ID GPX4_MOUSE Reviewed; 197 AA. AC O70325; O35560; Q8K4U8; Q91XR9; Q9JK35; DT 11-JAN-2001, integrated into UniProtKB/Swiss-Prot. DT 26-FEB-2008, sequence version 4. DT 27-MAR-2024, entry version 202. DE RecName: Full=Phospholipid hydroperoxide glutathione peroxidase GPX4 {ECO:0000303|PubMed:12745070, ECO:0000303|PubMed:9370288}; DE Short=PHGPx {ECO:0000303|PubMed:12745070, ECO:0000303|PubMed:9370288}; DE EC=1.11.1.12 {ECO:0000269|PubMed:29290465}; DE AltName: Full=Glutathione peroxidase 4 {ECO:0000303|PubMed:19417079}; DE Short=GPx-4 {ECO:0000303|PubMed:19417079}; DE Short=GSHPx-4 {ECO:0000303|PubMed:19417079}; DE EC=1.11.1.9 {ECO:0000269|PubMed:12566075}; DE Flags: Precursor; GN Name=Gpx4 {ECO:0000303|PubMed:19417079, ECO:0000312|MGI:MGI:104767}; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC STRAIN=CD-1; TISSUE=Testis; RX PubMed=9370288; DOI=10.1016/s0378-1119(97)00321-1; RA Nam S.-Y., Nakamuta N., Kurohmaru M., Hayashi Y.; RT "Cloning and sequencing of the cDNA encoding a phospholipid hydroperoxide RT glutathione peroxidase."; RL Gene 198:245-249(1997). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC STRAIN=C57BL/6N; RX PubMed=10100845; DOI=10.1016/s0014-5793(99)00221-5; RA Borchert A., Schnurr K., Thiele B.J., Kuehn H.; RT "Cloning of the mouse phospholipid hydroperoxide glutathione peroxidase RT gene."; RL FEBS Lett. 446:223-227(1999). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA]. RC STRAIN=BALB/cJ, and C57BL/6J; TISSUE=Myocardium, and Testis; RX PubMed=10341094; DOI=10.1007/s003359901053; RA Knopp E.A., Arndt T.L., Eng K.L., Caldwell M., LeBoeuf R.C., Deeb S.S., RA O'Brien K.D.; RT "Murine phospholipid hydroperoxide glutathione peroxidase: cDNA sequence, RT tissue expression, and mapping."; RL Mamm. Genome 10:601-605(1999). RN [4] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM NUCLEAR), SUBCELLULAR LOCATION (ISOFORM RP NUCLEAR), AND TISSUE SPECIFICITY. RC TISSUE=Testis; RX PubMed=11344099; DOI=10.1096/fj.00-0655fje; RA Pfeifer H., Conrad M., Roethlein D., Kyriakopoulos A., Brielmeier M., RA Bornkamm G.W., Behne D.; RT "Identification of a specific sperm nuclei selenoenzyme necessary for RT protamine thiol cross-linking during sperm maturation."; RL FASEB J. 15:1236-1238(2001). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND DISRUPTION PHENOTYPE. RC STRAIN=129/SvJ; TISSUE=Liver; RX PubMed=12745070; DOI=10.1016/s0006-291x(03)00734-4; RA Imai H., Hirao F., Sakamoto T., Sekine K., Mizukura Y., Saito M., RA Kitamoto T., Hayasaka M., Hanaoka K., Nakagawa Y.; RT "Early embryonic lethality caused by targeted disruption of the mouse PHGPx RT gene."; RL Biochem. Biophys. Res. Commun. 305:278-286(2003). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J; TISSUE=Testis; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [7] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND CATALYTIC ACTIVITY. RX PubMed=12566075; DOI=10.1016/s0891-5849(02)01360-6; RA Yant L.J., Ran Q., Rao L., Van Remmen H., Shibatani T., Belter J.G., RA Motta L., Richardson A., Prolla T.A.; RT "The selenoprotein GPX4 is essential for mouse development and protects RT from radiation and oxidative damage insults."; RL Free Radic. Biol. Med. 34:496-502(2003). RN [8] RP TISSUE SPECIFICITY. RX