GPX4

Last updated
GPX4
Protein GPX4 PDB 2gs3.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GPX4 , GPx-4, GSHPx-4, MCSP, PHGPx, snGPx, snPHGPx, SMDS, glutathione peroxidase 4
External IDs OMIM: 138322 MGI: 104767 HomoloGene: 134384 GeneCards: GPX4
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_002085
NM_001039847
NM_001039848
NM_001367832

NM_001037741
NM_008162
NM_001367995

RefSeq (protein)

NP_001034936
NP_001034937
NP_002076
NP_001354761

NP_001032830.2
NP_001032830
NP_032188
NP_001354924

Location (UCSC) Chr 19: 1.1 – 1.11 Mb Chr 10: 79.88 – 79.89 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Glutathione peroxidase 4, also known as GPX4, is an enzyme that in humans is encoded by the GPX4 gene. [5] GPX4 is a phospholipid hydroperoxidase that protects cells against membrane lipid peroxidation.

Contents

Discovery

GPX4 was first discovered in biochemistry laboratories of the University of Padua, where it was described as an enzyme capable of protecting against peroxidation. Its role as an inhibitor of cellular death was only discovered in 2012 by a research group Columbia University.

Function

The antioxidant enzyme glutathione peroxidase 4 (GPX4) belongs to the family of glutathione peroxidases, which consists of 8 known mammalian isoenzymes (GPX1–8). GPX4 catalyzes the reduction of hydrogen peroxide, organic hydroperoxides, and lipid peroxides at the expense of reduced glutathione and functions in the protection of cells against oxidative stress. The oxidized form of glutathione (glutathione disulfide), which is generated during the reduction of hydroperoxides by GPX4, is recycled by glutathione reductase and NADPH/H+. GPX4 differs from the other GPX family members in terms of its monomeric structure, a less restricted dependence on glutathione as reducing substrate, and the ability to reduce lipid-hydroperoxides inside biological membranes.

Inactivation of GPX4 leads to an accumulation of lipid peroxides, resulting in ferroptotic cell death. [6] [7] Mutations in GPX4 cause spondylometaphyseal dysplasia. [8]

Structure

Mammalian GPX1, GPX2, GPX3, and GPX4 (this protein) have been shown to be selenium-containing enzymes, whereas GPX6 is a selenoprotein in humans with cysteine-containing homologues in rodents. In selenoproteins, the amino acid selenocysteine is inserted in the nascent polypeptide chain during the process of translational recoding of the UGA stop codon. GPX4 shares the amino acid motif of selenocysteine, glutamine, and tryptophan (catalytic triad) with other glutathione peroxidases.

Reaction mechanism

GPX4 catalyzes the following reaction:

This reaction occurs at the selenocysteine within the catalytic center of GPX4. During the catalytic cycle of GPX4, the active selenol (-SeH) is oxidized by peroxides to selenenic acid (-SeOH), which is then reduced with glutathione (GSH) to an intermediate selenodisulfide (-Se-SG). GPX4 is eventually reactivated by a second glutathione molecule, releasing glutathione disulfide (GS-SG).

Subcellular distribution of isoforms

In mouse and rat, three distinct GPX4 isoforms with different subcellular localization are produced through alternative splicing and transcription initiation; cytosolic GPX4, mitochondrial GPX4 (mGPX4), and nuclear GPX4 (nGPX4). Cytosolic GPX4 has been identified as the only GPX4 isoform being essential for embryonic development and cell survival. The GPX4 isoforms mGPX4 and nGPX4 have been implicated in spermatogenesis and male fertility. [9] In humans, experimental evidence for alternative splicing exists; alternative transcription initiation and the cleavage sites of the mitochondrial and nuclear transit peptides need to be experimentally verified. [10]

Animal models

Knockout mice of GPX4 die at embryonic day 8 [11] [12] and conditional inducible deletion in adult mice (neurons) results in degeneration and death in less than a month. [13] Targeted disruption of the mitochondrial GPX4 isoform (mGPX4) caused infertility in male mice and disruption of the nuclear GPX4 isoform (nGPX4) reduced the structural stability of sperm chromatin, yet both knockout mouse models (for mGPX4 and nGPX4) were fully viable. Surprisingly, knockout of GPX4 heterozygously in mice (GPX4+/−) increases their median life span. [14] Knockout studies with GPX1, GPX2, or GPX3 deficient mice showed that cytosolic GPX4 is so far the only glutathione peroxidase that is indispensable for embryonic development and cell survival. As mechanisms to dispose of both hydrogen peroxide and lipid hydroperoxides are essential to life, this indicates that in contrast to the multiple metabolic pathways that can be utilized to dispose of hydrogen peroxide, pathways for the disposal of lipid hydroperoxides are limited.

