ID GPX4_HUMAN Reviewed; 197 AA. AC P36969; O43381; Q6PJ59; Q9UPK2; DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot. DT 26-FEB-2008, sequence version 3. DT 27-MAR-2024, entry version 225. DE RecName: Full=Phospholipid hydroperoxide glutathione peroxidase GPX4 {ECO:0000303|PubMed:36608588}; DE Short=PHGPx; DE EC=1.11.1.12 {ECO:0000269|PubMed:11115402, ECO:0000269|PubMed:36608588}; DE AltName: Full=Glutathione peroxidase 4 {ECO:0000303|PubMed:9705830}; DE Short=GPx-4 {ECO:0000303|PubMed:9705830}; DE Short=GSHPx-4 {ECO:0000303|PubMed:9705830}; DE EC=1.11.1.9 {ECO:0000269|PubMed:36608588}; DE Flags: Precursor; GN Name=GPX4 {ECO:0000303|PubMed:9705830, ECO:0000312|HGNC:HGNC:4556}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Testis; RX PubMed=8039723; DOI=10.1016/0378-1119(94)90400-6; RA Esworthy R.S., Doan K., Doroshow J.H., Chu F.-F.; RT "Cloning and sequencing of the cDNA encoding a human testis phospholipid RT hydroperoxide glutathione peroxidase."; RL Gene 144:317-318(1994). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND TISSUE SPECIFICITY. RX PubMed=9705830; DOI=10.1006/bbrc.1998.9086; RA Kelner M.J., Montoya M.A.; RT "Structural organization of the human selenium-dependent phospholipid RT hydroperoxide glutathione peroxidase gene (GPX4): chromosomal localization RT to 19p13.3."; RL Biochem. Biophys. Res. Commun. 249:53-55(1998). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ASN-2. RG NIEHS SNPs program; RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A., RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, Eye, Lung, Pancreas, and Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP FUNCTION, CATALYTIC ACTIVITY, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=11115402; RA Sutherland M., Shankaranarayanan P., Schewe T., Nigam S.; RT "Evidence for the presence of phospholipid hydroperoxide glutathione RT peroxidase in human platelets: implications for its involvement in the RT regulatory network of the 12-lipoxygenase pathway of arachidonic acid RT metabolism."; RL Biochem. J. 353:91-100(2001). RN [7] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [8] RP FUNCTION. RX PubMed=24439385; DOI=10.1016/j.cell.2013.12.010; RA Yang W.S., SriRamaratnam R., Welsch M.E., Shimada K., Skouta R., RA Viswanathan V.S., Cheah J.H., Clemons P.A., Shamji A.F., Clish C.B., RA Brown L.M., Girotti A.W., Cornish V.W., Schreiber S.L., Stockwell B.R.; RT "Regulation of ferroptotic cancer cell death by GPX4."; RL Cell 156:317-331(2014). RN [9] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [11] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=36608588; DOI=10.1016/j.redox.2022.102593; RA Schwarz M., Loeser A., Cheng Q., Wichmann-Costaganna M., Schaedel P., RA Werz O., Arner E.S., Kipp A.P.; RT "Side-by-side comparison of recombinant human glutathione peroxidases RT identifies overlapping substrate specificities for soluble RT hydroperoxides."; RL Redox Biol. 59:102593-102593(2023). RN [12] RP INTERACTION WITH FUNDC1. RX PubMed=36828120; DOI=10.1016/j.jare.2023.02.012; RA