PubMed=1668477; DOI=10.1074/jbc.M601195200; RA Borchert A., Wang C.C., Ufer C., Schiebel H., Savaskan N.E., Kuhn H.; RT "The role of phospholipid hydroperoxide glutathione peroxidase isoforms in RT murine embryogenesis."; RL J. Biol. Chem. 281:19655-19664(2006). RN [9] RP TISSUE SPECIFICITY. RX PubMed=17503194; DOI=10.1007/s10735-007-9092-7; RA Baek I.J., Seo D.S., Yon J.M., Lee S.R., Jin Y., Nahm S.S., Jeong J.H., RA Choo Y.K., Kang J.K., Lee B.J., Yun Y.W., Nam S.Y.; RT "Tissue expression and cellular localization of phospholipid hydroperoxide RT glutathione peroxidase (PHGPx) mRNA in male mice."; RL J. Mol. Histol. 38:237-244(2007). RN [10] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=18762024; DOI=10.1016/j.cmet.2008.07.005; RA Seiler A., Schneider M., Foerster H., Roth S., Wirth E.K., Culmsee C., RA Plesnila N., Kremmer E., Raadmark O., Wurst W., Bornkamm G.W., RA Schweizer U., Conrad M.; RT "Glutathione peroxidase 4 senses and translates oxidative stress into RT 12/15-lipoxygenase dependent- and AIF-mediated cell death."; RL Cell Metab. 8:237-248(2008). RN [11] RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE. RX PubMed=19417079; DOI=10.1096/fj.09-132795; RA Schneider M., Forster H., Boersma A., Seiler A., Wehnes H., Sinowatz F., RA Neumueller C., Deutsch M.J., Walch A., Hrabe de Angelis M., Wurst W., RA Ursini F., Roveri A., Maleszewski M., Maiorino M., Conrad M.; RT "Mitochondrial glutathione peroxidase 4 disruption causes male RT infertility."; RL FASEB J. 23:3233-3242(2009). RN [12] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=19783653; DOI=10.1074/jbc.m109.016139; RA Imai H., Hakkaku N., Iwamoto R., Suzuki J., Suzuki T., Tajima Y., RA Konishi K., Minami S., Ichinose S., Ishizaka K., Shioda S., Arata S., RA Nishimura M., Naito S., Nakagawa Y.; RT "Depletion of selenoprotein GPx4 in spermatocytes causes male infertility RT in mice."; RL J. Biol. Chem. 284:32522-32532(2009). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, RC Pancreas, Spleen, and Testis; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [14] RP DISRUPTION PHENOTYPE. RX PubMed=19890015; DOI=10.1096/fj.09-143974; RA Wirth E.K., Conrad M., Winterer J., Wozny C., Carlson B.A., Roth S., RA Schmitz D., Bornkamm G.W., Coppola V., Tessarollo L., Schomburg L., RA Koehrle J., Hatfield D.L., Schweizer U.; RT "Neuronal selenoprotein expression is required for interneuron development RT and prevents seizures and neurodegeneration."; RL FASEB J. 24:844-852(2010). RN [15] RP DISRUPTION PHENOTYPE. RX PubMed=24599700; DOI=10.1007/s12011-014-9920-z; RA Wirth E.K., Bharathi B.S., Hatfield D., Conrad M., Brielmeier M., RA Schweizer U.; RT "Cerebellar hypoplasia in mice lacking selenoprotein biosynthesis in RT neurons."; RL Biol. Trace Elem. Res. 158:203-210(2014). RN [16] 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 [17] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND DISRUPTION RP PHENOTYPE. RX PubMed=22207760; DOI=10.1074/jbc.m111.335174; RA Ueta T., Inoue T., Furukawa T., Tamaki Y., Nakagawa Y., Imai H., Yanagi Y.; RT "Glutathione peroxidase 4 is required for maturation of photoreceptor RT cells."; RL J. Biol. Chem. 287:7675-7682(2012). RN [18] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=25402683; DOI=10.1038/ncb3064; RA