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 26-FEB-2008, sequence version 3.
DT 03-AUG-2022, entry version 145.
DE RecName: Full=Phospholipid hydroperoxide glutathione peroxidase {ECO:0000303|PubMed:2386798, ECO:0000303|PubMed:8135530};
DE Short=PHGPx {ECO:0000303|PubMed:2386798, ECO:0000303|PubMed:8135530};
DE EC=1.11.1.12 {ECO:0000269|PubMed:2386798, ECO:0000269|PubMed:3978121, ECO:0000269|PubMed:8135530, ECO:0000269|PubMed:8617728};
DE AltName: Full=Glutathione peroxidase 4 {ECO:0000250|UniProtKB:O70325};
DE Short=GPx-4 {ECO:0000250|UniProtKB:O70325};
DE Short=GSHPx-4 {ECO:0000250|UniProtKB:O70325};
DE Flags: Precursor;
GN Name=GPX4 {ECO:0000250|UniProtKB:O70325};
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS MITOCHONDRIAL AND CYTOPLASMIC).
RX PubMed=8323565; DOI=10.1006/bbrc.1993.1711;
RA Sunde R.A., Dyer J.A., Moran T., Evenson J.K., Sugimoto M.;
RT "Phospholipid hydroperoxide glutathione peroxidase: full-length pig
RT blastocyst cDNA sequence and regulation by selenium status.";
RL Biochem. Biophys. Res. Commun. 193:905-911(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM CYTOPLASMIC), AND PARTIAL
RP PROTEIN SEQUENCE.
RC TISSUE=Heart, and Liver;
RX PubMed=8125951; DOI=10.1016/s0021-9258(17)37290-3;
RA Brigelius-Flohe R., Aumann K.-D., Bloecker H., Gross G., Kloeppel K.-D.,
RA Maiorino M., Roveri A., Schuckelt R., Ursini F., Wingender E., Flohe L.;
RT "Phospholipid-hydroperoxide glutathione peroxidase. Genomic DNA, cDNA, and
RT deduced amino acid sequence.";
RL J. Biol. Chem. 269:7342-7348(1994).
RN [3]
RP SEQUENCE REVISION TO 73.
RA Flohe L.;
RL Submitted (DEC-2010) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 40-197 (ISOFORM MITOCHONDRIAL), AND PARTIAL
RP PROTEIN SEQUENCE.
RC TISSUE=Heart;
RX PubMed=1778506; DOI=10.3109/10715769109093424;
RA Schuckelt R., Brigelius-Flohe R., Maiorino M., Roveri A., Reumkens J.,
RA Strassburger W., Ursini F., Wolf B., Flohe L.;
RT "Phospholipid hydroperoxide glutathione peroxidase is a selenoenzyme
RT distinct from the classical glutathione peroxidase as evident from cDNA and
RT amino acid sequencing.";
RL Free Radic. Res. Commun. 14:343-361(1991).
RN [5]
RP CATALYTIC ACTIVITY, SUBUNIT, AND SELENOCYSTEINE.
RC TISSUE=Heart;
RX PubMed=3978121; DOI=10.1016/0304-4165(85)90182-5;
RA Ursini F., Maiorino M., Gregolin C.;
RT "The selenoenzyme phospholipid hydroperoxide glutathione peroxidase.";
RL Biochim. Biophys. Acta 839:62-70(1985).
RN [6]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=2386798; DOI=10.1016/0005-2760(90)90128-k;
RA Thomas J.P., Geiger P.G., Maiorino M., Ursini F., Girotti A.W.;
RT "Enzymatic reduction of phospholipid and cholesterol hydroperoxides in
RT artificial bilayers and lipoproteins.";
RL Biochim. Biophys. Acta 1045:252-260(1990).