Bi Y., Liu S., Qin X., Abudureyimu M., Wang L., Zou R., Ajoolabady A., RA Zhang W., Peng H., Ren J., Zhang Y.; RT "FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic RT injury through a mitophagy-dependent manner."; RL J. Adv. Res. 0:0-0(2023). RN [13] RP X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) OF 29-197 (ISOFORM CYTOPLASMIC), RP SUBUNIT, MUTAGENESIS OF SEC-73, FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=17630701; DOI=10.1021/bi700840d; RA Scheerer P., Borchert A., Krauss N., Wessner H., Gerth C., Hoehne W., RA Kuhn H.; RT "Structural basis for catalytic activity and enzyme polymerization of RT phospholipid hydroperoxide glutathione peroxidase-4 (GPx4)."; RL Biochemistry 46:9041-9049(2007). RN [14] RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 36-197. RG Structural genomics consortium (SGC); RT "Crystal structure of the selenocysteine to glycine mutant of human RT glutathione peroxidase 4 (GPX4)."; RL Submitted (FEB-2009) to the PDB data bank. RN [15] {ECO:0007744|PDB:5H5Q, ECO:0007744|PDB:5H5R, ECO:0007744|PDB:5H5S} RP X-RAY CRYSTALLOGRAPHY (1.10 ANGSTROMS) OF 29-197 OF MUTANT CYS-73. RX PubMed=27836545; DOI=10.1016/j.bbrc.2016.11.035; RA Sakamoto K., Sogabe S., Kamada Y., Matsumoto S.I., Kadotani A., RA Sakamoto J.I., Tani A.; RT "Discovery of GPX4 inhibitory peptides from random peptide T7 phage display RT and subsequent structural analysis."; RL Biochem. Biophys. Res. Commun. 482:195-201(2017). RN [16] RP VARIANTS ASN-2 AND THR-120. RX PubMed=12606444; DOI=10.1095/biolreprod.102.007500; RA Maiorino M., Bosello V., Ursini F., Foresta C., Garolla A., Scapin M., RA Sztajer H., Flohe L.; RT "Genetic variations of gpx-4 and male infertility in humans."; RL Biol. Reprod. 68:1134-1141(2003). RN [17] RP VARIANT SMDS 90-TYR--PHE-197 DEL, AND INVOLVEMENT IN SMDS. RX PubMed=24706940; DOI=10.1136/jmedgenet-2013-102218; RG FORGE Canada Consortium; RA Smith A.C., Mears A.J., Bunker R., Ahmed A., MacKenzie M., RA Schwartzentruber J.A., Beaulieu C.L., Ferretti E., Majewski J., RA Bulman D.E., Celik F.C., Boycott K.M., Graham G.E.; RT "Mutations in the enzyme glutathione peroxidase 4 cause Sedaghatian-type RT spondylometaphyseal dysplasia."; RL J. Med. Genet. 51:470-474(2014). CC -!- FUNCTION: Essential antioxidant peroxidase that directly reduces CC phospholipid hydroperoxide even if they are incorporated in membranes CC and lipoproteins (By similarity). Can also reduce cholesterol CC hydroperoxide and thymine hydroperoxide (By similarity). Plays a key CC role in protecting cells from oxidative damage by preventing membrane CC lipid peroxidation (By similarity). Required to prevent cells from CC ferroptosis, a non-apoptotic cell death resulting from an iron- CC dependent accumulation of lipid reactive oxygen species CC (PubMed:24439385). The presence of selenocysteine (Sec) versus Cys at CC the 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 (PubMed:11115402). Reduces hydroperoxy CC ester lipids formed by a 15-lipoxygenase