Friedmann Angeli J.P., Schneider M., Proneth B., Tyurina Y.Y., Tyurin V.A., RA Hammond V.J., Herbach N., Aichler M., Walch A., Eggenhofer E., RA Basavarajappa D., Raadmark O., Kobayashi S., Seibt T., Beck H., Neff F., RA Esposito I., Wanke R., Foerster H., Yefremova O., Heinrichmeyer M., RA Bornkamm G.W., Geissler E.K., Thomas S.B., Stockwell B.R., O'Donnell V.B., RA Kagan V.E., Schick J.A., Conrad M.; RT "Inactivation of the ferroptosis regulator Gpx4 triggers acute renal RT failure in mice."; RL Nat. Cell Biol. 16:1180-1191(2014). RN [19] RP FUNCTION, MUTAGENESIS OF SEC-73, AND CATALYTIC ACTIVITY. RX PubMed=25922076; DOI=10.1074/jbc.m115.656363; RA Ingold I., Aichler M., Yefremova E., Roveri A., Buday K., Doll S., RA Tasdemir A., Hoffard N., Wurst W., Walch A., Ursini F., RA Friedmann Angeli J.P., Conrad M.; RT "Expression of a catalytically inactive mutant form of glutathione RT peroxidase 4 (Gpx4) confers a dominant-negative effect in male fertility."; RL J. Biol. Chem. 290:14668-14678(2015). RN [20] RP FUNCTION. RX PubMed=25824823; DOI=10.1084/jem.20140857; RA Matsushita M., Freigang S., Schneider C., Conrad M., Bornkamm G.W., RA Kopf M.; RT "T cell lipid peroxidation induces ferroptosis and prevents immunity to RT infection."; RL J. Exp. Med. 212:555-568(2015). RN [21] RP FUNCTION, CATALYTIC ACTIVITY, SELENOCYSTEINE, ACTIVE SITE, REACTION RP MECHANISM, AND MUTAGENESIS OF SEC-73. RX PubMed=29290465; DOI=10.1016/j.cell.2017.11.048; RA Ingold I., Berndt C., Schmitt S., Doll S., Poschmann G., Buday K., RA Roveri A., Peng X., Porto Freitas F., Seibt T., Mehr L., Aichler M., RA Walch A., Lamp D., Jastroch M., Miyamoto S., Wurst W., Ursini F., RA Arner E.S.J., Fradejas-Villar N., Schweizer U., Zischka H., RA Friedmann Angeli J.P., Conrad M.; RT "Selenium utilization by GPX4 is required to prevent hydroperoxide-induced RT ferroptosis."; RL Cell 0:0-0(2017). RN [22] RP REVIEW. RX PubMed=28204974; DOI=10.1007/82_2016_508; RA Imai H., Matsuoka M., Kumagai T., Sakamoto T., Koumura T.; RT "Lipid Peroxidation-Dependent Cell Death Regulated by GPx4 and RT Ferroptosis."; RL Curr. Top. Microbiol. Immunol. 403:143-170(2017). RN [23] {ECO:0007744|PDB:5L71} RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 29-197 OF MUTANT CYS-73 (ISOFORM RP CYTOPLASMIC). RX PubMed=27710939; DOI=10.1107/s2053230x16013686; RA Janowski R., Scanu S., Niessing D., Madl T.; RT "Crystal and solution structural studies of mouse phospholipid RT hydroperoxide glutathione peroxidase 4."; RL Acta Crystallogr. F 72:743-749(2016). CC -!- FUNCTION: Essential antioxidant peroxidase that directly reduces CC phospholipid hydroperoxide even if they are incorporated in membranes CC and lipoproteins (PubMed:29290465). Can also reduce fatty acid CC hydroperoxide, cholesterol hydroperoxide and thymine hydroperoxide (By CC similarity). Plays a key role in protecting cells from oxidative damage CC by preventing membrane lipid peroxidation (PubMed:12566075). Required CC to prevent cells from ferroptosis, a non-apoptotic cell death resulting CC from an iron-dependent accumulation of lipid reactive oxygen species CC (PubMed:12566075, PubMed:24439385, PubMed:25402683, PubMed:25922076, CC PubMed:29290465). 