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词条 GPX1
释义

  1. Structure

  2. Function

  3. Animal studies

  4. Clinical significance

  5. Interactions

  6. References

  7. Further reading

{{Infobox_gene}}Glutathione peroxidase 1, also known as GPx1, is an enzyme that in humans is encoded by the GPX1 gene on chromosome 3.[1] 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.[2]

Structure

This gene encodes a member of the glutathione peroxidase family, consisting of eight known glutathione peroxidases (GPx1-8) in humans. Mammalian Gpx1 (this gene), Gpx2, Gpx3, and Gpx4 have been shown to be selenium-containing enzymes, whereas Gpx6 is a selenoprotein in humans with cysteine-containing homologues in rodents.[2][2][3] In selenoproteins, the 21st amino acid selenocysteine is inserted in the nascent polypeptide chain during the process of translational recoding of the UGA stop codon.[2][4] In addition to the UGA-codon, a cis-acting element in the mRNA, called SECIS, binds SBP2 to recruit other proteins, such as eukaryotic elongation factor selenocysteine-tRNA specific, to form the complex responsible for the recoding process.[3]

The protein encoded by this gene forms a homotetramer structure. As with other glutathione peroxidases, GPx1 has a conserved catalytic tetrad composed of Sec or Cys, Gln, Trp, and Asn, where the Sec is surrounded by four arginines (R 57, 103, 184, 185; bovine numbering) and a lysine of an adjacent subunit (K 91'). These 5 residues bind glutathione (GSH) and are only present in GPx1.[2]

Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[2]

Glutathione peroxidase 1 is characterized in a polyalanine sequence polymorphism in the N-terminal region, which includes three alleles with five, six or seven alanine (Ala) repeats in this sequence. The allele with five Ala repeats is significantly associated with breast cancer risk.[5]

Function

GPX1 is ubiquitously expressed in many tissues, where it protects cells from oxidative stress.[2][3] Within cells, it localizes to the cytoplasm and mitochondria.[2] As a glutathione peroxidase, GPx1 functions in the detoxification of hydrogen peroxide, specifically by catalyzing the reduction of hydrogen peroxide to water. The glutathione peroxidase also catalyzes the reduction of other organic hydroperoxides, such as lipid peroxides, to the corresponding alcohols.[5][2][6] GPx1 typically uses glutathione (GSH) as the reductant, but when glutathione synthetase (GSS) is, as in brain mitochondria, γ-glutamylcysteine can serve as the reductant instead.[2] The protein encoded by this gene protects from CD95-induced apoptosis in cultured breast cancer cells and inhibits 5-lipoxygenase in blood cells, and its overexpression delays endothelial cell death and increases resistance to toxic challenges, especially oxidative stress.[3][6][7][8] This protein is one of only a few proteins known in higher vertebrates to contain selenocysteine, which occurs at the active site of glutathione peroxidase and is coded by the nonsense (stop) codon TGA.[5][3]

GPX1 forms a highly reactive selenenic acid intermediate, providing insight into the way that the protein environment stabilizes these intermediates and paving the way for new therapeutics. Selenenic acid is protected by the protein environment from reactive groups within the protein. The mechanism of action is based on selenenic acid reacting with the amid or amine bond of another protein, forming a senyladmide bond, suggesting a role for this bond new bond in protecting the reactivity of GPX1.[9]

Animal studies

GPX1 helps to prevent cardiac dysfunction after ischemia-reperfusion injuries. Mitochondrial ROS production and oxidative mtDNA damage is increased during reoxygenation in the GPX1 knockout mice, in addition to structural abnormalities in cardiac mitochondria and myocytes, suggesting GPX1 may play an important role in protecting cardiac mitochondria from reoxygenation damage in vivo.[10]

In GPX1 (-/-) mice, oxidant formation is increased, endothelial NO synthase is deregulated, and adhesion of leukocytes to cultured endothelial cells is increased. Experimental GPX1 deficiency amplifies certain aspects of aging, namely endothelial dysfunction, vascular remodeling, and invasion of leukocytes in cardiovascular tissue.[11]

