Biology:Glutathione peroxidase 4

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Short description: Mammalian protein found in Homo sapiens

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Glutathione peroxidase 4, also known as GPX4, is an enzyme that in humans is encoded by the GPX4 gene.[1] GPX4 is a phospholipid hydroperoxidase that protects cells against membrane lipid peroxidation.

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.[2][3] Mutations in GPX4 cause spondylometaphyseal dysplasia.[4] In vitro studies suggest that GPX4 protects cells against cold-induced cell death.[5]

Therapy-resistant cancer cells in a high-mesenchymal state depend on a lipid peroxidase pathway to suppress ferroptosis, indicating a critical survival mechanism in this cellular context.[6] Drug-tolerant persister cells exhibit a specific dependency on the lipid hydroperoxidase GPX4 for survival; inhibition of GPX4 induces ferroptotic cell death in these cells.[7]

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.[8] 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.[9]

Animal models

Knockout mice of GPX4 die at embryonic day 8[10][11] and conditional inducible deletion in adult mice (neurons) results in degeneration and death in less than a month.[12] 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.[13] 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.[14] 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,[15] GPX4a is the most highly expressed selenoprotein mRNA (in contrast to mammals where it is GPX1 mRNA)[16] and GPX4a appears to be highly inducible to changes within the cellular environment, such as changes in methylmercury and selenium status.[17]

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.[18]

References

  1. ↑ "Cloning and sequencing of the cDNA encoding a human testis phospholipid hydroperoxide glutathione peroxidase". Gene 144 (2): 317–318. July 1994. doi:10.1016/0378-1119(94)90400-6. PMID 8039723. 
  2. ↑ "Regulation of ferroptotic cancer cell death by GPX4". Cell 156 (1–2): 317–331. January 2014. doi:10.1016/j.cell.2013.12.010. PMID 24439385. 
  3. ↑ "Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice". Nature Cell Biology 16 (12): 1180–1191. December 2014. doi:10.1038/ncb3064. PMID 25402683. 
  4. ↑ "Mutations in the enzyme glutathione peroxidase 4 cause Sedaghatian-type spondylometaphyseal dysplasia". Journal of Medical Genetics 51 (7): 470–474. July 2014. doi:10.1136/jmedgenet-2013-102218. PMID 24706940. 
  5. ↑ Kajderowicz, Kathrin M.; Lam, Breanna; Keys, Heather R.; Roessler, Julian M.; Frenkel, Evgeni M.; Kirkland, Adina; Bisht, Punam; El-Brolosy, Mohamed A. et al. (2024). "Multi-species genome-wide CRISPR screens identify conserved suppressors of cold-induced cell death". eLife. doi:10.7554/eLife.102310.1. PMID 39091747. 
  6. ↑ "Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway". Nature 547 (7664): 453–457. July 2017. doi:10.1038/nature23007. PMID 28678785. 
  7. ↑ "Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition". Nature 551 (7679): 247–250. November 2017. doi:10.1038/nature24297. PMID 29088702. Bibcode: 2017Natur.551..247H. 
  8. ↑ "Mitochondrial glutathione peroxidase 4 disruption causes male infertility". FASEB Journal 23 (9): 3233–3242. September 2009. doi:10.1096/fj.09-132795. PMID 19417079. 
  9. ↑ "Entrez Gene: GPX4 glutathione peroxidase 4 (phospholipid hydroperoxidase)". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=2879. 
  10. ↑ "The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults". Free Radical Biology & Medicine 34 (4): 496–502. February 2003. doi:10.1016/S0891-5849(02)01360-6. PMID 12566075. 
  11. ↑ "Trends in oxidative aging theories". Free Radical Biology & Medicine 43 (4): 477–503. August 2007. doi:10.1016/j.freeradbiomed.2007.03.034. PMID 17640558. 
  12. ↑ "Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death". Cell Metabolism 8 (3): 237–248. September 2008. doi:10.1016/j.cmet.2008.07.005. PMID 18762024. 
  13. ↑ "Reduction in glutathione peroxidase 4 increases life span through increased sensitivity to apoptosis". The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 62 (9): 932–942. September 2007. doi:10.1093/gerona/62.9.932. PMID 17895430. 
  14. ↑ "Composition and evolution of the vertebrate and mammalian selenoproteomes". PLOS ONE 7 (3). 2012. doi:10.1371/journal.pone.0033066. PMID 22479358. Bibcode: 2012PLoSO...733066M. 
  15. ↑ "Relationship between oxidizable fatty acid content and level of antioxidant glutathione peroxidases in marine fish". The Journal of Experimental Biology 214 (Pt 22): 3751–3759. November 2011. doi:10.1242/jeb.058214. PMID 22031739. Bibcode: 2011JExpB.214.3751G. 
  16. ↑ "Transcriptomic analyses of sexual dimorphism of the zebrafish liver and the effect of sex hormones". PLOS ONE 8 (1). 2013. doi:10.1371/journal.pone.0053562. PMID 23349717. Bibcode: 2013PLoSO...853562Z. 
  17. ↑ "Selenium prevents downregulation of antioxidant selenoprotein genes by methylmercury". Free Radical Biology & Medicine 75: 95–104. October 2014. doi:10.1016/j.freeradbiomed.2014.07.019. PMID 25064324. 
  18. ↑ "GPX4 in cell death, autophagy, and disease". Autophagy 19 (10): 2621–2638. October 2023. doi:10.1080/15548627.2023.2218764. PMID 37272058. 