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 (PubMed:29290465). 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 (PubMed:29290465). CC May be required to protect cells from the toxicity of ingested lipid CC hydroperoxides (PubMed:12566075). Required for normal sperm development CC and male fertility (PubMed:19783653, PubMed:25922076). Essential for CC maturation and survival of photoreceptor cells (PubMed:22207760). Plays CC a role in a primary T-cell response to viral and parasitic infection by CC protecting T-cells from ferroptosis and by supporting T-cell expansion CC (PubMed:25824823). Plays a role of glutathione peroxidase in platelets CC in the arachidonic acid metabolism (By similarity). 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 also reduce small soluble hydroperoxides such as H2O2 and tert-butyl CC hydroperoxide (PubMed:12566075). {ECO:0000250|UniProtKB:P36968, CC ECO:0000250|UniProtKB:P36969, ECO:0000269|PubMed:12566075, CC ECO:0000269|PubMed:18762024, ECO:0000269|PubMed:19783653, CC ECO:0000269|PubMed:22207760, ECO:0000269|PubMed:24439385, CC ECO:0000269|PubMed:25402683, ECO:0000269|PubMed:25824823, CC ECO:0000269|PubMed:25922076, ECO:0000269|PubMed:29290465}. CC -!- FUNCTION: [Isoform Cytoplasmic]: Specifically able to suppress the CC production of leukotriene and prostaglandin in response to several CC stimuli by reducing fatty acid hydroperoxide. CC {ECO:0000250|UniProtKB:P36970}. CC -!- FUNCTION: [Isoform Mitochondrial]: Specifically required to prevent CC mitochondrial cell death by mediating reduction of cardiolipin CC hydroperoxide (By similarity). Also required for normal sperm CC development and male fertility (PubMed:19417079). CC {ECO:0000250|UniProtKB:P36970, ECO:0000269|PubMed:19417079}. CC -!- FUNCTION: [Isoform Nuclear]: Required for male fertility by stabilizing CC the condensed chromatin in sperm nuclei (PubMed:12566075). CC {ECO:0000269|PubMed:12566075}. 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:29290465}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19058; CC Evidence={ECO:0000305}; 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:12566075}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16834; CC Evidence={ECO:0000305|PubMed:12566075}; 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:12566075}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:69413; CC Evidence={ECO:0000305|PubMed:12566075}; 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:0000250|UniProtKB:P36969}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:69652; CC Evidence={ECO:0000250|UniProtKB:P36969}; 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:0000250|UniProtKB:P36969}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76688; CC Evidence={ECO:0000250|UniProtKB:P36969}; 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:0000250|UniProtKB:P36969}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48889; CC Evidence={ECO:0000250|UniProtKB:P36969}; 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:0000250|UniProtKB:P36969}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48621; CC Evidence={ECO:0000250|UniProtKB:P36969}; 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:0000250|UniProtKB:P36969}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76692; CC Evidence={ECO:0000250|UniProtKB:P36969}; 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 -!