that may play a role as down- CC regulator of the cellular 15-lipoxygenase pathway (By similarity). Can CC reduce fatty acid-derived hydroperoxides (PubMed:11115402, CC PubMed:36608588). Can also reduce small soluble hydroperoxides such as CC H2O2, cumene hydroperoxide and tert-butyl hydroperoxide CC (PubMed:36608588, PubMed:17630701). {ECO:0000250|UniProtKB:O70325, CC ECO:0000250|UniProtKB:P36968, ECO:0000269|PubMed:11115402, CC ECO:0000269|PubMed:17630701, ECO:0000269|PubMed:24439385, CC ECO:0000269|PubMed:36608588}. 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:11115402, CC ECO:0000269|PubMed:36608588}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19058; CC Evidence={ECO:0000305|PubMed:36608588}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2 glutathione + H2O2 = glutathione disulfide + 2 H2O; CC Xref=Rhea:RHEA:16833, ChEBI:CHEBI:15377, ChEBI:CHEBI:16240, CC ChEBI:CHEBI:57925, ChEBI:CHEBI:58297; EC=1.11.1.9; CC Evidence={ECO:0000269|PubMed:36608588}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16834; CC Evidence={ECO:0000269|PubMed:36608588}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2 glutathione + tert-butyl hydroperoxide = glutathione CC disulfide + H2O + tert-butanol; Xref=Rhea:RHEA:69412, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:45895, ChEBI:CHEBI:57925, CC ChEBI:CHEBI:58297, ChEBI:CHEBI:64090; CC Evidence={ECO:0000269|PubMed:17630701, ECO:0000269|PubMed:36608588}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:69413; CC Evidence={ECO:0000269|PubMed:36608588}; CC -!- CATALYTIC ACTIVITY: CC Reaction=cumene hydroperoxide + 2 glutathione = 2-phenylpropan-2-ol + CC glutathione disulfide + H2O; Xref=Rhea:RHEA:69651, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:57925, ChEBI:CHEBI:58297, ChEBI:CHEBI:78673, CC ChEBI:CHEBI:131607; Evidence={ECO:0000269|PubMed:36608588}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:69652; CC Evidence={ECO:0000269|PubMed:36608588}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(9S)-hydroperoxy-(10E,12Z)-octadecadienoate + 2 glutathione = CC (9S)-hydroxy-(10E,12Z)-octadecadienoate + glutathione disulfide + CC H2O; Xref=Rhea:RHEA:76687, ChEBI:CHEBI:15377, ChEBI:CHEBI:57925, CC ChEBI:CHEBI:58297, ChEBI:CHEBI:60955, ChEBI:CHEBI:77852; CC Evidence={ECO:0000269|PubMed:36608588}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76688; CC Evidence={ECO:0000305|PubMed:36608588}; 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:36608588}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48889; CC Evidence={ECO:0000305|PubMed:36608588}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(5S)-hydroperoxy-(6E,8Z,11Z,14Z)-eicosatetraenoate + 2 CC glutathione = (5S)-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoate + CC glutathione disulfide + H2O; Xref=Rhea:RHEA:48620, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:57450, ChEBI:CHEBI:57925, ChEBI:CHEBI:58297, CC ChEBI:CHEBI:90632; Evidence={ECO:0000269|PubMed:36608588}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48621; CC