RN [7]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=8135530; DOI=10.1006/abbi.1994.1105;
RA Sattler W., Maiorino M., Stocker R.;
RT "Reduction of HDL- and LDL-associated cholesterylester and phospholipid
RT hydroperoxides by phospholipid hydroperoxide glutathione peroxidase and
RT Ebselen (PZ 51).";
RL Arch. Biochem. Biophys. 309:214-221(1994).
RN [8]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=8617728; DOI=10.1074/jbc.271.9.4653;
RA Schnurr K., Belkner J., Ursini F., Schewe T., Kuehn H.;
RT "The selenoenzyme phospholipid hydroperoxide glutathione peroxidase
RT controls the activity of the 15-lipoxygenase with complex substrates and
RT preserves the specificity of the oxygenation products.";
RL J. Biol. Chem. 271:4653-4658(1996).
CC -!- FUNCTION: Essential antioxidant peroxidase that directly reduces
CC phospholipid hydroperoxide even if they are incorporated in membranes
CC and lipoproteins (PubMed:3978121, PubMed:2386798, PubMed:8135530). Can
CC also reduce fatty acid hydroperoxide, cholesterol hydroperoxide and
CC thymine hydroperoxide (PubMed:8135530, PubMed:2386798, PubMed:3978121).
CC Plays a key role in protecting cells from oxidative damage by
CC preventing membrane lipid peroxidation (By similarity). Required to
CC prevent cells from ferroptosis, a non-apoptotic cell death resulting
CC from an iron-dependent accumulation of lipid reactive oxygen species
CC (By similarity). The presence of selenocysteine (Sec) versus Cys at the
CC active site is essential for life: it provides resistance to
CC overoxidation and prevents cells against ferroptosis (By similarity).
CC The presence of Sec at the active site is also essential for the
CC survival of a specific type of parvalbumin-positive interneurons,
CC thereby preventing against fatal epileptic seizures (By similarity).
CC May be required to protect cells from the toxicity of ingested lipid
CC hydroperoxides (By similarity). Required for normal sperm development
CC and male fertility (By similarity). Essential for maturation and
CC survival of photoreceptor cells (By similarity). Plays a role in a
CC primary T-cell response to viral and parasitic infection by protecting
CC T-cells from ferroptosis and by supporting T-cell expansion (By
CC similarity). Plays a role of glutathione peroxidase in platelets in the
CC arachidonic acid metabolism (By similarity). Reduces hydroperoxy ester
CC lipids formed by a 15-lipoxygenase that may play a role as down-
CC regulator of the cellular 15-lipoxygenase pathway (PubMed:8617728).
CC {ECO:0000250|UniProtKB:O70325, ECO:0000250|UniProtKB:P36969,
CC ECO:0000269|PubMed:2386798, ECO:0000269|PubMed:3978121,
CC ECO:0000269|PubMed:8135530, ECO:0000269|PubMed:8617728}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a hydroperoxy polyunsaturated fatty acid + 2 glutathione = a
CC hydroxy polyunsaturated fatty acid + glutathione disulfide + H2O;
CC Xref=Rhea:RHEA:19057, ChEBI:CHEBI:15377, ChEBI:CHEBI:57925,
CC ChEBI:CHEBI:58297, ChEBI:CHEBI:131871, ChEBI:CHEBI:134019;
CC EC=1.11.1.12; Evidence={ECO:0000269|PubMed:2386798,
CC ECO:0000269|PubMed:3978121, ECO:0000269|PubMed:8135530,
CC ECO:0000269|PubMed:8617728};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19058;
CC Evidence={ECO:0000305|PubMed:8617728};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(13S)-hydroperoxy-(9Z,11E)-octadecadienoate + 2 glutathione =
CC (13S)-hydroxy-(9Z,11E)-octadecadienoate + glutathione disulfide +
CC H2O; Xref=Rhea:RHEA:48888, ChEBI:CHEBI:15377, ChEBI:CHEBI:57466,
CC ChEBI:CHEBI:57925, ChEBI:CHEBI:58297, ChEBI:CHEBI:90850;
CC Evidence={ECO:0000269|PubMed:8617728};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48889;
CC Evidence={ECO:0000305|PubMed:8617728};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(12S)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate + 2
CC glutathione = (12S)-hydroxy-(5Z,8Z,10E,14Z)-eicosatetraenoate +
CC glutathione disulfide + H2O; Xref=Rhea:RHEA:50708, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:57444, ChEBI:CHEBI:57925, ChEBI:CHEBI:58297,
CC ChEBI:CHEBI:90680; Evidence={ECO:0000250|UniProtKB:P36969};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50709;
CC Evidence={ECO:0000250|UniProtKB:P36969};
CC -!- SUBUNIT: Monomer (PubMed:3978121). Has a tendency to form higher mass
CC oligomers (By similarity). {ECO:0000250|UniProtKB:P36969,
CC ECO:0000269|PubMed:3978121}.
