|Glutathione peroxidase 1|
PDB rendering based on 2f8a.
|Symbols||; GPXD; GSHPX1|
Glutathione peroxidase 1 also known as GPx-1 is an enzyme that in humans is encoded by the GPX1 gene. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.
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. 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.
Glutathione peroxidase functions in the detoxification of hydrogen peroxide, and is one of the most important antioxidant enzymes in humans. It has been reported that 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 growth and increases resistance to toxic challenges. 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.
After many decades of speculation, it was found that 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. Analysis of the structure shows that 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.
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.
GPX1 helps to prevent cardiac dysfunction after ischemia-reperfusion injuries. Han and colleagues analyzed the effects of reoxygenation on cardiac protein in GPX1 knockout mouse hearts. Mitochondrial ROS production and oxidative mtDNA damage were 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.
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.
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).
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.
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.
Recent work by 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.
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.
In a study observing the effects of age-related vascular dysfunction in GPX1 (-/-) mice, oxidant formation increased, endothelial NO synthase was deregulated, and adhesion of leukocytes to cultured endothelial cells was increased. This data suggests that GPX1 amplifies certain aspects of aging, namely endothelial dysfunction, vascular remodeling, and invasion of leukocytes in cardiovascular tissue.
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.
- 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 (Jun 1998). "Assignment of the ARHA and GPX1 genes to human chromosome bands 3p21.3 by in situ hybridization and with somatic cell hybrids". Cytogenet Cell Genet 79 (3–4): 228–30. doi:10.1159/000134729. PMID 9605859.
- "Entrez Gene: GPX1 glutathione peroxidase 1".
- Li, F; Liu, J; Rozovsky, S (November 2014). "Glutathione peroxidase's reaction intermediate selenenic acid is stabilized by the protein microenvironment.". Free radical biology & medicine 76: 127–35. doi:10.1016/j.freeradbiomed.2014.07.041. PMID 25124921.
- Thu, VT; Kim, HK; Ha, SH; Yoo, JY; Park, WS; Kim, N; Oh, GT; Han, J (June 2010). "Glutathione peroxidase 1 protects mitochondria against hypoxia/reoxygenation damage in mouse hearts.". Pflugers Archiv : European journal of physiology 460 (1): 55–68. doi:10.1007/s00424-010-0811-7. PMID 20306076.
- Cengiz, M; Bayoglu, B; Alansal, NO; Cengiz, S; Dirican, A; Kocabasoglu, N (9 February 2015). "Pro198Leu polymorphism in the oxidative stress gene, glutathione peroxidase-1, is associated with a gender-specific risk for panic disorder.". International journal of psychiatry in clinical practice: 1–24. PMID 25666858.
- Nalkiran, I; Turan, S; Arikan, S; Kahraman, ÖT; Acar, L; Yaylim, I; Ergen, A (January 2015). "Determination of gene expression and serum levels of MnSOD and GPX1 in colorectal cancer.". Anticancer research 35 (1): 255–9. PMID 25550558.
- Gan, X; Chen, B; Shen, Z; Liu, Y; Li, H; Xie, X; Xu, X; Li, H; Huang, Z; Chen, J (2014). "High GPX1 expression promotes esophageal squamous cell carcinoma invasion, migration, proliferation and cisplatin-resistance but can be reduced by vitamin D.". International journal of clinical and experimental medicine 7 (9): 2530–40. PMID 25356106.
- Vats, P; Sagar, N; Singh, TP; Banerjee, M (January 2015). "Association of Superoxide dismutases (SOD1 and SOD2) and Glutathione peroxidase 1 (GPx1) gene polymorphisms with type 2 diabetes mellitus.". Free radical research 49 (1): 17–24. doi:10.3109/10715762.2014.971782. PMID 25283363.
- Bera, S; Weinberg, F; Ekoue, DN; Ansenberger-Fricano, K; Mao, M; Bonini, MG; Diamond, AM (15 September 2014). "Natural allelic variations in glutathione peroxidase-1 affect its subcellular localization and function.". Cancer research 74 (18): 5118–26. doi:10.1158/0008-5472.can-14-0660. PMID 25047527.
- Szebeni, A; Szebeni, K; DiPeri, T; Chandley, MJ; Crawford, JD; Stockmeier, CA; Ordway, GA (October 2014). "Shortened telomere length in white matter oligodendrocytes in major depression: potential role of oxidative stress.". The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP) 17 (10): 1579–89. doi:10.1017/s1461145714000698. PMID 24967945.
- 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 (February 2014). "Glutathione peroxidase-1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging.". Hypertension 63 (2): 390–6. doi:10.1161/hypertensionaha.113.01602. PMID 24296279.
- Cao C, Leng Y, Huang W, Liu X, Kufe D (October 2003). "Glutathione peroxidase 1 is regulated by the c-Abl and Arg tyrosine kinases". J. Biol. Chem. 278 (41): 39609–14. doi:10.1074/jbc.M305770200. PMID 12893824.
