| IED ID | IndEnz0018000016 |
| Enzyme Type ID | peroxidase000016 |
| Protein Name |
Phospholipid hydroperoxide glutathione peroxidase PHGPx EC 1.11.1.12 Glutathione peroxidase 4 GPx-4 GSHPx-4 |
| Gene Name | Gpx4 |
| Organism | Mus musculus (Mouse) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Glires (Rodents and rabbits) Rodentia Myomorpha (mice and others) Muroidea Muridae Murinae Mus Mus Mus musculus (Mouse) |
| Enzyme Sequence | MSWGRLSRLLKPALLCGALAAPGLAGTMCASRDDWRCARSMHEFSAKDIDGHMVCLDKYRGFVCIVTNVASQUGKTDVNYTQLVDLHARYAECGLRILAFPCNQFGRQEPGSNQEIKEFAAGYNVKFDMYSKICVNGDDAHPLWKWMKVQPKGRGMLGNAIKWNFTKFLIDKNGCVVKRYGPMEEPQVIEKDLPCYL |
| Enzyme Length | 197 |
| Uniprot Accession Number | O70325 |
| Absorption | |
| Active Site | ACT_SITE 73; /evidence=ECO:0000269|PubMed:29290465 |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=a hydroperoxy polyunsaturated fatty acid + 2 glutathione = a hydroxy polyunsaturated fatty acid + glutathione disulfide + H2O; Xref=Rhea:RHEA:19057, ChEBI:CHEBI:15377, ChEBI:CHEBI:57925, ChEBI:CHEBI:58297, ChEBI:CHEBI:131871, ChEBI:CHEBI:134019; EC=1.11.1.12; Evidence={ECO:0000269|PubMed:29290465};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19058; Evidence={ECO:0000305}; CATALYTIC ACTIVITY: Reaction=(12S)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate + 2 glutathione = (12S)-hydroxy-(5Z,8Z,10E,14Z)-eicosatetraenoate + glutathione disulfide + H2O; Xref=Rhea:RHEA:50708, ChEBI:CHEBI:15377, ChEBI:CHEBI:57444, ChEBI:CHEBI:57925, ChEBI:CHEBI:58297, ChEBI:CHEBI:90680; Evidence={ECO:0000250|UniProtKB:P36969};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50709; Evidence={ECO:0000250|UniProtKB:P36969}; CATALYTIC ACTIVITY: Reaction=(13S)-hydroperoxy-(9Z,11E)-octadecadienoate + 2 glutathione = (13S)-hydroxy-(9Z,11E)-octadecadienoate + glutathione disulfide + H2O; Xref=Rhea:RHEA:48888, ChEBI:CHEBI:15377, ChEBI:CHEBI:57466, ChEBI:CHEBI:57925, ChEBI:CHEBI:58297, ChEBI:CHEBI:90850; Evidence={ECO:0000250|UniProtKB:P36968};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48889; Evidence={ECO:0000250|UniProtKB:P36968}; |
| DNA Binding | |
| EC Number | 1.11.1.12 |
| Enzyme Function | FUNCTION: Essential antioxidant peroxidase that directly reduces phospholipid hydroperoxide even if they are incorporated in membranes and lipoproteins (PubMed:29290465). Can also reduce fatty acid hydroperoxide, cholesterol hydroperoxide and thymine hydroperoxide (By similarity). Plays a key role in protecting cells from oxidative damage by preventing membrane lipid peroxidation (PubMed:12566075). Required to prevent cells from ferroptosis, a non-apoptotic cell death resulting from an iron-dependent accumulation of lipid reactive oxygen species (PubMed:12566075, PubMed:24439385, PubMed:25402683, PubMed:25922076, PubMed:29290465). The presence of selenocysteine (Sec) versus Cys at the active site is essential for life: it provides resistance to overoxidation and prevents cells against ferroptosis (PubMed:29290465). The presence of Sec at the active site is also essential for the survival of a specific type of parvalbumin-positive interneurons, thereby preventing against fatal epileptic seizures (PubMed:29290465). May be required to protect cells from the toxicity of ingested lipid hydroperoxides (PubMed:12566075). Required for normal sperm development and male fertility (PubMed:19783653, PubMed:25922076). Essential for maturation and survival of photoreceptor cells (PubMed:22207760). Plays a role in a primary T-cell response to viral and parasitic infection by protecting T-cells from ferroptosis and by supporting T-cell