Clinical significance

The GPx1 allele with five Ala repeats is significantly associated with breast cancer risk.[5]

Kocabasoglu, et al., sought to investigate connections between oxidative stress genes, including GPX1, and Panic Disorder, an anxiety disorder characterized by random and unexpected attacks of intense fear. Although the GPX1 Pro198Leu polymorphism, in general, did not significantly correlate with panic disorder risk, the study found a plausible association of the C allele of the GPX1 Pro198Leu polymorphism, found to be more frequent in the female cohort, with PD development.[12]

Ergen and colleagues analyzed gene expression of oxidative stress genes, specifically GPX1, in colorectal tumors in comparison to healthy colorectal tissues. ELISA was utilized to quantify GPX1 protein expression levels in both tissue types, highlighting a 2-fold decrease in tumor tissue (p<0.05).[13]

In esophageal cancer, Chen and colleagues found that vitamin D, a known suppressor of GPX1 expression via the NF-kB signaling pathway, could help to decrease the proliferative, migratory, and invasive capabilities of esophageal cancer cells. Unlike in colorectal cancer, GPX1 expression in esophageal cancer cells is thought to drive aggressive growth and metastasis, but Vitamin D-mediated decrease in GPX1 prevents such growth.[14]

In a study looking at gene polymorphisms of GPX1 and other oxidative stress genes in relation to prevalence of Type 2 diabetes mellitus, Banerjee, et al, found that while no association was found in expression of most GPX1 polymorphisms and risk of Type 2 diabetes mellitus, having the C allele of GPX1 led to a 1.362 times higher risk of the disease, highlighting the importance of finding individuals in the population with this gene variant to help treat them early on.[15]

Recent work by Alan M. Diamond and colleagues has shown that allelic variations of GPX1, like the codon 198 polymorphism that results in leucine or proline and an increase in alanine repeat codons, can result in different localization levels in MCF-7 human breast carcinoma cells. For instance, the allele expressing the leucine-198 polymorphism and 7 alanine repeats generates GPX-1 localization that is disproportionately in the cytoplasm as compared to other allelic variants. To further understand the effects of these variants on GPX-1 function, mutant GPX-1 with mitochondrial localization sequences were generated and the GPX-1 infused cells were analyzed for their response to oxidative stress, energy metabolism and cancer-associated signaling molecules. Ultimately, GPX-1 variants heavily influenced cellular biology, suggesting that different GPX-1 variants affect cancer risk differently.[16]

An analysis of GPX1 expression in oligodendrocytes from patients with major depressive disorder and control patients showed that GPX1 levels were significantly decreased in patients with the disorder, but not in their astrocytes. Shortening of telomeres and decreased expression of telomerase were also evident in these oligodendrocytes, but not in the astrocytes in these patients. This suggests that decreased oxidative stress protection, as observed by decreased GPX1 levels, and decreased telomerase expression may help give rise to telomere shortening in patients suffering from MDD.[17]

Interactions

GPX1 has been shown to interact with ABL and GSH.[2][18]

A recently discovered suppressor for GPX1 is S-adenosylhomocysteine, which when accumulated in endothelial cells can cause tRNA(Sec) hypomethylation, reducing the expression of GPX1 and other selenoproteins. The decreased GPX-1 expression can then lead to inflammatory activating of endothelial cells, helping give rise to a proatherogenic endothelial phenotype.[19]

