GPX4_MOUSE
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 03-AUG-2022, entry version 193.
DE RecName: Full=Phospholipid hydroperoxide glutathione peroxidase {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 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, AND TISSUE SPECIFICITY.
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, Pancreas,
RC 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, AND MUTAGENESIS OF SEC-73.
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).
CC {ECO:0000250|UniProtKB:P36968, ECO:0000250|UniProtKB:P36969,
CC ECO:0000269|PubMed:12566075, ECO:0000269|PubMed:18762024,
CC ECO:0000269|PubMed:19783653, ECO:0000269|PubMed:22207760,
CC ECO:0000269|PubMed:24439385, ECO:0000269|PubMed:25402683,
CC ECO:0000269|PubMed:25824823, ECO:0000269|PubMed:25922076,
CC 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=(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=(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:P36968};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48889;
CC Evidence={ECO:0000250|UniProtKB:P36968};
CC -!- SUBUNIT: Monomer. Has a tendency to form higher mass oligomers.
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). Isoform Mitochondrial and isoform
CC Cytoplasmic: Highly expressed during embryogenesis, while isoform
CC Nuclear is weakly expressed (PubMed:1668477). Isoform Mitochondrial and
CC isoform Nuclear are down-regulated between 14.5 dpc and 17.5 dpc, while
CC isoform Cytoplasmic remains constant (PubMed:1668477). Isoform Nuclear:
CC Mainly expressed in sperm (PubMed:11344099).
CC {ECO:0000269|PubMed:11344099, ECO:0000269|PubMed:12566075,
CC ECO:0000269|PubMed:1668477, ECO:0000269|PubMed:17503194,
CC ECO:0000269|PubMed:19417079, ECO:0000269|PubMed:22207760}.
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). Isoform mitochondrial: Selective
CC disruption of isoform mitochondrial causes sperm abnormalities and male
CC infertility (PubMed:19417079). Conditional knockout mice lacking Gpx4
CC 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:19417079, ECO:0000269|PubMed:19783653,
CC ECO:0000269|PubMed:19890015, ECO:0000269|PubMed:22207760,
CC ECO:0000269|PubMed:24599700, ECO:0000269|PubMed:25402683}.
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/";
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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 iPTMnet; O70325; -.
DR PhosphoSitePlus; O70325; -.
DR SwissPalm; O70325; -.
DR EPD; O70325; -.
DR jPOST; O70325; -.
DR PeptideAtlas; O70325; -.
DR PRIDE; O70325; -.
DR ProteomicsDB; 271319; -. [O70325-1]
DR ProteomicsDB; 271320; -. [O70325-2]
DR ProteomicsDB; 271321; -. [O70325-3]
DR ABCD; O70325; 1 sequenced antibody.
DR Antibodypedia; 3263; 366 antibodies from 41 providers.
DR DNASU; 625249; -.
DR Ensembl; ENSMUST00000097227; ENSMUSP00000094863; ENSMUSG00000075706. [O70325-3]
DR Ensembl; ENSMUST00000105372; ENSMUSP00000101011; ENSMUSG00000075706. [O70325-1]
DR GeneID; 625249; -.
DR KEGG; mmu:625249; -.
DR UCSC; uc007gbk.2; mouse. [O70325-1]
DR CTD; 2879; -.
DR MGI; MGI:104767; Gpx4.
DR VEuPathDB; HostDB:ENSMUSG00000075706; -.
DR eggNOG; KOG1651; Eukaryota.
DR GeneTree; ENSGT00940000161913; -.
DR OMA; FPMMSKI; -.
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 76 CRISPR screens.
DR ChiTaRS; Gpx4; mouse.
DR PRO; PR:O70325; -.
DR Proteomes; UP000000589; Chromosome 10.
DR Bgee; ENSMUSG00000075706; Expressed in spermatid and 128 other tissues.
DR ExpressionAtlas; O70325; baseline and differential.
DR Genevisible; O70325; MM.
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:0004601; F:peroxidase activity; IBA:GO_Central.
DR GO; GO:0047066; F:phospholipid-hydroperoxide glutathione peroxidase activity; IDA:UniProtKB.
DR GO; GO:0008430; F:selenium binding; ISO:MGI.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0019369; P:arachidonic acid metabolic process; ISS:UniProtKB.
DR GO; GO:0006325; P:chromatin organization; IDA:MGI.
DR GO; GO:0006749; P:glutathione metabolic process; ISO: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:0050727; P:regulation of inflammatory response; 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 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 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 /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
