Paraoksonaz Enzim Ailesi Enzimlerinden Homosistein Tiyolaktonaz, Paraoksonaz ve Aril Esteraz Aktivitelerine Genel Bir Bakış
Özet
Homosistein vaskülotoksik ve trombojenik bir aminoasittir. Homosistein düzeyleri çeşitli nedenlere bağlı olarak yükseldiği zaman, homosistein metabolizmasında bir ara ürün olan, homosistein tiyolakton oluşumuna neden olur. Homosistein tiyolakton, reaktif oksijen türlerinin birikmesine ve proteinlerin posttranslasyonal modifikasyonlarına yol açarak ateroskleroz gibi zararlı etkilere sebep olabilir ve vasküler hastalıkların, özellikle koroner arter hastalığının ve inme riskinin bir belirteci olarak kabul edilmektedir. Paraoksonaz enzim ailesi homosistein tiyolaktonun ve diğer zararlı bileşiklerin detoksifikasyonunda yer alır. Paraoksonaz enzim ailesi, PON-1, PON-2 ve PON-3 olmak üzere üç izoformdan oluşur. Bu izoformların antioksidan, anti-enflamatuvar ve vasküloprotektif özellikleri bulunmaktadır. PON-1, HDL üzerinde taşınan özellikle organofosfatlı bileşiklerin ve lipitlerin peroksidasyonunu önleyen izoformdur. Ayrıca, homosistein tiyolaktonu detoksifiye eder ve homosisteinlenmiş proteinleri parçalar. PON-1 aktivitesi bireyler arasında değişkenlik gösterir ve bu değişkenliklerin kardiyovasküler hastalıklarla ilişkili olduğu gösterilmiştir. Paraoksonaz enzim ailesinin aktiviteleri arasında paraoksonaz, homosistein tiyolaktonaz ve aril esteraz bulunur. Bu aktiviteler, toksik maddelerin metabolize edilmesi, homosistein düzeylerinin düzenlenmesi ve oksidatif stresin azaltılması gibi birçok biyolojik süreçte kritik rol oynar. Genel olarak, homosistein tiyolakton ve paraoksonaz enzim ailesi, vasküler hastalıkların patofizyolojisinde ve tedavisinde önemli bir rol oynarlar. Bu nedenle, bu molekül ve enzimler üzerindeki araştırmalar, potansiyel olarak vasküler hastalıkların önlenmesi ve tedavisine ışık tutabilir.
Homocysteine is a vasculotoxic and thrombogenic amino acid. When homocysteine levels increase due to various reasons, it causes the formation of homocysteine thiolactone, an intermediate product in homocysteine metabolism. Homocysteine thiolactone can lead to accumulation of reactive oxygen species and posttranslational modifications of proteins, causing harmful effects such as atherosclerosis, and is considered a marker of vascular diseases, especially coronary artery disease and stroke risk. The paraoxonase enzyme family is involved in the detoxification of homocysteine thiolactone and other harmful compounds. The paraoxonase enzyme family consists of three isoforms: PON-1, PON-2 and PON-3. These isoforms have antioxidant, anti-inflammatory and vasculoprotective properties. PON-1 is the isoform that prevents the peroxidation of especially organophosphate compounds and lipids carried on HDL. Additionally, homocysteine detoxifies thiolactone and breaks down homocysteinated proteins. PON-1 activity varies between individuals, and these variations have been shown to be associated with cardiovascular diseases. Activities of the paraoxonase enzyme family include paraoxonase, homocysteine thiolactonase, and arylesterase. These activities play critical roles in many biological processes, such as metabolizing toxic substances, regulating homocysteine levels and reducing oxidative stress. In general, homocysteine thiolactone and the paraoxonase enzyme family play an important role in the pathophysiology and treatment of vascular diseases. Therefore, research on these molecules and enzymes could potentially shed light on the prevention and treatment of vascular diseases.
Referanslar
Austin RC, Lentz SR, Werstuck GH. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ. 2004;11(Suppl 1):S56–S64. doi:10.1038/sj.cdd.4401451
Lehotský J, Tothová B, Kovalská M, Dobrota D, Beňová A, Kalenská D, Kaplán P. Role of homocysteine in the ischemic stroke and development of ischemic tolerance. Front Neurosci. 2016;10:538. doi:10.3389/fnins.2016.00538
Jakubowski H. The pathophysiological hypothesis of homocysteine thiolactone-mediated vascular disease. J Physiol Pharmacol. 2008;59(Suppl 9):155–167.
