GPX1
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Location (UCSC) | Chr 3: 49.36 – 49.36 Mb | Chr 9: 108.22 – 108.22 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Glutathione peroxidase 1, also known as GPx1, is an enzyme that in humans is encoded by the GPX1 gene on chromosome 3.[5] 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.[6]
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),
The protein encoded by this gene forms a
Two
Glutathione peroxidase 1 is characterized in a poly
Function
GPX1 is ubiquitously expressed in many tissues, where it protects cells from
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.[13]
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.[14]
Clinical significance
The GPx1 allele with five Ala repeats is significantly associated with breast cancer risk.[6]
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.[15]
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).[16]
In esophageal cancer, Chen and colleagues found that vitamin D, a known suppressor of GPX1 expression via the NF-κB 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.[17]
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.[18]
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.[19]
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 with MDD.[20]
Interactions
GPX1 has been shown to
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.[22]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000233276 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000063856 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 9605859.
- ^ a b c d e f g h "Entrez Gene: GPX1 glutathione peroxidase 1".
- ^ PMID 23201771.
- ^ PMID 23261989.
- PMID 8955902.
- ^ PMID 23287791.
- PMID 12221075.
- PMID 10880344.
- S2CID 2922452.
- PMID 24296279.
- S2CID 41231004.
- PMID 25550558.
- PMID 25356106.
- S2CID 21960657.
- PMID 25047527.
- PMID 24967945.
- PMID 12893824.
- PMID 24719327.
Further reading
- Moscow JA, Morrow CS, He R, Mullenbach GT, Cowan KH (Mar 1992). "Structure and function of the 5'-flanking sequence of the human cytosolic selenium-dependent glutathione peroxidase gene (hgpx1)". The Journal of Biological Chemistry. 267 (9): 5949–58. PMID 1556108.
- Chada S, Le Beau MM, Casey L, Newburger PE (Feb 1990). "Isolation and chromosomal localization of the human glutathione peroxidase gene". Genomics. 6 (2): 268–71. PMID 2307470.
- Mullenbach GT, Tabrizi A, Irvine BD, Bell GI, Hallewell RA (Jul 1987). "Sequence of a cDNA coding for human glutathione peroxidase confirms TGA encodes active site selenocysteine". Nucleic Acids Research. 15 (13): 5484. PMID 2955287.
- Mullenbach GT, Tabrizi A, Irvine BD, Bell GI, Tainer JA, Hallewell RA (Sep 1988). "Selenocysteine's mechanism of incorporation and evolution revealed in cDNAs of three glutathione peroxidases". Protein Engineering. 2 (3): 239–46. PMID 2976939.
- Sukenaga Y, Ishida K, Takeda T, Takagi K (Sep 1987). "cDNA sequence coding for human glutathione peroxidase". Nucleic Acids Research. 15 (17): 7178. PMID 3658677.
- Ishida K, Morino T, Takagi K, Sukenaga Y (Dec 1987). "Nucleotide sequence of a human gene for glutathione peroxidase". Nucleic Acids Research. 15 (23): 10051. PMID 3697069.
- Moscow JA, Schmidt L, Ingram DT, Gnarra J, Johnson B, Cowan KH (Dec 1994). "Loss of heterozygosity of the human cytosolic glutathione peroxidase I gene in lung cancer". Carcinogenesis. 15 (12): 2769–73. PMID 8001233.
- Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. PMID 8125298.
- Chu FF, Doroshow JH, Esworthy RS (Feb 1993). "Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GI". The Journal of Biological Chemistry. 268 (4): 2571–6. PMID 8428933.
- Esworthy RS, Ho YS, Chu FF (Apr 1997). "The Gpx1 gene encodes mitochondrial glutathione peroxidase in the mouse liver". Archives of Biochemistry and Biophysics. 340 (1): 59–63. PMID 9126277.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. PMID 9373149.
- Opalenik SR, Ding Q, Mallery SR, Thompson JA (Mar 1998). "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. 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". Human Mutation. 13 (4): 294–300. S2CID 23075151.
- Choi J, Liu RM, Kundu RK, Sangiorgi F, Wu W, Maxson R, Forman HJ (Feb 2000). "Molecular mechanism of decreased glutathione content in human immunodeficiency virus type 1 Tat-transgenic mice". The Journal of Biological Chemistry. 275 (5): 3693–8. PMID 10652368.
- Legault J, Carrier C, Petrov P, Renard P, Remacle J, Mirault ME (Jun 2000). "Mitochondrial GPx1 decreases induced but not basal oxidative damage to mtDNA in T47D cells". Biochemical and Biophysical Research Communications. 272 (2): 416–22. PMID 10833429.
- Straif D, Werz O, Kellner R, Bahr U, Steinhilber D (Jul 2000). "Glutathione peroxidase-1 but not -4 is involved in the regulation of cellular 5-lipoxygenase activity in monocytic cells". The Biochemical Journal. 349 (Pt 2): 455–61. PMID 10880344.
- Richard MJ, Guiraud P, Didier C, Seve M, Flores SC, Favier A (Feb 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". Archives of Biochemistry and Biophysics. 386 (2): 213–20. PMID 11368344.
- Ishibashi N, Prokopenko O, Reuhl KR, Mirochnitchenko O (Feb 2002). "Inflammatory response and glutathione peroxidase in a model of stroke". Journal of Immunology. 168 (4): 1926–33. PMID 11823528.
- Gouaze V, Andrieu-Abadie N, Cuvillier O, Malagarie-Cazenave S, Frisach MF, Mirault ME, Levade T (Nov 2002). "Glutathione peroxidase-1 protects from CD95-induced apoptosis". The Journal of Biological Chemistry. 277 (45): 42867–74. PMID 12221075.