While mammals have only one copy of the GPX4 gene, fish have two copies, GPX4a and GPX4b. [15] The GPX4's appear to play a greater role in the fish GPX system than in mammals. For example, in fish GPX4 activity contributes to a greater extent to total GPX activity, [16] GPX4a is the most highly expressed selenoprotein mRNA (in contrast to mammals where it is GPX1 mRNA) [17] and GPX4a appears to be highly inducible to changes within the cellular environment, such as changes in methylmercury and selenium status. [18]

Pathology

The interaction of GPX4 with the autophagic degradation pathway further modulates cell's response to oxidative stress. Impaired GPX4 function plays a role in tumorigenesis, neurodegeneration, infertility, inflammation, immune disorders, and ischemia-reperfusion injury. Additionally, the R152H mutation in GPX4 is involved in the development of Sedaghatian-type spinal metaphyseal dysplasia, a rare and fatal disease in newborn babies. [19]

Related Research Articles

Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants are frequently added to industrial products, such as polymers, fuels, and lubricants, to extend their usable lifetimes. Food are also treated with antioxidants to forestall spoilage, in particular the rancidification of oils and fats. In cells, antioxidants such as glutathione, mycothiol or bacillithiol, and enzyme systems like superoxide dismutase, can prevent damage from oxidative stress.

<span class="mw-page-title-main">Peroxidase</span> Peroxide-decomposing enzyme

Peroxidases or peroxide reductases are a large group of enzymes which play a role in various biological processes. They are named after the fact that they commonly break up peroxides.

<span class="mw-page-title-main">Glutathione peroxidase</span> Enzyme family protecting the organism from oxidative damages

Glutathione peroxidase (GPx) is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid hydroperoxides to their corresponding alcohols and to reduce free hydrogen peroxide to water.

In molecular biology a selenoprotein is any protein that includes a selenocysteine amino acid residue. Among functionally characterized selenoproteins are five glutathione peroxidases (GPX) and three thioredoxin reductases, (TrxR/TXNRD) which both contain only one Sec. Selenoprotein P is the most common selenoprotein found in the plasma. It is unusual because in humans it contains 10 Sec residues, which are split into two domains, a longer N-terminal domain that contains 1 Sec, and a shorter C-terminal domain that contains 9 Sec. The longer N-terminal domain is likely an enzymatic domain, and the shorter C-terminal domain is likely a means of safely transporting the very reactive selenium atom throughout the body.

<span class="mw-page-title-main">Lipid peroxidation</span> Reaction(s) leading to production of (phospho)lipid peroxides

Lipid peroxidation is the chain of reactions of oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism. It most often affects polyunsaturated fatty acids, because they contain multiple double bonds in between which lie methylene bridges (-CH2-) that possess especially reactive hydrogen atoms. As with any radical reaction, the reaction consists of three major steps: initiation, propagation, and termination. The chemical products of this oxidation are known as lipid peroxides or lipid oxidation products (LOPs).

<span class="mw-page-title-main">Peroxiredoxin</span> Family of antioxidant enzymes

Peroxiredoxins are a ubiquitous family of antioxidant enzymes that also control cytokine-induced peroxide levels and thereby mediate signal transduction in mammalian cells. The family members in humans are PRDX1, PRDX2, PRDX3, PRDX4, PRDX5, and PRDX6. The physiological importance of peroxiredoxins is indicated by their relative abundance. Their function is the reduction of peroxides, specifically hydrogen peroxide, alkyl hydroperoxides, and peroxynitrite.

<span class="mw-page-title-main">GPX1</span> Protein-coding gene in the species Homo sapiens

Glutathione peroxidase 1, also known as GPx1, is an enzyme that in humans is encoded by the GPX1 gene on chromosome 3. This gene encodes a member of the glutathione peroxidase family. Glutathione peroxidase functions in the detoxification of hydrogen peroxide, and is one of the most important antioxidant enzymes in humans.