CC -!- SUBCELLULAR LOCATION: [Isoform Mitochondrial]: Mitochondrion
CC {ECO:0000250|UniProtKB:O70325}.
CC -!- SUBCELLULAR LOCATION: [Isoform Cytoplasmic]: Cytoplasm
CC {ECO:0000250|UniProtKB:O70325}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Name=Mitochondrial;
CC IsoId=P36968-1; Sequence=Displayed;
CC Name=Cytoplasmic;
CC IsoId=P36968-2; Sequence=VSP_018744;
CC -!- SIMILARITY: Belongs to the glutathione peroxidase family.
CC {ECO:0000305}.
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DR EMBL; L12743; AAA31098.2; -; mRNA.
DR EMBL; L12743; AAA31099.2; -; mRNA.
DR EMBL; X76008; CAA53595.2; -; Genomic_DNA.
DR EMBL; X76009; CAA53596.2; -; mRNA.
DR EMBL; S80257; AAB21327.2; -; mRNA.
DR PIR; JN0608; JN0608.
DR RefSeq; NP_999572.1; NM_214407.1. [P36968-1]
DR STRING; 9823.ENSSSCP00000021702; -.
DR SwissLipids; SLP:000001475; -.
DR PeroxiBase; 3723; SscGPx04.
DR PaxDb; P36968; -.
DR PeptideAtlas; P36968; -.
DR PRIDE; P36968; -.
DR Ensembl; ENSSSCT00000051893; ENSSSCP00000046912; ENSSSCG00000024052. [P36968-1]
DR Ensembl; ENSSSCT00030021984; ENSSSCP00030009935; ENSSSCG00030015859. [P36968-1]
DR Ensembl; ENSSSCT00040076156; ENSSSCP00040032715; ENSSSCG00040056197. [P36968-1]
DR Ensembl; ENSSSCT00045060762; ENSSSCP00045042685; ENSSSCG00045035370. [P36968-1]
DR Ensembl; ENSSSCT00050085532; ENSSSCP00050036727; ENSSSCG00050062797. [P36968-1]
DR Ensembl; ENSSSCT00060023935; ENSSSCP00060010026; ENSSSCG00060017858. [P36968-1]
DR GeneID; 399537; -.
DR KEGG; ssc:399537; -.
DR CTD; 2879; -.
DR eggNOG; KOG1651; Eukaryota.
DR GeneTree; ENSGT00940000161913; -.
DR HOGENOM; CLU_2782607_0_0_1; -.
DR InParanoid; P36968; -.
DR OMA; FPMMSKI; -.
DR OrthoDB; 1483113at2759; -.
DR Reactome; R-SSC-2142712; Synthesis of 12-eicosatetraenoic acid derivatives.
DR Reactome; R-SSC-2142770; Synthesis of 15-eicosatetraenoic acid derivatives.
DR Reactome; R-SSC-9018676; Biosynthesis of D-series resolvins.
DR Reactome; R-SSC-9018896; Biosynthesis of E-series 18(S)-resolvins.