References

1. ^{{cite journal | vauthors = Kiss C, Li J, Szeles A, Gizatullin RZ, Kashuba VI, Lushnikova T, Protopopov AI, Kelve M, Kiss H, Kholodnyuk ID, Imreh S, Klein G, Zabarovsky ER | title = Assignment of the ARHA and GPX1 genes to human chromosome bands 3p21.3 by in situ hybridization and with somatic cell hybrids | journal = Cytogenetics and Cell Genetics | volume = 79 | issue = 3–4 | pages = 228–30 | date = Jun 1998 | pmid = 9605859 | pmc = | doi = 10.1159/000134729 }}
2. ^1 2 3 4 5 6 {{cite journal | vauthors = Brigelius-Flohé R, Maiorino M | title = Glutathione peroxidases | journal = Biochimica et Biophysica Acta | volume = 1830 | issue = 5 | pages = 3289–303 | date = May 2013 | pmid = 23201771 | doi = 10.1016/j.bbagen.2012.11.020 }}
3. ^1 2 3 4 {{cite journal | vauthors = Higashi Y, Pandey A, Goodwin B, Delafontaine P | title = Insulin-like growth factor-1 regulates glutathione peroxidase expression and activity in vascular endothelial cells: Implications for atheroprotective actions of insulin-like growth factor-1 | journal = Biochimica et Biophysica Acta | volume = 1832 | issue = 3 | pages = 391–9 | date = Mar 2013 | pmid = 23261989 | doi = 10.1016/j.bbadis.2012.12.005 | pmc=3557755}}
4. ^{{cite journal | vauthors = Hubert N, Walczak R, Sturchler C, Myslinski E, Schuster C, Westhof E, Carbon P, Krol A | title = RNAs mediating cotranslational insertion of selenocysteine in eukaryotic selenoproteins | journal = Biochimie | volume = 78 | issue = 7 | pages = 590–6 | date = 1996 | pmid = 8955902 | doi=10.1016/s0300-9084(96)80005-8}}
5. ^1 2 3 4 5 6 7 {{cite web | title = Entrez Gene: GPX1 glutathione peroxidase 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2876| accessdate = }}
6. ^1 {{cite journal | vauthors = Tan SM, Stefanovic N, Tan G, Wilkinson-Berka JL, de Haan JB | title = Lack of the antioxidant glutathione peroxidase-1 (GPx1) exacerbates retinopathy of prematurity in mice | journal = Investigative Ophthalmology & Visual Science | volume = 54 | issue = 1 | pages = 555–62 | date = Jan 2013 | pmid = 23287791 | doi = 10.1167/iovs.12-10685 }}
7. ^{{cite journal | vauthors = Gouaze V, Andrieu-Abadie N, Cuvillier O, Malagarie-Cazenave S, Frisach MF, Mirault ME, Levade T | title = Glutathione peroxidase-1 protects from CD95-induced apoptosis | journal = The Journal of Biological Chemistry | volume = 277 | issue = 45 | pages = 42867–74 | date = Nov 2002 | pmid = 12221075 | doi = 10.1074/jbc.M203067200 }}
8. ^{{cite journal | vauthors = Straif D, Werz O, Kellner R, Bahr U, Steinhilber D | title = Glutathione peroxidase-1 but not -4 is involved in the regulation of cellular 5-lipoxygenase activity in monocytic cells | journal = The Biochemical Journal | volume = 349 | issue = Pt 2 | pages = 455–61 | date = Jul 2000 | pmid = 10880344 | doi=10.1042/bj3490455 | pmc=1221168}}
9. ^{{cite journal | vauthors = Li F, Liu J, Rozovsky S | title = Glutathione peroxidase's reaction intermediate selenenic acid is stabilized by the protein microenvironment | journal = Free Radical Biology & Medicine | volume = 76 | pages = 127–35 | date = Nov 2014 | pmid = 25124921 | doi = 10.1016/j.freeradbiomed.2014.07.041 | pmc=4253559}}
10. ^{{cite journal | vauthors = Thu VT, Kim HK, Ha SH, Yoo JY, Park WS, Kim N, Oh GT, Han J | title = Glutathione peroxidase 1 protects mitochondria against hypoxia/reoxygenation damage in mouse hearts | journal = Pflügers Archiv | volume = 460 | issue = 1 | pages = 55–68 | date = Jun 2010 | pmid = 20306076 | doi = 10.1007/s00424-010-0811-7 }}