expansion (PubMed:25824823). Plays a role of glutathione peroxidase in platelets in the arachidonic acid metabolism (By similarity). Reduces hydroperoxy ester lipids formed by a 15-lipoxygenase that may play a role as down-regulator of the cellular 15-lipoxygenase pathway (By similarity). {ECO:0000250|UniProtKB:P36968, ECO:0000250|UniProtKB:P36969, ECO:0000269|PubMed:12566075, ECO:0000269|PubMed:18762024, ECO:0000269|PubMed:19783653, ECO:0000269|PubMed:22207760, ECO:0000269|PubMed:24439385, ECO:0000269|PubMed:25402683, ECO:0000269|PubMed:25824823, ECO:0000269|PubMed:25922076, ECO:0000269|PubMed:29290465}.; FUNCTION: [Isoform Cytoplasmic]: Specifically able to suppress the production of leukotriene and prostaglandin in response to several stimuli by reducing fatty acid hydroperoxide. {ECO:0000250|UniProtKB:P36970}.; FUNCTION: [Isoform Mitochondrial]: Specifically required to prevent mitochondrial cell death by mediating reduction of cardiolipin hydroperoxide (By similarity). Also required for normal sperm development and male fertility (PubMed:19417079). {ECO:0000250|UniProtKB:P36970, ECO:0000269|PubMed:19417079}.; FUNCTION: [Isoform Nuclear]: Required for male fertility by stabilizing the condensed chromatin in sperm nuclei (PubMed:12566075). {ECO:0000269|PubMed:12566075}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (1); Alternative sequence (2); Beta strand (9); Chain (1); Helix (9); Modified residue (1); Mutagenesis (2); Non-standard residue (1); Sequence conflict (3); Transit peptide (1); Turn (2) |
| Keywords | 3D-structure;Alternative initiation;Alternative splicing;Cytoplasm;Developmental protein;Lipid metabolism;Mitochondrion;Nucleus;Oxidoreductase;Peroxidase;Phosphoprotein;Reference proteome;Selenocysteine;Transit peptide |
| Interact With | |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: [Isoform Mitochondrial]: Mitochondrion {ECO:0000269|PubMed:12566075, ECO:0000269|PubMed:22207760}.; SUBCELLULAR LOCATION: [Isoform Cytoplasmic]: Cytoplasm {ECO:0000269|PubMed:12566075}.; SUBCELLULAR LOCATION: [Isoform Nuclear]: Nucleus {ECO:0000269|PubMed:11344099}. |
| Modified Residue | MOD_RES 40; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:P36970 |
| Post Translational Modification | |
| Signal Peptide | |
| Structure 3D | X-ray crystallography (1) |
| Cross Reference PDB | 5L71; |
| Mapped Pubmed ID | 10464096; 10984455; 11217851; 12152197; 12427732; 12466851; 12865426; 12888488; 12904583; 14572612; 14575705; 14610273; 14651853; 14681479; 15226823; 15496407; 15637642; 15831471; 15888450; 15901730; 16107710; 16246897; 16445905; 16458079; 16684775; 17395155; 17540721; 17895430; 17967808; 18206984; 18593884; 18614015; 18680556; 18799693; 18823256; 19007875; 19433132; 19447173; 19455133; 19744930; 19769463; 20798033; 21267068; 21402720; 21618532; 21717270; 22326323; 22401858; 22719900; 23364477; 23408027; 23695217; 23770613; 24191733; 24194600; 24803591; 24897344; 25313597; 25843658; 26042203; 26050606; 26083388; 26400084; 26463424; 27262435; 27317670; 27634046; 27689697; 28212525; 28627418; 29232557; 29937272; 30226473; 30289974; 30938680; 31248967; 31316058; 31534007; 31775041; 32286299; 32290105; 32374849; 32376803; 32457486; 32541831; 32583428; 33414455; 34131139; 34133924; 34145375; 34206421; 34279220; 34285231; 34339707; 34360557; 34385713; 34568331; 34626772; 34914312; 34999258; 35173188; 7798170; 9792801; |
| Motif | |
| Gene Encoded By | |
| Mass | 22,229 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | RHEA:19057; RHEA:19058; RHEA:50708; RHEA:50709; RHEA:48888; RHEA:48889 |
| Cross Reference Brenda | 1.11.1.12; |