- 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:0000250|UniProtKB:P36969}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76696; CC Evidence={ECO:0000250|UniProtKB:P36969}; 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:0000250|UniProtKB:P36969}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76700; CC Evidence={ECO:0000250|UniProtKB:P36969}; 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:0000250|UniProtKB:P36969}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76704; CC Evidence={ECO:0000250|UniProtKB:P36969}; 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:0000250|UniProtKB:P36969}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76708; CC Evidence={ECO:0000250|UniProtKB:P36969}; 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:0000250|UniProtKB:P36969}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76712; CC Evidence={ECO:0000250|UniProtKB:P36969}; 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:0000250|UniProtKB:P36969}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76716; CC Evidence={ECO:0000250|UniProtKB:P36969}; 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:25922076}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76732; CC Evidence={ECO:0000305|PubMed:25922076}; CC -!- SUBUNIT: Monomer. Has a tendency to form higher mass oligomers. CC Interacts with FUNDC1; this interaction promotes GPX4 recruitment into CC mitochondria through TOM/TIM complex where it is degraded by mitophagy. CC {ECO:0000250|UniProtKB:P36969}. CC -!- SUBCELLULAR LOCATION: [Isoform Mitochondrial]: Mitochondrion CC {ECO:0000269|PubMed:12566075, ECO:0000269|PubMed:22207760}. CC -!- SUBCELLULAR LOCATION: [Isoform Cytoplasmic]: Cytoplasm CC {ECO:0000269|PubMed:12566075}. CC -!- SUBCELLULAR LOCATION: [Isoform Nuclear]: Nucleus CC {ECO:0000269|PubMed:11344099}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing, Alternative initiation; Named isoforms=3; CC Name=Mitochondrial; Synonyms=mGPx4 {ECO:0000303|PubMed:28204974}; CC IsoId=O70325-1; Sequence=Displayed; CC Name=Cytoplasmic; Synonyms=cGPx4 {ECO:0000303|PubMed:28204974}; CC IsoId=O70325-2; Sequence=VSP_018743; CC Name=Nuclear; Synonyms=nGPx4 {ECO:0000303|PubMed:28204974}; CC IsoId=O70325-3; Sequence=VSP_059349; CC -!- TISSUE SPECIFICITY: Widely expressed with the highest levels in testis, CC heart, cerebrum, ileum, stomach, liver, jejunum and epididymis CC (PubMed:17503194). Expressed primarily in testis and sperm midpiece (at CC protein level) (PubMed:19417079, PubMed:12566075). Expressed in brain CC (at protein level) (PubMed:22207760, PubMed:12566075). Expressed in CC heart, liver and kidney (at protein level) (PubMed:12566075). Expressed CC in retina, especially in inner segments of photoreceptor cells (at CC protein level) (PubMed:22207760). {ECO:0000269|PubMed:11344099, CC ECO:0000269|PubMed:12566075, ECO:0000269|PubMed:17503194, CC ECO:0000269|PubMed:19417079, ECO:0000269|PubMed:22207760}. CC -!- TISSUE SPECIFICITY: [Isoform Mitochondrial]: Highly expressed during CC embryogenesis (PubMed:1668477). Down-regulated between 14.5 dpc and CC 17.5 dpc (PubMed:1668477). {ECO:0000269|PubMed:1668477}. CC -!