11. ^{{cite journal | vauthors = Oelze M, Kröller-Schön S, Steven S, Lubos E, Doppler C, Hausding M, Tobias S, Brochhausen C, Li H, Torzewski M, Wenzel P, Bachschmid M, Lackner KJ, Schulz E, Münzel T, Daiber A | title = Glutathione peroxidase-1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging | journal = Hypertension | volume = 63 | issue = 2 | pages = 390–6 | date = Feb 2014 | pmid = 24296279 | doi = 10.1161/hypertensionaha.113.01602 }}
12. ^{{Unreliable medical source|sure=y|date=July 2015}} {{cite journal | vauthors = Cengiz M, Bayoglu B, Alansal NO, Cengiz S, Dirican A, Kocabasoglu N | title = Pro198Leu polymorphism in the oxidative stress gene, glutathione peroxidase-1, is associated with a gender-specific risk for panic disorder | journal = International Journal of Psychiatry in Clinical Practice | pages = 1–7 | date = Mar 2015 | pmid = 25666858 | doi = 10.3109/13651501.2015.1016973 | volume=19}}
13. ^{{Unreliable medical source|sure=y|date=July 2015}} {{cite journal | vauthors = Nalkiran I, Turan S, Arikan S, Kahraman ÖT, Acar L, Yaylim I, Ergen A | title = Determination of gene expression and serum levels of MnSOD and GPX1 in colorectal cancer | journal = Anticancer Research | volume = 35 | issue = 1 | pages = 255–9 | date = Jan 2015 | pmid = 25550558 }}
14. ^{{Unreliable medical source|sure=y|date=July 2015}} {{cite journal | vauthors = Gan X, Chen B, Shen Z, Liu Y, Li H, Xie X, Xu X, Li H, Huang Z, Chen J | title = High GPX1 expression promotes esophageal squamous cell carcinoma invasion, migration, proliferation and cisplatin-resistance but can be reduced by vitamin D | journal = International Journal of Clinical and Experimental Medicine | volume = 7 | issue = 9 | pages = 2530–40 | date = 2014 | pmid = 25356106 | pmc=4211756}}
15. ^{{Unreliable medical source|sure=y|date=July 2015}} {{cite journal | vauthors = Vats P, Sagar N, Singh TP, Banerjee M | title = Association of Superoxide dismutases (SOD1 and SOD2) and Glutathione peroxidase 1 (GPx1) gene polymorphisms with type 2 diabetes mellitus | journal = Free Radical Research | volume = 49 | issue = 1 | pages = 17–24 | date = Jan 2015 | pmid = 25283363 | doi = 10.3109/10715762.2014.971782 }}
16. ^{{Unreliable medical source|sure=y|date=July 2015}} {{cite journal | vauthors = Bera S, Weinberg F, Ekoue DN, Ansenberger-Fricano K, Mao M, Bonini MG, Diamond AM | title = Natural allelic variations in glutathione peroxidase-1 affect its subcellular localization and function | journal = Cancer Research | volume = 74 | issue = 18 | pages = 5118–26 | date = Sep 2014 | pmid = 25047527 | doi = 10.1158/0008-5472.can-14-0660 | pmc=4167490}}
17. ^{{Unreliable medical source|sure=y|date=July 2015}} {{cite journal | vauthors = Szebeni A, Szebeni K, DiPeri T, Chandley MJ, Crawford JD, Stockmeier CA, Ordway GA | title = Shortened telomere length in white matter oligodendrocytes in major depression: potential role of oxidative stress | journal = The International Journal of Neuropsychopharmacology | volume = 17 | issue = 10 | pages = 1579–89 | date = Oct 2014 | pmid = 24967945 | doi = 10.1017/s1461145714000698 }}
18. ^{{cite journal | vauthors = Cao C, Leng Y, Huang W, Liu X, Kufe D | title = Glutathione peroxidase 1 is regulated by the c-Abl and Arg tyrosine kinases | journal = The Journal of Biological Chemistry | volume = 278 | issue = 41 | pages = 39609–14 | date = Oct 2003 | pmid = 12893824 | doi = 10.1074/jbc.M305770200 }}
19. ^{{cite journal | vauthors = Barroso M, Florindo C, Kalwa H, Silva Z, Turanov AA, Carlson BA, de Almeida IT, Blom HJ, Gladyshev VN, Hatfield DL, Michel T, Castro R, Loscalzo J, Handy DE | title = Inhibition of cellular methyltransferases promotes endothelial cell activation by suppressing glutathione peroxidase 1 protein expression | journal = The Journal of Biological Chemistry | volume = 289 | issue = 22 | pages = 15350–62 | date = May 2014 | pmid = 24719327 | doi = 10.1074/jbc.m114.549782 | pmc=4140892}}