In enzymology, a phospholipid-hydroperoxide glutathione peroxidase (EC 1.11.1.12) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Peroxiredoxin 2</span> Protein found in humans

Peroxiredoxin-2 is a protein that in humans is encoded by the PRDX2 gene.

<span class="mw-page-title-main">PRDX6</span> Protein-coding gene in the species Homo sapiens

Peroxiredoxin-6 is a protein that in humans is encoded by the PRDX6 gene. It is a member of the peroxiredoxin family of antioxidant enzymes.

<span class="mw-page-title-main">SEPP1</span> Protein-coding gene in the species Homo sapiens

Selenoprotein P is a protein that in humans is encoded by the SEPP1 gene.

<span class="mw-page-title-main">GPX2 (gene)</span> Protein-coding gene in the species Homo sapiens

Glutathione peroxidase 2 is an enzyme that in humans is encoded by the GPX2 gene.

<span class="mw-page-title-main">GSTZ1</span> Protein-coding gene in the species Homo sapiens

Glutathione S-transferase Zeta 1 is an enzyme that in humans is encoded by the GSTZ1 gene on chromosome 14.

<span class="mw-page-title-main">GPX7</span> Protein-coding gene in the species Homo sapiens

Glutathione peroxidase 7 is an enzyme that in humans is encoded by the GPX7 gene.

Selenium deficiency occurs when an organism lacks the required levels of selenium, a critical nutrient in many species. Deficiency, although relatively rare in healthy well-nourished individuals, can have significant negative results, affecting the health of the heart and the nervous system; contributing to depression, anxiety, and dementia; and interfering with reproduction and gestation.

<span class="mw-page-title-main">GPX3</span> Enzyme in humans

Glutathione peroxidase 3 (GPx-3), also known as plasma glutathione peroxidase (GPx-P) or extracellular glutathione peroxidase is an enzyme that in humans is encoded by the GPX3 gene.

<span class="mw-page-title-main">GPX5</span> Protein-coding gene in the species Homo sapiens

Glutathione peroxidase 5 (GPx-5), also known as epididymal secretory glutathione peroxidase is an enzyme that in humans is encoded by the GPX5 gene.

<span class="mw-page-title-main">GPX6</span> Protein-coding gene in the species Homo sapiens

Glutathione peroxidase 6 (GPx-6) is an enzyme that in humans is encoded by the GPX6 gene.

<span class="mw-page-title-main">Selenenic acid</span> Class of chemical compounds

A selenenic acid is an organoselenium compound and an oxoacid with the general formula RSeOH, where R ≠ H. It is the first member of the family of organoselenium oxoacids, which also include seleninic acids and selenonic acids, which are RSeO2H and RSeO3H, respectively. Selenenic acids derived from selenoenzymes are thought to be responsible for the antioxidant activity of these enzymes. This functional group is sometimes called SeO-selenoperoxol.