Gurda D, Handschuh L, Kotkowiak W, Jakubowski H. Homocysteine thiolactone and N-homocysteinylated protein induce pro-atherogenic changes in gene expression in human vascular endothelial cells. Amino Acids. 2015;47(7):1319–1339. doi:10.1007/s00726-015-1956-7
Braekke K, Ueland PM, Harsem NK, Karlsen A, Blomhoff R, Staff AC. Homocysteine, cysteine, and related metabolites in maternal and fetal plasma in preeclampsia. Pediatr Res. 2007;62(3):319-324. doi: 10.1203/PDR.0b013e318123fba2
Jakubowski H. Homocysteine thiolactone: metabolic origin and protein homocysteinylation in humans. J Nutr. 2000;130(2S Suppl):377S–381S. doi:10.1093/jn/130.2.377S
Jakubowski H, Zhang L, Bardeguez A, Aviv A. Homocysteine thiolactone and protein homocysteinylation in human endothelial cells: implications for atherosclerosis. Circ Res. 2000;87(1):45–51. doi:10.1161/01.res.87.1.45
Jakubowski H. Metabolism of homocysteine thiolactone in human cell cultures. Possible mechanism for pathological consequences of elevated homocysteine levels. J Biol Chem. 1997;272(3):1935–1942.
Yilmaz N. Relationship between paraoxonase and homocysteine: crossroads of oxidative diseases. Arch Med Sci. 2012;8(1):138–153. doi:10.5114/aoms.2012.27294
Undas A, Jankowski M, Twardowska M, Padjas A, Jakubowski H, Szczeklik A. Antibodies to N-Homocysteinylated Albumin as a Marker for Early-Onset Coronary Artery Disease in Men. Thromb Haemost. 2005;93(2):346-50.
Refsum H, Ueland PM. Homocysteine and homocysteine thiolactone in human health and disease. J Inherit Metab Dis. 1985;8(S1):53-61.
Mazur A. An enzyme in animal tissues capable of hydrolysing the phosphorus-fluorine bond of alkyl fluorophosphates. J Biol Chem. 1946;164:271–289.
Aldridge WN. Serum Esterases. I. Two Types of Esterase (a and B) Hydrolysing P-Nitrophenyl Acetate, Propionate and Butyrate, and a Method for Their Determination. Biochem J. 1953;53(1):110-7.
Uriel J. [Characterization of Cholinesterase and Other Carboxylic Esterases after Electrophoresis and Immunoelectrophoresis on Agar. I. Application to the Study of Esterases of Normal Human Serum]. Ann Inst Pasteur (Paris). 1961;101:104-19.
Levy D, Reichert CO, Bydlowski SP. Paraoxonases Activities and Polymorphisms in Elderly and Old-Age Diseases: An Overview. Antioxidants. 2019;8(5).
Li WF, Costa LG, Furlong CE. Serum Paraoxonase Status: A Major Factor in Determining Resistance to Organophosphates. J Toxicol Environ Health. 1993;40(2-3):337-46.
Rajkovic MG, Rumora L, Barisic K. The paraoxonase 1, 2 and 3 in humans. Biochem Med. 2011;21(2):122–130. doi:10.11613/bm.2011.020
Vitarius JA, Sultatos LG. The role of calcium in the hydrolysis of the organophosphate paraoxon by human serum A-esterase. Life Sci. 1995;56(2):125–134. doi:10.1016/0024-3205(94)00422-o
Pasdar A, Adams HR, Cumming A, Cheung J, Whalley L, St Clair D, MacLeod MJ. Paraoxonase Gene Polymorphisms and Haplotype Analysis in a Stroke Population. BMC Med Genet. 2006;7(28):1-6.
Mackness M and Sozmen EY. A critical review on human serum paraoxonase-1 in the literature: truths and misconception. Turk J Biochem 2021;46(1):3-8
Blatter Garin MC, James RW, Dussoix P, et al. Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes. J Clin Invest. 1997;99(1):62–66.
Dounousi E, Bouba I, Spoto B, Pappas K, Tripepi G, Georgiou I, Tselepis A, Elisaf M, Tsakiris D, Zoccali C, Siamopoulos K. A Genetic Biomarker of Oxidative Stress, the Paraoxonase-1 Q192R Gene Variant, Associates with Cardiomyopathy in CKD: A Longitudinal Study. Oxid Med Cell Longev. 2016;2016:1507270. doi:10.1155/2016/1507270
Mackness B, Turkie W, Mackness M. Paraoxonase-1 (PON1) promoter region polymorphisms, serum PON1 status and coronary heart disease. Arch Med Sci. 2013;9(1):8–13. doi:10.5114/aoms.2013.33189
Eckerson HW, Wyte CM, La Du BN. The human serum paraoxonase/arylesterase polymorphism. Am J Hum Genet. 1983;35(6):1126–1138.
Jakubowski H, Ambrosius WT, Pratt JH. Genetic determinants of homocysteine thiolactonase activity in humans: implications for atherosclerosis. FEBS Lett. 2001;491(1-2):35–39. doi:10.1016/s0014-5793(01)02143-3
Jakubowski H, Zhang L, Bardeguez A, Aviv A. Homocysteine thiolactone and protein homocysteinylation in human endothelial cells: implications for atherosclerosis. Circ Res. 2000;87(1):45–51. doi:10.1161/01.res.87.1.45
Eckerson HW, Wyte CM, La Du BN. The human serum paraoxonase/arylesterase polymorphism. Am J Hum Genet. 1983;35(6):1126–1138.
