5l71

Structural highlights

Function

GPX4_MOUSE 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).[UniProtKB:P36968][UniProtKB:P36969]^{[1] [2] [3] [4] [5] [6] [7] [8] [9]} Specifically able to suppress the production of leukotriene and prostaglandin in response to several stimuli by reducing fatty acid hydroperoxide.[UniProtKB:P36970] 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).[UniProtKB:P36970]^[10] Required for male fertility by stabilizing the condensed chromatin in sperm nuclei (PubMed:12566075).^[11]

See Also

• Glutathione peroxidase

References

1. ↑ Yant LJ, Ran Q, Rao L, Van Remmen H, Shibatani T, Belter JG, Motta L, Richardson A, Prolla TA. The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic Biol Med. 2003 Feb 15;34(4):496-502. PMID:12566075
2. ↑ Seiler A, Schneider M, Forster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E, Radmark O, Wurst W, Bornkamm GW, Schweizer U, Conrad M. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 2008 Sep;8(3):237-48. PMID:18762024 doi:http://dx.doi.org/S1550-4131(08)00212-X
3. ↑ Imai H, Hakkaku N, Iwamoto R, Suzuki J, Suzuki T, Tajima Y, Konishi K, Minami S, Ichinose S, Ishizaka K, Shioda S, Arata S, Nishimura M, Naito S, Nakagawa Y. Depletion of selenoprotein GPx4 in spermatocytes causes male infertility in mice. J Biol Chem. 2009 Nov 20;284(47):32522-32. PMID:19783653 doi:10.1074/jbc.M109.016139
4. ↑ Ueta T, Inoue T, Furukawa T, Tamaki Y, Nakagawa Y, Imai H, Yanagi Y. Glutathione peroxidase 4 is required for maturation of photoreceptor cells. J Biol Chem. 2012 Mar 2;287(10):7675-82. doi: 10.1074/jbc.M111.335174. Epub 2011 , Dec 29. PMID:22207760 doi:http://dx.doi.org/10.1074/jbc.M111.335174
5. ↑ Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM, Girotti AW, Cornish VW, Schreiber SL, Stockwell BR. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014 Jan 16;156(1-2):317-331. PMID:24439385 doi:10.1016/j.cell.2013.12.010
6. ↑ Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A, Eggenhofer E, Basavarajappa D, Rådmark O, Kobayashi S, Seibt T, Beck H, Neff F, Esposito I, Wanke R, Förster H, Yefremova O, Heinrichmeyer M, Bornkamm GW, Geissler EK, Thomas SB, Stockwell BR, O'Donnell VB, Kagan VE, Schick JA, Conrad M. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014 Dec;16(12):1180-91. PMID:25402683 doi:10.1038/ncb3064
7. ↑ Matsushita M, Freigang S, Schneider C, Conrad M, Bornkamm GW, Kopf M. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J Exp Med. 2015 Apr 6;212(4):555-68. doi: 10.1084/jem.20140857. Epub 2015 Mar 30. PMID:25824823 doi:http://dx.doi.org/10.1084/jem.20140857
8. ↑ Ingold I, Aichler M, Yefremova E, Roveri A, Buday K, Doll S, Tasdemir A, Hoffard N, Wurst W, Walch A, Ursini F, Friedmann Angeli JP, Conrad M. Expression of a Catalytically Inactive Mutant Form of Glutathione Peroxidase 4 (Gpx4) Confers a Dominant-negative Effect in Male Fertility. J Biol Chem. 2015 Jun 5;290(23):14668-78. PMID:25922076 doi:10.1074/jbc.M115.656363
9. ↑ Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, Roveri A, Peng X, Porto Freitas F, Seibt T, Mehr L, Aichler M, Walch A, Lamp D, Jastroch M, Miyamoto S, Wurst W, Ursini F, Arnér ESJ, Fradejas-Villar N, Schweizer U, Zischka H, Friedmann Angeli JP, Conrad M. Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. Cell. 2018 Jan 25;172(3):409-422.e21. PMID:29290465 doi:10.1016/j.cell.2017.11.048
10. ↑ Schneider M, Forster H, Boersma A, Seiler A, Wehnes H, Sinowatz F, Neumuller C, Deutsch MJ, Walch A, Hrabe de Angelis M, Wurst W, Ursini F, Roveri A, Maleszewski M, Maiorino M, Conrad M. Mitochondrial glutathione peroxidase 4 disruption causes male infertility. FASEB J. 2009 Sep;23(9):3233-42. doi: 10.1096/fj.09-132795. Epub 2009 May 5. PMID:19417079 doi:http://dx.doi.org/10.1096/fj.09-132795
11. ↑ Yant LJ, Ran Q, Rao L, Van Remmen H, Shibatani T, Belter JG, Motta L, Richardson A, Prolla TA. The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic Biol Med. 2003 Feb 15;34(4):496-502. PMID:12566075
12. ↑ Janowski R, Scanu S, Niessing D, Madl T. Crystal and solution structural studies of mouse phospholipid hydroperoxide glutathione peroxidase 4. Acta Crystallogr F Struct Biol Commun. 2016 Oct 1;72(Pt 10):743-749. Epub 2016, Sep 22. PMID:27710939 doi:http://dx.doi.org/10.1107/S2053230X16013686