Oxytosis/ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides, and is genetically and biochemically distinct from other forms of regulated cell death such as apoptosis. Oxytosis/ferroptosis is initiated by the failure of the glutathione-dependent antioxidant defenses, resulting in unchecked lipid peroxidation and eventual cell death. Lipophilic antioxidants and iron chelators can prevent ferroptotic cell death. Although the connection between iron and lipid peroxidation has been appreciated for years, it was not until 2012 that Brent Stockwell and Scott J. Dixon coined the term ferroptosis and described several of its key features. Pamela Maher and David Schubert discovered the process in 2001 and called it oxytosis. While they did not describe the involvement of iron at the time, oxytosis and ferroptosis are today thought to be the same cell death mechanism.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000167468 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000075706 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Esworthy RS, Doan K, Doroshow JH, Chu FF (July 1994). "Cloning and sequencing of the cDNA encoding a human testis phospholipid hydroperoxide glutathione peroxidase". Gene. 144 (2): 317–8. doi:10.1016/0378-1119(94)90400-6. PMID   8039723.
  6. 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 (16 January 2014). "Regulation of ferroptotic cancer cell death by GPX4". Cell. 156 (1–2): 317–31. doi:10.1016/j.cell.2013.12.010. PMC   4076414 . PMID   24439385.
  7. 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 (17 November 2014). "Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice". Nature Cell Biology. 16 (12): 1180–1191. doi:10.1038/ncb3064. PMC   4894846 . PMID   25402683.
  8. Smith AC, Mears AJ, Bunker R, Ahmed A, MacKenzie M, Schwartzentruber JA, Beaulieu CL, Ferretti E, Majewski J, Bulman DE, Celik FC, Boycott KM, Graham GE, Graham GE (2014). "Mutations in the enzyme glutathione peroxidase 4 cause Sedaghatian-type spondylometaphyseal dysplasia". Journal of Medical Genetics. 51 (7): 470–4. doi:10.1136/jmedgenet-2013-102218. PMID   24706940. S2CID   22887914.
  9. Schneider M, Förster H, Boersma A, Seiler A, Wehnes H, Sinowatz F, Neumüller C, Deutsch MJ, Walch A, Hrabé de Angelis M, Wurst W, Ursini F, Roveri A, Maleszewski M, Maiorino M, Conrad M (May 2009). "Mitochondrial glutathione peroxidase 4 disruption causes male infertility" (PDF). FASEB J. 23 (9): 3233–42. doi:10.1096/fj.09-132795. PMID   19417079. S2CID   11610232.
  10. "Entrez Gene: GPX4 glutathione peroxidase 4 (phospholipid hydroperoxidase)".
  11. Yant LJ, Ran Q, Rao L, Van Remmen H, Shibatani T, Belter JG, Motta L, Richardson A, Prolla TA (February 2003). "The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults". Free Radic. Biol. Med. 34 (4): 496–502. doi:10.1016/S0891-5849(02)01360-6. PMID   12566075.
  12. Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H (2007). "Trends in oxidative aging theories". Free Radic. Biol. Med. 43 (4): 477–503. doi:10.1016/j.freeradbiomed.2007.03.034. PMID   17640558.
  13. Seiler A, Schneider M, Förster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E, Rådmark O, Wurst W, Bornkamm GW, Schweizer U, Conrad M (September 2008). "Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death". Cell Metab. 8 (3): 237–48. doi: 10.1016/j.cmet.2008.07.005 . PMID   18762024.
  14. Ran Q, Liang H, Ikeno Y, Qi W, Prolla TA, Roberts LJ, Wolf N, Van Remmen H, VanRemmen H, Richardson A (2007). "Reduction in glutathione peroxidase 4 increases life span through increased sensitivity to apoptosis". J. Gerontol. A Biol. Sci. Med. Sci. 62 (9): 932–42. doi: 10.1093/gerona/62.9.932 . PMID   17895430.
  15. Mariotti M, Ridge PG, Zhang Y, Lobanov AV, Pringle TH, Guigo R, Hatfield DL, Gladyshev VN (2012). "Composition and evolution of the vertebrate and mammalian selenoproteomes". PLOS ONE. 7 (3): e33066. Bibcode:2012PLoSO...733066M. doi: 10.1371/journal.pone.0033066 . PMC   3316567 . PMID   22479358.
  16. Grim JM, Hyndman KA, Kriska T, Girotti AW, Crockett EL (2011). "Relationship between oxidizable fatty acid content and level of antioxidant glutathione peroxidases in marine fish". The Journal of Experimental Biology. 214 (22): 3751–3759. doi:10.1242/jeb.058214. PMC   3202513 . PMID   22031739.
  17. Zheng W, Xu H, Lam SH, Luo H, Karuturi RK, Gong Z (2013). "Transcriptomic analyses of sexual dimorphism of the zebrafish liver and the effect of sex hormones". PLOS ONE. 8 (1): e53562. Bibcode:2013PLoSO...853562Z. doi: 10.1371/journal.pone.0053562 . PMC   3547925 . PMID   23349717.
  18. Penglase S, Hamre K, Ellingsen S (2014). "Selenium prevents downregulation of antioxidant selenoprotein genes by methylmercury". Free Radical Biology and Medicine. 75: 95–104. doi:10.1016/j.freeradbiomed.2014.07.019. hdl: 1956/8708 . PMID   25064324.
  19. Xie Y, Kang R, Klionsky DJ, Tang D (2023). "GPX4 in cell death, autophagy, and disease". Autophagy. 19 (10): 2621–2638. doi:10.1080/15548627.2023.2218764. PMC   10472888 . PMID   37272058.

Further reading