- TISSUE SPECIFICITY: [Isoform Cytoplasmic]: Highly expressed during CC embryogenesis (PubMed:1668477). In contrast to isoform Mitochondrial CC and isoform Nuclear, which are down-regulated between 14.5 dpc and 17.5 CC dpc, remains constant (PubMed:1668477). {ECO:0000269|PubMed:1668477}. CC -!- TISSUE SPECIFICITY: [Isoform Nuclear]: Mainly expressed in sperm CC (PubMed:11344099). Weakly expressed during embryogenesis CC (PubMed:1668477). Down-regulated between 14.5 dpc and 17.5 dpc CC (PubMed:1668477). {ECO:0000269|PubMed:11344099, CC ECO:0000269|PubMed:1668477}. CC -!- DISRUPTION PHENOTYPE: Embryonic lethality in utero at midgestation, CC caused by inability to initiate gastrulation and the absence of CC embryonic cavities (PubMed:12745070). Conditional knockout mice lacking CC Gpx4 in spermatocytes causes sperm abnormalities and male infertility CC (PubMed:19783653). Conditional knockout mice lacking Gpx4 in CC photoreceptor cells causes retinal degeneration, decreased CC mitochondrial biomass and decreased number of connecting cilia in these CC cells (PubMed:22207760). Mice display neurodegeneration CC (PubMed:18762024). Conditional knockout mice lacking Gpx4 in neurons CC show reduced parvalbumin-positive interneurons and develop phenotypes, CC such as cerebellar hypoplasia and seizures (PubMed:19890015, CC PubMed:24599700). Induced disruption of Gpx4 in mice causes acute renal CC failure and early death due to ferroptosis (PubMed:25402683). CC {ECO:0000269|PubMed:12745070, ECO:0000269|PubMed:18762024, CC ECO:0000269|PubMed:19783653, ECO:0000269|PubMed:19890015, CC ECO:0000269|PubMed:22207760, ECO:0000269|PubMed:24599700, CC ECO:0000269|PubMed:25402683}. CC -!- DISRUPTION PHENOTYPE: [Isoform Mitochondrial]: Isoform mitochondrial: CC Selective disruption of isoform mitochondrial causes sperm CC abnormalities and male infertility (PubMed:19417079). CC {ECO:0000269|PubMed:19417079}. CC -!- MISCELLANEOUS: The presence of selenolate in the active site is CC essential for resistance to overoxidation: in the absence of reducing CC equivalents, the enzyme can form a selenylamide intermediate during its CC catalytic cycle, thereby preventing its irreversible overoxidation. CC {ECO:0000269|PubMed:29290465}. CC -!- MISCELLANEOUS: [Isoform Cytoplasmic]: Produced by alternative CC initiation at Met-28 of isoform Mitochondrial. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the glutathione peroxidase family. CC {ECO:0000305}. 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; D87896; BAA22780.1; -; mRNA. DR EMBL; AJ012104; CAB42657.2; -; Genomic_DNA. DR EMBL; AF045768; AAC15832.1; -; mRNA. DR EMBL; AF045769; AAC15833.1; -; mRNA. DR EMBL; AF274027; AAK74112.1; -; mRNA. DR EMBL; AF044056; AAC14560.1; -; Genomic_DNA. DR EMBL; AB030643; BAC06507.1; -; Genomic_DNA. DR EMBL; AB030643; BAC06508.1; -; Genomic_DNA. DR EMBL; AB030643; BAC06509.1; -; Genomic_DNA. DR EMBL; AB030728; BAC06511.1; -; Genomic_DNA. DR EMBL; AK006441; BAC55251.1; -; mRNA. DR CCDS; CCDS24007.1; -. [O70325-3] DR CCDS; CCDS35973.1; -. [O70325-1] DR RefSeq; NP_001032830.2; NM_001037741.3. [O70325-3] DR RefSeq; NP_032188.3; NM_008162.3. [O70325-1] DR PDB; 5L71; X-ray; 1.80 A; A=29-197. DR PDBsum; 5L71; -. DR