Evidence={ECO:0000305|PubMed:36608588}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(12R)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate + 2 CC glutathione = (12R)-hydroxy-(5Z,8Z,10E,14Z)-eicosatetraenoate + CC glutathione disulfide + H2O; Xref=Rhea:RHEA:76691, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:57925, ChEBI:CHEBI:58297, ChEBI:CHEBI:75230, CC ChEBI:CHEBI:83343; Evidence={ECO:0000269|PubMed:36608588}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76692; CC Evidence={ECO:0000305|PubMed:36608588}; 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:0000269|PubMed:11115402, CC ECO:0000269|PubMed:36608588}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50709; CC Evidence={ECO:0000305|PubMed:11115402}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate + 2 CC glutathione = (15S)-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoate + CC glutathione disulfide + H2O; Xref=Rhea:RHEA:76695, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:57409, ChEBI:CHEBI:57446, ChEBI:CHEBI:57925, CC ChEBI:CHEBI:58297; Evidence={ECO:0000269|PubMed:36608588}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76696; CC Evidence={ECO:0000305|PubMed:36608588}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(5S)-hydroperoxy-(6E,8Z,11Z,14Z,17Z)-eicosapentaenoate + 2 CC glutathione = (5S)-hydroxy-(6E,8Z,11Z,14Z,17Z)-eicosapentaenoate + CC glutathione disulfide + H2O; Xref=Rhea:RHEA:76699, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:57925, ChEBI:CHEBI:58297, ChEBI:CHEBI:195399, CC ChEBI:CHEBI:195400; Evidence={ECO:0000269|PubMed:36608588}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76700; CC Evidence={ECO:0000305|PubMed:36608588}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(12S)-hydroperoxy-(5Z,8Z,10E,14Z,17Z)-eicosapentaenoate + 2 CC glutathione = (12S)-hydroxy-(5Z,8Z,10E,14Z,17Z)-eicosapentaenoate + CC glutathione disulfide + H2O; Xref=Rhea:RHEA:76703, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:57925, ChEBI:CHEBI:58297, ChEBI:CHEBI:90772, CC ChEBI:CHEBI:195401; Evidence={ECO:0000269|PubMed:36608588}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76704; CC Evidence={ECO:0000305|PubMed:36608588}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(15S)-hydroperoxy-(5Z,8Z,11Z,13E,17Z)-eicosapentaenoate + 2 CC glutathione = (15S)-hydroxy-(5Z,8Z,11Z,13E,17Z)-eicosapentaenoate + CC glutathione disulfide + H2O; Xref=Rhea:RHEA:76707, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:57925, ChEBI:CHEBI:58297, ChEBI:CHEBI:132087, CC ChEBI:CHEBI:194369; Evidence={ECO:0000269|PubMed:36608588}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76708; CC Evidence={ECO:0000305|PubMed:36608588}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(15S)-hydroperoxy-(11Z,13E)-eicosadienoate + 2 glutathione = CC (15S)-hydroxy-(11Z,13E)-eicosadienoate + glutathione disulfide + H2O; CC Xref=Rhea:RHEA:76711, ChEBI:CHEBI:15377, ChEBI:CHEBI:57925, CC ChEBI:CHEBI:58297, ChEBI:CHEBI:144832, ChEBI:CHEBI:195402; CC