- 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 (30 May 2014). "Inhibition of cellular methyltransferases promotes endothelial cell activation by suppressing glutathione peroxidase 1 protein expression.". The Journal of biological chemistry 289 (22): 15350–62. doi:10.1074/jbc.m114.549782. PMID 24719327.
- Moscow JA, Morrow CS, He R et al. (1992). "Structure and function of the 5'-flanking sequence of the human cytosolic selenium-dependent glutathione peroxidase gene (hgpx1)". J. Biol. Chem. 267 (9): 5949–58. PMID 1556108.
- Chada S, Le Beau MM, Casey L, Newburger PE (1990). "Isolation and chromosomal localization of the human glutathione peroxidase gene". Genomics 6 (2): 268–71. doi:10.1016/0888-7543(90)90566-D. PMID 2307470.
- Mullenbach GT, Tabrizi A, Irvine BD et al. (1987). "Sequence of a cDNA coding for human glutathione peroxidase confirms TGA encodes active site selenocysteine". Nucleic Acids Res. 15 (13): 5484. doi:10.1093/nar/15.13.5484. PMC 305979. PMID 2955287.
- Mullenbach GT, Tabrizi A, Irvine BD et al. (1989). "Selenocysteine's mechanism of incorporation and evolution revealed in cDNAs of three glutathione peroxidases". Protein Eng. 2 (3): 239–46. doi:10.1093/protein/2.3.239. PMID 2976939.
- Sukenaga Y, Ishida K, Takeda T, Takagi K (1987). "cDNA sequence coding for human glutathione peroxidase". Nucleic Acids Res. 15 (17): 7178. doi:10.1093/nar/15.17.7178. PMC 306203. PMID 3658677.
- Ishida K, Morino T, Takagi K, Sukenaga Y (1988). "Nucleotide sequence of a human gene for glutathione peroxidase". Nucleic Acids Res. 15 (23): 10051. doi:10.1093/nar/15.23.10051. PMC 306556. PMID 3697069.
- Moscow JA, Schmidt L, Ingram DT et al. (1995). "Loss of heterozygosity of the human cytosolic glutathione peroxidase I gene in lung cancer". Carcinogenesis 15 (12): 2769–73. doi:10.1093/carcin/15.12.2769. PMID 8001233.
- Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Chu FF, Doroshow JH, Esworthy RS (1993). "Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GI". J. Biol. Chem. 268 (4): 2571–6. PMID 8428933.
- Esworthy RS, Ho YS, Chu FF (1997). "The Gpx1 gene encodes mitochondrial glutathione peroxidase in the mouse liver". Arch. Biochem. Biophys. 340 (1): 59–63. doi:10.1006/abbi.1997.9901. PMID 9126277.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Opalenik SR, Ding Q, Mallery SR, Thompson JA (1998). "Glutathione depletion associated with the HIV-1 TAT protein mediates the extracellular appearance of acidic fibroblast growth factor". Arch. Biochem. Biophys. 351 (1): 17–26. doi:10.1006/abbi.1997.0566. PMID 9501919.
- Forsberg L, de Faire U, Morgenstern R (1999). "Low yield of polymorphisms from EST blast searching: analysis of genes related to oxidative stress and verification of the P197L polymorphism in GPX1". Hum. Mutat. 13 (4): 294–300. doi:10.1002/(SICI)1098-1004(1999)13:4<294::AID-HUMU6>3.0.CO;2-5. PMID 10220143.
- Choi J, Liu RM, Kundu RK et al. (2000). "Molecular mechanism of decreased glutathione content in human immunodeficiency virus type 1 Tat-transgenic mice". J. Biol. Chem. 275 (5): 3693–8. doi:10.1074/jbc.275.5.3693. PMID 10652368.
- Legault J, Carrier C, Petrov P et al. (2000). "Mitochondrial GPx1 decreases induced but not basal oxidative damage to mtDNA in T47D cells". Biochem. Biophys. Res. Commun. 272 (2): 416–22. doi:10.1006/bbrc.2000.2800. PMID 10833429.
- Straif D, Werz O, Kellner R et al. (2001). "Glutathione peroxidase-1 but not -4 is involved in the regulation of cellular 5-lipoxygenase activity in monocytic cells". Biochem. J. 349 (Pt 2): 455–61. doi:10.1042/0264-6021:3490455. PMC 1221168. PMID 10880344.
- Richard MJ, Guiraud P, Didier C et al. (2001). "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". Arch. Biochem. Biophys. 386 (2): 213–20. doi:10.1006/abbi.2000.2197. PMID 11368344.
- Ishibashi N, Prokopenko O, Reuhl KR, Mirochnitchenko O (2002). "Inflammatory response and glutathione peroxidase in a model of stroke". J. Immunol. 168 (4): 1926–33. doi:10.4049/jimmunol.168.4.1926. PMID 11823528.
- Gouaze V, Andrieu-Abadie N, Cuvillier O et al. (2003). "Glutathione peroxidase-1 protects from CD95-induced apoptosis". J. Biol. Chem. 277 (45): 42867–74. doi:10.1074/jbc.M203067200. PMID 12221075.