Further reading

{{refbegin|33em}}
  • {{cite journal | vauthors = Moscow JA, Morrow CS, He R, Mullenbach GT, Cowan KH | title = Structure and function of the 5'-flanking sequence of the human cytosolic selenium-dependent glutathione peroxidase gene (hgpx1) | journal = The Journal of Biological Chemistry | volume = 267 | issue = 9 | pages = 5949–58 | date = Mar 1992 | pmid = 1556108 | doi = }}
  • {{cite journal | vauthors = Chada S, Le Beau MM, Casey L, Newburger PE | title = Isolation and chromosomal localization of the human glutathione peroxidase gene | journal = Genomics | volume = 6 | issue = 2 | pages = 268–71 | date = Feb 1990 | pmid = 2307470 | doi = 10.1016/0888-7543(90)90566-D }}
  • {{cite journal | vauthors = Mullenbach GT, Tabrizi A, Irvine BD, Bell GI, Hallewell RA | title = Sequence of a cDNA coding for human glutathione peroxidase confirms TGA encodes active site selenocysteine | journal = Nucleic Acids Research | volume = 15 | issue = 13 | page = 5484 | date = Jul 1987 | pmid = 2955287 | pmc = 305979 | doi = 10.1093/nar/15.13.5484 }}
  • {{cite journal | vauthors = Mullenbach GT, Tabrizi A, Irvine BD, Bell GI, Tainer JA, Hallewell RA | title = Selenocysteine's mechanism of incorporation and evolution revealed in cDNAs of three glutathione peroxidases | journal = Protein Engineering | volume = 2 | issue = 3 | pages = 239–46 | date = Sep 1988 | pmid = 2976939 | doi = 10.1093/protein/2.3.239 }}
  • {{cite journal | vauthors = Sukenaga Y, Ishida K, Takeda T, Takagi K | title = cDNA sequence coding for human glutathione peroxidase | journal = Nucleic Acids Research | volume = 15 | issue = 17 | page = 7178 | date = Sep 1987 | pmid = 3658677 | pmc = 306203 | doi = 10.1093/nar/15.17.7178 }}
  • {{cite journal | vauthors = Ishida K, Morino T, Takagi K, Sukenaga Y | title = Nucleotide sequence of a human gene for glutathione peroxidase | journal = Nucleic Acids Research | volume = 15 | issue = 23 | page = 10051 | date = Dec 1987 | pmid = 3697069 | pmc = 306556 | doi = 10.1093/nar/15.23.10051 }}
  • {{cite journal | vauthors = Moscow JA, Schmidt L, Ingram DT, Gnarra J, Johnson B, Cowan KH | title = Loss of heterozygosity of the human cytosolic glutathione peroxidase I gene in lung cancer | journal = Carcinogenesis | volume = 15 | issue = 12 | pages = 2769–73 | date = Dec 1994 | pmid = 8001233 | doi = 10.1093/carcin/15.12.2769 }}
  • {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | date = Jan 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
  • {{cite journal | vauthors = Chu FF, Doroshow JH, Esworthy RS | title = Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GI | journal = The Journal of Biological Chemistry | volume = 268 | issue = 4 | pages = 2571–6 | date = Feb 1993 | pmid = 8428933 | doi = }}
  • {{cite journal | vauthors = Esworthy RS, Ho YS, Chu FF | title = The Gpx1 gene encodes mitochondrial glutathione peroxidase in the mouse liver | journal = Archives of Biochemistry and Biophysics | volume = 340 | issue = 1 | pages = 59–63 | date = Apr 1997 | pmid = 9126277 | doi = 10.1006/abbi.1997.9901 }}