SMR; O70325; -. DR BioGRID; 551619; 4. DR IntAct; O70325; 1. DR STRING; 10090.ENSMUSP00000094863; -. DR ChEMBL; CHEMBL4523148; -. DR PeroxiBase; 3714; MmGPx04-A. DR PeroxiBase; 3865; MmGPx04-B. DR PeroxiBase; 3867; MmGPx04-C. DR GlyGen; O70325; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O70325; -. DR PhosphoSitePlus; O70325; -. DR SwissPalm; O70325; -. DR EPD; O70325; -. DR jPOST; O70325; -. DR PaxDb; 10090-ENSMUSP00000094863; -. DR PeptideAtlas; O70325; -. DR ProteomicsDB; 271319; -. [O70325-1] DR ProteomicsDB; 271320; -. [O70325-2] DR ProteomicsDB; 271321; -. [O70325-3] DR Pumba; O70325; -. DR ABCD; O70325; 1 sequenced antibody. DR Antibodypedia; 3263; 417 antibodies from 41 providers. DR DNASU; 625249; -. DR Ensembl; ENSMUST00000097227.11; ENSMUSP00000094863.5; ENSMUSG00000075706.12. [O70325-3] DR Ensembl; ENSMUST00000105372.9; ENSMUSP00000101011.3; ENSMUSG00000075706.12. [O70325-1] DR GeneID; 625249; -. DR KEGG; mmu:625249; -. DR UCSC; uc007gbk.2; mouse. [O70325-1] DR AGR; MGI:104767; -. DR CTD; 2879; -. DR MGI; MGI:104767; Gpx4. DR VEuPathDB; HostDB:ENSMUSG00000075706; -. DR eggNOG; KOG1651; Eukaryota. DR GeneTree; ENSGT00940000161913; -. DR InParanoid; O70325; -. DR OMA; TFPMTEK; -. DR OrthoDB; 67394at2759; -. DR BRENDA; 1.11.1.12; 3474. DR Reactome; R-MMU-2142712; Synthesis of 12-eicosatetraenoic acid derivatives. DR Reactome; R-MMU-2142770; Synthesis of 15-eicosatetraenoic acid derivatives. DR Reactome; R-MMU-9018676; Biosynthesis of D-series resolvins. DR Reactome; R-MMU-9018896; Biosynthesis of E-series 18(S)-resolvins. DR Reactome; R-MMU-9020265; Biosynthesis of aspirin-triggered D-series resolvins. DR Reactome; R-MMU-9023661; Biosynthesis of E-series 18(R)-resolvins. DR BioGRID-ORCS; 625249; 18 hits in 81 CRISPR screens. DR ChiTaRS; Gpx4; mouse. DR PRO; PR:O70325; -. DR Proteomes; UP000000589; Chromosome 10. DR Bgee; ENSMUSG00000075706; Expressed in spermatid and 131 other cell types or tissues. DR ExpressionAtlas; O70325; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:MGI. DR GO; GO:0005743; C:mitochondrial inner membrane; HDA:MGI. DR GO; GO:0005739; C:mitochondrion; IDA:MGI. DR GO; GO:0005635; C:nuclear envelope; IDA:MGI. DR GO; GO:0005634; C:nucleus; IDA:MGI. DR GO; GO:0032991; C:protein-containing complex; ISO:MGI. DR GO; GO:0004602; F:glutathione peroxidase activity; IDA:MGI. DR GO; GO:0042802; F:identical protein binding; ISO:MGI. DR GO; GO:0047066; F:phospholipid-hydroperoxide glutathione peroxidase activity; IDA:UniProtKB. DR GO; GO:0008430; F:selenium binding; ISO:MGI. DR GO; GO:0019369; P:arachidonic acid metabolic process; ISS:UniProtKB. DR GO; GO:0006325; P:chromatin organization; IDA:MGI. DR GO; GO:0019372; P:lipoxygenase pathway; ISS:UniProtKB. DR GO; GO:0110076; P:negative regulation of ferroptosis; IMP:UniProtKB. DR GO; GO:0051258; P:protein polymerization; ISO:MGI. DR GO; GO:0032355; P:response to estradiol; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; IMP:UniProtKB. DR GO; GO:0007283; P:spermatogenesis; IDA:MGI. 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 PRINTS; PR01011; GLUTPROXDASE. 