DR Reactome; R-SSC-9020265; Biosynthesis of aspirin-triggered D-series resolvins.
DR Reactome; R-SSC-9023661; Biosynthesis of E-series 18(R)-resolvins.
DR Proteomes; UP000008227; Chromosome 2.
DR Proteomes; UP000314985; Unplaced.
DR Bgee; ENSSSCG00000024052; Expressed in testis and 46 other tissues.
DR Genevisible; P36968; SS.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR GO; GO:0005635; C:nuclear envelope; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0032991; C:protein-containing complex; IEA:Ensembl.
DR GO; GO:0004602; F:glutathione peroxidase activity; IBA:GO_Central.
DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
DR GO; GO:0004601; F:peroxidase activity; IBA:GO_Central.
DR GO; GO:0047066; F:phospholipid-hydroperoxide glutathione peroxidase activity; IDA:UniProtKB.
DR GO; GO:0019369; P:arachidonic acid metabolic process; ISS:UniProtKB.
DR GO; GO:0006325; P:chromatin organization; IEA:Ensembl.
DR GO; GO:0019372; P:lipoxygenase pathway; ISS:UniProtKB.
DR GO; GO:0110076; P:negative regulation of ferroptosis; ISS:UniProtKB.
DR GO; GO:0051258; P:protein polymerization; IEA:Ensembl.
DR GO; GO:0006979; P:response to oxidative stress; IDA:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; ISS:UniProtKB.
DR CDD; cd00340; GSH_Peroxidase; 1.
DR InterPro; IPR000889; Glutathione_peroxidase.
DR InterPro; IPR029759; GPX_AS.
DR InterPro; IPR029760; GPX_CS.
DR InterPro; IPR036249; Thioredoxin-like_sf.
DR PANTHER; PTHR11592; PTHR11592; 1.
DR Pfam; PF00255; GSHPx; 1.
DR PIRSF; PIRSF000303; Glutathion_perox; 1.
DR PRINTS; PR01011; GLUTPROXDASE.
DR SUPFAM; SSF52833; SSF52833; 1.
DR PROSITE; PS00460; GLUTATHIONE_PEROXID_1; 1.
DR PROSITE; PS00763; GLUTATHIONE_PEROXID_2; 1.
DR PROSITE; PS51355; GLUTATHIONE_PEROXID_3; 1.
PE 1: Evidence at protein level;
KW Alternative initiation; Cytoplasm; Developmental protein;
KW Direct protein sequencing; Lipid metabolism; Mitochondrion; Oxidoreductase;
KW Peroxidase; Phosphoprotein; Reference proteome; Selenocysteine;
KW Transit peptide.
FT TRANSIT 1..?
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN ?..197
FT /note="Phospholipid hydroperoxide glutathione peroxidase"
FT /id="PRO_0000013071"
FT ACT_SITE 73
FT /evidence="ECO:0000269|PubMed:3978121"
FT NON_STD 73
FT /note="Selenocysteine"
FT /evidence="ECO:0000269|PubMed:3978121"
FT MOD_RES 40
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P36970"
FT VAR_SEQ 1..27
FT /note="Missing (in isoform Cytoplasmic)"
FT /evidence="ECO:0000303|PubMed:8125951,
FT ECO:0000303|PubMed:8323565"
FT /id="VSP_018744"
SQ SEQUENCE 197 AA; 22337 MW; 34865B0BEBFA69D0 CRC64;
MSFSRLFRLL KPTLLCGTLA VPGLAGTMCA SRDDWRCARS MHEFSAKDID GHMVNLDKYR
GYVCIVTNVA SQUGKTEVNY TQLVDLHARY AECGLRILAF PCNQFGRQEP GSDAEIKEFA
AGYNVKFDMF SKICVNGDDA HPLWKWMKVQ PKGRGMLGNA IKWNFTKFLI DKNGCVVKRY
GPMEEPQVIE KDLPCYL