  • {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–56 | date = Oct 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
  • {{cite journal | vauthors = Opalenik SR, Ding Q, Mallery SR, Thompson JA | title = Glutathione depletion associated with the HIV-1 TAT protein mediates the extracellular appearance of acidic fibroblast growth factor | journal = Archives of Biochemistry and Biophysics | volume = 351 | issue = 1 | pages = 17–26 | date = Mar 1998 | pmid = 9501919 | doi = 10.1006/abbi.1997.0566 }}
  • {{cite journal | vauthors = Forsberg L, de Faire U, Morgenstern R | title = Low yield of polymorphisms from EST blast searching: analysis of genes related to oxidative stress and verification of the P197L polymorphism in GPX1 | journal = Human Mutation | volume = 13 | issue = 4 | pages = 294–300 | year = 1999 | pmid = 10220143 | doi = 10.1002/(SICI)1098-1004(1999)13:4<294::AID-HUMU6>3.0.CO;2-5 }}
  • {{cite journal | vauthors = Choi J, Liu RM, Kundu RK, Sangiorgi F, Wu W, Maxson R, Forman HJ | title = Molecular mechanism of decreased glutathione content in human immunodeficiency virus type 1 Tat-transgenic mice | journal = The Journal of Biological Chemistry | volume = 275 | issue = 5 | pages = 3693–8 | date = Feb 2000 | pmid = 10652368 | doi = 10.1074/jbc.275.5.3693 }}
  • {{cite journal | vauthors = Legault J, Carrier C, Petrov P, Renard P, Remacle J, Mirault ME | title = Mitochondrial GPx1 decreases induced but not basal oxidative damage to mtDNA in T47D cells | journal = Biochemical and Biophysical Research Communications | volume = 272 | issue = 2 | pages = 416–22 | date = Jun 2000 | pmid = 10833429 | doi = 10.1006/bbrc.2000.2800 }}
  • {{cite journal | vauthors = Straif D, Werz O, Kellner R, Bahr U, Steinhilber D | title = Glutathione peroxidase-1 but not -4 is involved in the regulation of cellular 5-lipoxygenase activity in monocytic cells | journal = The Biochemical Journal | volume = 349 | issue = Pt 2 | pages = 455–61 | date = Jul 2000 | pmid = 10880344 | pmc = 1221168 | doi = 10.1042/bj3490455 }}
  • {{cite journal | vauthors = Richard MJ, Guiraud P, Didier C, Seve M, Flores SC, Favier A | title = 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 | journal = Archives of Biochemistry and Biophysics | volume = 386 | issue = 2 | pages = 213–20 | date = Feb 2001 | pmid = 11368344 | doi = 10.1006/abbi.2000.2197 }}
  • {{cite journal | vauthors = Ishibashi N, Prokopenko O, Reuhl KR, Mirochnitchenko O | title = Inflammatory response and glutathione peroxidase in a model of stroke | journal = Journal of Immunology | volume = 168 | issue = 4 | pages = 1926–33 | date = Feb 2002 | pmid = 11823528 | doi = 10.4049/jimmunol.168.4.1926 }}
  • {{cite journal | vauthors = Gouaze V, Andrieu-Abadie N, Cuvillier O, Malagarie-Cazenave S, Frisach MF, Mirault ME, Levade T | title = Glutathione peroxidase-1 protects from CD95-induced apoptosis | journal = The Journal of Biological Chemistry | volume = 277 | issue = 45 | pages = 42867–74 | date = Nov 2002 | pmid = 12221075 | doi = 10.1074/jbc.M203067200 }}
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2 : EC 1.11.1|Selenoproteins
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