Evidence={ECO:0000269|PubMed:36608588}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76712; CC Evidence={ECO:0000305|PubMed:36608588}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(17S)-hydroperoxy-(4Z,7Z,10Z,13Z,15E,19Z)-docosahexaenoate + 2 CC glutathione = (17S)-hydroxy-(4Z,7Z,10Z,13Z,15E,19Z)-docosahexaenoate CC + glutathione disulfide + H2O; Xref=Rhea:RHEA:76715, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:57925, ChEBI:CHEBI:58297, CC ChEBI:CHEBI:133795, ChEBI:CHEBI:195403; CC Evidence={ECO:0000269|PubMed:36608588}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76716; CC Evidence={ECO:0000305|PubMed:36608588}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a hydroperoxy-1,2-diacyl-glycero-3-phosphocholine + 2 CC glutathione = a hydroxy-1,2-diacyl-glycero-3-phosphocholine + CC glutathione disulfide + H2O; Xref=Rhea:RHEA:76731, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:57925, ChEBI:CHEBI:58297, ChEBI:CHEBI:195423, CC ChEBI:CHEBI:195424; Evidence={ECO:0000269|PubMed:36608588}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76732; CC Evidence={ECO:0000305|PubMed:36608588}; CC -!- SUBUNIT: Monomer. Has a tendency to form higher mass oligomers CC (PubMed:17630701). Interacts with FUNDC1; this interaction promotes CC GPX4 recruitment into mitochondria through TOM/TIM complex where it is CC degraded by mitophagy (PubMed:36828120). {ECO:0000269|PubMed:17630701, CC ECO:0000269|PubMed:36828120}. CC -!- SUBCELLULAR LOCATION: [Isoform Mitochondrial]: Mitochondrion CC {ECO:0000250|UniProtKB:O70325}. CC -!- SUBCELLULAR LOCATION: [Isoform Cytoplasmic]: Cytoplasm CC {ECO:0000269|PubMed:11115402}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative initiation; Named isoforms=2; CC Name=Mitochondrial; CC IsoId=P36969-1; Sequence=Displayed; CC Name=Cytoplasmic; CC IsoId=P36969-2; Sequence=VSP_018740; CC -!- TISSUE SPECIFICITY: Present primarily in testis. Expressed in platelets CC (at protein level) (PubMed:11115402). {ECO:0000269|PubMed:11115402, CC ECO:0000269|PubMed:9705830}. CC -!- DISEASE: Spondylometaphyseal dysplasia, Sedaghatian type (SMDS) CC [MIM:250220]: A form of spondylometaphyseal dysplasia, a group of short CC stature disorders distinguished by abnormalities in the vertebrae and CC the metaphyses of the tubular bones. SMDS is a neonatal lethal form CC characterized by severe metaphyseal chondrodysplasia with mild limb CC shortening, platyspondyly, cardiac conduction defects, and central CC nervous system abnormalities. {ECO:0000269|PubMed:24706940}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the glutathione peroxidase family. CC {ECO:0000305}. CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/gpx4/"; CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Life, a subtle balance CC - Issue 205 of July 2018; CC URL="https://web.expasy.org/spotlight/back_issues/205/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X71973; CAA50793.1; -; mRNA. DR EMBL; AF060972; AAC32261.1; -; Genomic_DNA. DR