Further reading

  • "Role of mitochondrial phospholipid hydroperoxide glutathione peroxidase (PHGPx) as an antiapoptotic factor". Biological & Pharmaceutical Bulletin 27 (7): 956–960. July 2004. doi:10.1248/bpb.27.956. PMID 15256721. 
  • "Cloning and sequencing of the cDNA encoding a human testis phospholipid hydroperoxide glutathione peroxidase". Gene 144 (2): 317–318. July 1994. doi:10.1016/0378-1119(94)90400-6. PMID 8039723. 
  • "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–174. January 1994. doi:10.1016/0378-1119(94)90802-8. PMID 8125298. 
  • "The human glutathione peroxidase genes GPX2, GPX3, and GPX4 map to chromosomes 14, 5, and 19, respectively". Cytogenetics and Cell Genetics 66 (2): 96–98. 1994. doi:10.1159/000133675. PMID 8287691. 
  • "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. September 1996. doi:10.1101/gr.6.9.791. PMID 8889548. 
  • "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–156. October 1997. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149. 
  • "Glutathione depletion associated with the HIV-1 TAT protein mediates the extracellular appearance of acidic fibroblast growth factor". Archives of Biochemistry and Biophysics 351 (1): 17–26. March 1998. doi:10.1006/abbi.1997.0566. PMID 9501919. 
  • "Structural organization of the human selenium-dependent phospholipid hydroperoxide glutathione peroxidase gene (GPX4): chromosomal localization to 19p13.3". Biochemical and Biophysical Research Communications 249 (1): 53–55. August 1998. doi:10.1006/bbrc.1998.9086. PMID 9705830. Bibcode: 1998BBRC..249...53K. 
  • "Dual function of the selenoprotein PHGPx during sperm maturation". Science 285 (5432): 1393–1396. August 1999. doi:10.1126/science.285.5432.1393. PMID 10464096. 
  • "Molecular mechanism of decreased glutathione content in human immunodeficiency virus type 1 Tat-transgenic mice". The Journal of Biological Chemistry 275 (5): 3693–3698. February 2000. doi:10.1074/jbc.275.5.3693. PMID 10652368. 
  • "Human immunodeficiency virus type 1 Tat protein impairs selenoglutathione peroxidase expression and activity by a mechanism independent of cellular selenium uptake: consequences on cellular resistance to UV-A radiation". Archives of Biochemistry and Biophysics 386 (2): 213–220. February 2001. doi:10.1006/abbi.2000.2197. PMID 11368344. 
  • "Expression of Human Phospholipid Hydroperoxide Glutathione Peroxidase". Oxidants and Antioxidants. Methods Mol. Biol.. 196. 2003. pp. 195–9. doi:10.1385/1-59259-274-0:195. ISBN 1-59259-274-0. 
  • "Male fertility is linked to the selenoprotein phospholipid hydroperoxide glutathione peroxidase". Biology of Reproduction 67 (3): 967–971. September 2002. doi:10.1095/biolreprod.102.003822. PMID 12193409. 
  • "Regulation of expression of the phospholipid hydroperoxide/sperm nucleus glutathione peroxidase gene. Tissue-specific expression pattern and identification of functional cis- and trans-regulatory elements". The Journal of Biological Chemistry 278 (4): 2571–2580. January 2003. doi:10.1074/jbc.M209064200. PMID 12427732. 
  • "A novel single nucleotide polymorphism in the 3' untranslated region of human glutathione peroxidase 4 influences lipoxygenase metabolism". Blood Cells, Molecules & Diseases 29 (2): 174–178. 2003. doi:10.1006/bcmd.2002.0556. PMID 12490284. 
  • "Genetic variations of gpx-4 and male infertility in humans". Biology of Reproduction 68 (4): 1134–1141. April 2003. doi:10.1095/biolreprod.102.007500. PMID 12606444. 
  • "Phospholipid hydroperoxide glutathione peroxidase induces a delay in G1 of the cell cycle". Free Radical Research 37 (6): 621–630. June 2003. doi:10.1080/1071576031000088283. PMID 12868489. 
  • "Depletion of phospholipid hydroperoxide glutathione peroxidase up-regulates arachidonate metabolism by 12S-lipoxygenase and cyclooxygenase 1 in human epidermoid carcinoma A431 cells". FASEB Journal 17 (12): 1694–1696. September 2003. doi:10.1096/fj.02-0847fje. PMID 12958179. 
  • "Regulation of selenoprotein GPx4 expression and activity in human endothelial cells by fatty acids, cytokines and antioxidants". Atherosclerosis 171 (1): 57–65. November 2003. doi:10.1016/j.atherosclerosis.2003.08.008. PMID 14642406. 
  • Overview of all the structural information available in the PDB for UniProt: P36969 (Phospholipid hydroperoxide glutathione peroxidase) at the PDBe-KB.



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