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 Genevisible; O70325; MM. PE 1: Evidence at protein level; KW 3D-structure; Alternative initiation; Alternative splicing; Cytoplasm; KW Developmental protein; Lipid metabolism; Mitochondrion; Nucleus; KW Oxidoreductase; Peroxidase; Phosphoprotein; Reference proteome; KW 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_0000013069" FT ACT_SITE 73 FT /evidence="ECO:0000269|PubMed:29290465" FT NON_STD 73 FT /note="Selenocysteine" FT /evidence="ECO:0000269|PubMed:29290465" FT MOD_RES 40 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P36970" FT VAR_SEQ 1..28 FT /note="MSWGRLSRLLKPALLCGALAAPGLAGTM -> MGRAAARKRGRCRQRGGSPR FT GRRRRGPGRQSPRKRPGPRRRKARARRRRRARPRRMEPIPEPFNPGPLLQEPPQYCNSS FT EFLGL (in isoform Nuclear)" FT /id="VSP_059349" FT VAR_SEQ 1..27 FT /note="Missing (in isoform Cytoplasmic)" FT /evidence="ECO:0000305" FT /id="VSP_018743" FT MUTAGEN 73 FT /note="U->C: Mice develop normally and were born at the FT expected Mendelian ratio. Homozygous mice however lose body FT weight by P14-P16 and are susceptible to fatal epileptic FT seizures. Cells are extremely sensitive to peroxide-induced FT cell death because the enzyme is inactivated: The enzyme FT undergoes overoxidation and irreversible inactivation in FT the presence of exceeding concentrations of its substrates. FT Unlike the wild-type enzyme, which can form a selenylamide FT in the absence of reducing equivalents, thereby preventing FT its irreversible overoxidation, the mutant fails to form FT such an intermediate during its catalytic cycle." FT /evidence="ECO:0000269|PubMed:29290465" FT MUTAGEN 73 FT /note="U->S: Early embryonic lethality in homozygous mice. FT Male subfertility in heterozygous mice due to impaired FT spermatogenesis." FT /evidence="ECO:0000269|PubMed:25922076" FT CONFLICT 39 FT /note="R -> A (in Ref. 1; BAA22780)" FT /evidence="ECO:0000305" FT CONFLICT 176 FT /note="V -> E (in Ref. 4; AAK74112)" FT /evidence="ECO:0000305" FT CONFLICT 191 FT /note="K -> R (in Ref. 4; AAK74112)" FT /evidence="ECO:0000305" FT HELIX 35..37 FT /evidence="ECO:0007829|PDB:5L71" FT HELIX 41..43 FT /evidence="ECO:0007829|PDB:5L71" FT STRAND 45..48 FT /evidence="ECO:0007829|PDB:5L71" FT STRAND 53..55 FT /evidence="ECO:0007829|PDB:5L71" FT HELIX 56..59 FT /evidence="ECO:0007829|PDB:5L71" FT STRAND 62..69 FT /evidence="ECO:0007829|PDB:5L71" FT STRAND 71..73 FT /evidence="ECO:0007829|PDB:5L71" FT HELIX 76..90 FT /evidence="ECO:0007829|PDB:5L71" FT TURN 91..94 FT /evidence="ECO:0007829|PDB:5L71" FT STRAND 95..101 FT /evidence="ECO:0007829|PDB:5L71" FT TURN 104..107 FT /evidence="ECO:0007829|PDB:5L71" FT HELIX 113..122 FT /evidence="ECO:0007829|PDB:5L71" FT STRAND 127..130 FT /evidence="ECO:0007829|PDB:5L71" FT HELIX 142..148 FT /evidence="ECO:0007829|PDB:5L71" FT HELIX 151..153 FT /evidence="ECO:0007829|PDB:5L71" FT STRAND 156..160 FT /evidence="ECO:0007829|PDB:5L71" FT STRAND 167..170 FT /evidence="ECO:0007829|PDB:5L71" FT STRAND 176..180 FT /evidence="ECO:0007829|PDB:5L71" FT HELIX 187..190 FT /evidence="ECO:0007829|PDB:5L71" FT HELIX 191..195 FT /evidence="ECO:0007829|PDB:5L71" SQ SEQUENCE 197 AA; 22229 MW; 5CED4991A484F31C CRC64; MSWGRLSRLL KPALLCGALA APGLAGTMCA SRDDWRCARS MHEFSAKDID GHMVCLDKYR GFVCIVTNVA SQUGKTDVNY TQLVDLHARY AECGLRILAF PCNQFGRQEP GSNQEIKEFA AGYNVKFDMY SKICVNGDDA HPLWKWMKVQ PKGRGMLGNA IKWNFTKFLI DKNGCVVKRY GPMEEPQVIE KDLPCYL //