EMBL; AY324108; AAP72965.1; -; Genomic_DNA. DR EMBL; AC004151; AAC03239.1; -; Genomic_DNA. DR EMBL; AC005390; AAC28920.1; -; Genomic_DNA. DR EMBL; BC011836; AAH11836.1; -; mRNA. DR EMBL; BC021567; AAH21567.1; -; mRNA. DR EMBL; BC022071; AAH22071.1; -; mRNA. DR EMBL; BC032695; AAH32695.3; -; mRNA. DR EMBL; BC039849; AAH39849.1; -; mRNA. DR CCDS; CCDS42457.1; -. [P36969-1] DR CCDS; CCDS92476.1; -. [P36969-2] DR PIR; T02747; T02747. DR RefSeq; NP_001034936.1; NM_001039847.2. DR RefSeq; NP_002076.2; NM_002085.4. [P36969-1] DR PDB; 2GS3; X-ray; 1.90 A; A=36-197. DR PDB; 2OBI; X-ray; 1.55 A; A=29-197. DR PDB; 5H5Q; X-ray; 1.10 A; A=29-197. DR PDB; 5H5R; X-ray; 1.20 A; A=29-197. DR PDB; 5H5S; X-ray; 1.85 A; A=29-197. DR PDB; 6ELW; X-ray; 1.30 A; A=29-197. DR PDB; 6HKQ; X-ray; 1.54 A; A=28-197. DR PDB; 6HN3; X-ray; 1.01 A; A=28-197. DR PDB; 7L8K; X-ray; 1.38 A; A=30-197. DR PDB; 7L8L; X-ray; 1.61 A; A=30-197. DR PDB; 7L8M; X-ray; 2.07 A; A=30-197. DR PDB; 7L8Q; X-ray; 1.48 A; A=30-197. DR PDB; 7L8R; X-ray; 1.52 A; A/B=30-197. DR PDB; 7U4I; X-ray; 1.97 A; A/B=30-197. DR PDB; 7U4J; X-ray; 1.81 A; A=30-197. DR PDB; 7U4K; X-ray; 1.69 A; A=30-197. DR PDB; 7U4L; X-ray; 2.25 A; A/B/C/D=30-197. DR PDB; 7U4M; X-ray; 1.93 A; A=30-197. DR PDB; 7U4N; X-ray; 1.60 A; A/B=30-197. DR PDBsum; 2GS3; -. DR PDBsum; 2OBI; -. DR PDBsum; 5H5Q; -. DR PDBsum; 5H5R; -. DR PDBsum; 5H5S; -. DR PDBsum; 6ELW; -. DR PDBsum; 6HKQ; -. DR PDBsum; 6HN3; -. DR PDBsum; 7L8K; -. DR PDBsum; 7L8L; -. DR PDBsum; 7L8M; -. DR PDBsum; 7L8Q; -. DR PDBsum; 7L8R; -. DR PDBsum; 7U4I; -. DR PDBsum; 7U4J; -. DR PDBsum; 7U4K; -. DR PDBsum; 7U4L; -. DR PDBsum; 7U4M; -. DR PDBsum; 7U4N; -. DR SMR; P36969; -. DR BioGRID; 109137; 97. DR DIP; DIP-53543N; -. DR IntAct; P36969; 18. DR MINT; P36969; -. DR STRING; 9606.ENSP00000346103; -. DR BindingDB; P36969; -. DR ChEMBL; CHEMBL4295754; -. DR DrugBank; DB09096; Benzoyl peroxide. DR DrugBank; DB00143; Glutathione. DR DrugBank; DB03310; Glutathione disulfide. DR GuidetoPHARMACOLOGY; 3239; -. DR SwissLipids; SLP:000001633; -. DR MoonProt; P36969; -. DR PeroxiBase; 3603; HsGPx04-A. DR PeroxiBase; 3632; HsGPx04-B. DR PeroxiBase; 3633; HsGPx04-C. DR iPTMnet; P36969; -. DR MetOSite; P36969; -. DR PhosphoSitePlus; P36969; -. DR SwissPalm; P36969; -. DR BioMuta; GPX4; -. DR DMDM; 172045844; -. DR REPRODUCTION-2DPAGE; IPI00304814; -. DR EPD; P36969; -. DR jPOST; P36969; -. DR MassIVE; P36969; -. DR MaxQB; P36969; -. DR PaxDb; 9606-ENSP00000346103; -. DR PeptideAtlas; P36969; -. DR ProteomicsDB; 55250; -. [P36969-1] DR ProteomicsDB; 55251; -. [P36969-2] DR Pumba; P36969; -. DR ABCD; P36969; 1 sequenced antibody. DR Antibodypedia; 3263; 417 antibodies from 41 providers. DR DNASU; 2879; -. DR Ensembl; ENST00000354171.13; ENSP00000346103.7; ENSG00000167468.20. [P36969-1] DR Ensembl; ENST00000611653.4; ENSP00000483655.1; ENSG00000167468.20. [P36969-2] DR GeneID; 2879; -. DR KEGG; hsa:2879; -. DR MANE-Select; ENST00000354171.13; ENSP00000346103.7; NM_002085.5; NP_002076.2. DR UCSC; uc021umg.3; human. [P36969-1] DR AGR; HGNC:4556; -. DR CTD; 2879; -. DR DisGeNET; 2879; -. DR GeneCards; GPX4; -. DR HGNC; HGNC:4556; GPX4. DR HPA; ENSG00000167468; Low tissue specificity. DR MalaCards; GPX4; -. DR MIM; 138322; gene. DR MIM; 250220; phenotype. DR neXtProt; NX_P36969; -. DR OpenTargets; ENSG00000167468; -. DR Orphanet; 93317; Spondylometaphyseal dysplasia, Sedaghatian type. DR PharmGKB; PA28952; -. DR VEuPathDB; HostDB:ENSG00000167468; -. DR eggNOG; KOG1651; Eukaryota. DR GeneTree; ENSGT00940000161913; -. DR InParanoid; P36969; -. DR OMA; TFPMTEK; -. DR OrthoDB; 67394at2759; -. DR PhylomeDB; P36969; -. DR TreeFam; TF338735; -. DR BioCyc; MetaCyc:HS09562-MONOMER; -. DR BRENDA; 1.11.1.12; 2681. DR PathwayCommons; P36969; -. DR Reactome; R-HSA-2142688; Synthesis of 5-eicosatetraenoic acids. DR Reactome; R-HSA-2142712; Synthesis of 12-eicosatetraenoic acid derivatives. DR Reactome; R-HSA-2142770; Synthesis of 15-eicosatetraenoic acid derivatives. DR Reactome; R-HSA-9018676; Biosynthesis of D-series resolvins. [P36969-2] DR Reactome; R-HSA-9018896; Biosynthesis of E-series 18(S)-resolvins. [P36969-2] DR Reactome; R-HSA-9020265; Biosynthesis of aspirin-triggered D-series resolvins. [P36969-2] DR Reactome; R-HSA-9023661; Biosynthesis of E-series 18(R)-resolvins. [P36969-2] DR SABIO-RK; P36969; -. DR SignaLink; P36969; -. DR BioGRID-ORCS; 2879; 428 hits in 1164 CRISPR screens. DR ChiTaRS; GPX4; human. DR EvolutionaryTrace; P36969; -. DR GeneWiki; GPX4; -. DR GenomeRNAi; 2879; -. DR Pharos; P36969; Tchem. DR PRO; PR:P36969; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; P36969; Protein. DR Bgee; ENSG00000167468; Expressed in left testis and 203 other cell types or tissues. DR ExpressionAtlas; P36969; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA: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; HDA:UniProtKB. DR GO; GO:0032991; C:protein-containing complex; IMP:CAFA. DR GO; GO:0004602; F:glutathione peroxidase activity; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IMP:CAFA. DR GO; GO:0047066; F:phospholipid-hydroperoxide glutathione peroxidase activity; IDA:UniProtKB. DR GO; GO:0008430; F:selenium binding; IEA:Ensembl. DR GO; GO:0019369; P:arachidonic acid metabolic process; IDA:UniProtKB. DR GO; GO:0006325; P:chromatin organization; IEA:Ensembl. DR GO; GO:0019372; P:lipoxygenase pathway; IDA:UniProtKB. DR GO; GO:0042759; P:long-chain fatty acid biosynthetic process; TAS:Reactome. DR GO; GO:0110076; P:negative regulation of ferroptosis; ISS:UniProtKB. DR GO; GO:0006644; P:phospholipid metabolic process; TAS:UniProtKB. DR GO; GO:0051258; P:protein polymerization; IMP:CAFA. DR GO; GO:0032355; P:response to estradiol; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; ISS:UniProtKB. DR GO; GO:0007283; P:spermatogenesis; ISS:UniProtKB. DR CDD; cd00340; GSH_Peroxidase; 1. DR Gene3D; 3.40.30.10; Glutaredoxin; 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; GLUTATHIONE PEROXIDASE; 1. DR PANTHER; PTHR11592:SF78; PHOSPHOLIPID HYDROPEROXIDE GLUTATHIONE PEROXIDASE; 1. DR Pfam; PF00255; GSHPx; 1. DR PIRSF; PIRSF000303; Glutathion_perox; 1. DR SUPFAM; SSF52833; Thioredoxin-like; 1. DR PROSITE; PS00460; GLUTATHIONE_PEROXID_1; 1. DR PROSITE; PS00763; GLUTATHIONE_PEROXID_2; 1. DR PROSITE; PS51355; GLUTATHIONE_PEROXID_3; 1. DR UCD-2DPAGE; P36969; -. DR Genevisible; P36969; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative initiation; Cytoplasm; Developmental protein; KW Dwarfism; Lipid metabolism; Mitochondrion; Oxidoreductase; Peroxidase; KW Phosphoprotein; Reference proteome; Selenocysteine; Transit peptide. FT TRANSIT 1..? FT /note="Mitochondrion" FT /evidence="ECO:0000255" FT CHAIN ?..197 FT /note="Phospholipid hydroperoxide glutathione peroxidase FT GPX4" FT /id="PRO_0000013067" FT ACT_SITE 73 FT /evidence="ECO:0000250|UniProtKB:O70325" FT NON_STD 73 FT /note="Selenocysteine" FT /evidence="ECO:0000305|PubMed:8039723, FT ECO:0000305|PubMed:9705830" 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:0000305" FT /id="VSP_018740" FT VARIANT 2 FT /note="S -> N (in dbSNP:rs8178967)" FT /evidence="ECO:0000269|PubMed:12606444, ECO:0000269|Ref.3" FT /id="VAR_017063" FT VARIANT 90..197 FT /note="Missing (in SMDS)" FT /evidence="ECO:0000269|PubMed:24706940" FT /id="VAR_080140" FT VARIANT 120 FT /note="A -> T (in a patient affected by cryptorchidism; FT dbSNP:rs76201145)" FT /evidence="ECO:0000269|PubMed:12606444" FT /id="VAR_017064" FT MUTAGEN 73 FT /note="U->A: Loss of enzyme activity." FT /evidence="ECO:0000269|PubMed:17630701" FT MUTAGEN 73 FT /note="U->C: Almost complete loss of enzyme activity." FT /evidence="ECO:0000269|PubMed:17630701" FT TURN 35..37 FT /evidence="ECO:0007829|PDB:6HN3" FT HELIX 41..43 FT /evidence="ECO:0007829|PDB:6HN3" FT STRAND 45..48 FT /evidence="ECO:0007829|PDB:6HN3" FT STRAND 53..55 FT /evidence="ECO:0007829|PDB:6HN3" FT HELIX 56..59 FT /evidence="ECO:0007829|PDB:6HN3" FT STRAND 62..69 FT /evidence="ECO:0007829|PDB:6HN3" FT STRAND 71..73 FT /evidence="ECO:0007829|PDB:6HN3" FT HELIX 76..90 FT /evidence="ECO:0007829|PDB:6HN3" FT HELIX 91..93 FT /evidence="ECO:0007829|PDB:6HN3" FT STRAND 95..101 FT /evidence="ECO:0007829|PDB:6HN3" FT TURN 104..107 FT /evidence="ECO:0007829|PDB:6HN3" FT HELIX 113..121 FT /evidence="ECO:0007829|PDB:6HN3" FT TURN 122..124 FT /evidence="ECO:0007829|PDB:6HN3" FT STRAND 127..130 FT /evidence="ECO:0007829|PDB:6HN3" FT STRAND 135..137 FT /evidence="ECO:0007829|PDB:7U4J" FT HELIX 142..149 FT /evidence="ECO:0007829|PDB:6HN3" FT HELIX 151..153 FT /evidence="ECO:0007829|PDB:6HN3" FT STRAND 158..160 FT /evidence="ECO:0007829|PDB:6HN3" FT STRAND 167..170 FT /evidence="ECO:0007829|PDB:6HN3" FT STRAND 176..180 FT /evidence="ECO:0007829|PDB:6HN3" FT HELIX 186..192 FT /evidence="ECO:0007829|PDB:6HN3" FT HELIX 195..197 FT /evidence="ECO:0007829|PDB:6HN3" SQ SEQUENCE 197 AA; 22175 MW; 1AE3BC7AE42FDDB1 CRC64; MSLGRLCRLL KPALLCGALA APGLAGTMCA SRDDWRCARS MHEFSAKDID GHMVNLDKYR GFVCIVTNVA SQUGKTEVNY TQLVDLHARY AECGLRILAF PCNQFGKQEP GSNEEIKEFA AGYNVKFDMF SKICVNGDDA HPLWKWMKIQ PKGKGILGNA IKWNFTKFLI DKNGCVVKRY GPMEEPLVIE KDLPHYF //