Zargari M, Sharafeddin F, Mahrooz A, Alizadeh A, Masoumi P. The common variant Q192R at the paraoxonase 1 (PON1) gene and its activity are responsible for a portion of the altered antioxidant status in type 2 diabetes. Exp Biol Med. 2016;241(14):1489–1496.
Referanslar
Austin RC, Lentz SR, Werstuck GH. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ. 2004;11(Suppl 1):S56–S64. doi:10.1038/sj.cdd.4401451
Lehotský J, Tothová B, Kovalská M, Dobrota D, Beňová A, Kalenská D, Kaplán P. Role of homocysteine in the ischemic stroke and development of ischemic tolerance. Front Neurosci. 2016;10:538. doi:10.3389/fnins.2016.00538
Jakubowski H. The pathophysiological hypothesis of homocysteine thiolactone-mediated vascular disease. J Physiol Pharmacol. 2008;59(Suppl 9):155–167.
Gurda D, Handschuh L, Kotkowiak W, Jakubowski H. Homocysteine thiolactone and N-homocysteinylated protein induce pro-atherogenic changes in gene expression in human vascular endothelial cells. Amino Acids. 2015;47(7):1319–1339. doi:10.1007/s00726-015-1956-7
Braekke K, Ueland PM, Harsem NK, Karlsen A, Blomhoff R, Staff AC. Homocysteine, cysteine, and related metabolites in maternal and fetal plasma in preeclampsia. Pediatr Res. 2007;62(3):319-324. doi: 10.1203/PDR.0b013e318123fba2
Jakubowski H. Homocysteine thiolactone: metabolic origin and protein homocysteinylation in humans. J Nutr. 2000;130(2S Suppl):377S–381S. doi:10.1093/jn/130.2.377S
Jakubowski H, Zhang L, Bardeguez A, Aviv A. Homocysteine thiolactone and protein homocysteinylation in human endothelial cells: implications for atherosclerosis. Circ Res. 2000;87(1):45–51. doi:10.1161/01.res.87.1.45
Jakubowski H. Metabolism of homocysteine thiolactone in human cell cultures. Possible mechanism for pathological consequences of elevated homocysteine levels. J Biol Chem. 1997;272(3):1935–1942.
Yilmaz N. Relationship between paraoxonase and homocysteine: crossroads of oxidative diseases. Arch Med Sci. 2012;8(1):138–153. doi:10.5114/aoms.2012.27294
Undas A, Jankowski M, Twardowska M, Padjas A, Jakubowski H, Szczeklik A. Antibodies to N-Homocysteinylated Albumin as a Marker for Early-Onset Coronary Artery Disease in Men. Thromb Haemost. 2005;93(2):346-50.
Refsum H, Ueland PM. Homocysteine and homocysteine thiolactone in human health and disease. J Inherit Metab Dis. 1985;8(S1):53-61.
Mazur A. An enzyme in animal tissues capable of hydrolysing the phosphorus-fluorine bond of alkyl fluorophosphates. J Biol Chem. 1946;164:271–289.
Aldridge WN. Serum Esterases. I. Two Types of Esterase (a and B) Hydrolysing P-Nitrophenyl Acetate, Propionate and Butyrate, and a Method for Their Determination. Biochem J. 1953;53(1):110-7.
Uriel J. [Characterization of Cholinesterase and Other Carboxylic Esterases after Electrophoresis and Immunoelectrophoresis on Agar. I. Application to the Study of Esterases of Normal Human Serum]. Ann Inst Pasteur (Paris). 1961;101:104-19.
Levy D, Reichert CO, Bydlowski SP. Paraoxonases Activities and Polymorphisms in Elderly and Old-Age Diseases: An Overview. Antioxidants. 2019;8(5).
Li WF, Costa LG, Furlong CE. Serum Paraoxonase Status: A Major Factor in Determining Resistance to Organophosphates. J Toxicol Environ Health. 1993;40(2-3):337-46.
Rajkovic MG, Rumora L, Barisic K. The paraoxonase 1, 2 and 3 in humans. Biochem Med. 2011;21(2):122–130. doi:10.11613/bm.2011.020
Vitarius JA, Sultatos LG. The role of calcium in the hydrolysis of the organophosphate paraoxon by human serum A-esterase. Life Sci. 1995;56(2):125–134. doi:10.1016/0024-3205(94)00422-o
Pasdar A, Adams HR, Cumming A, Cheung J, Whalley L, St Clair D, MacLeod MJ. Paraoxonase Gene Polymorphisms and Haplotype Analysis in a Stroke Population. BMC Med Genet. 2006;7(28):1-6.
Mackness M and Sozmen EY. A critical review on human serum paraoxonase-1 in the literature: truths and misconception. Turk J Biochem 2021;46(1):3-8
Blatter Garin MC, James RW, Dussoix P, et al. Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes. J Clin Invest. 1997;99(1):62–66.
Dounousi E, Bouba I, Spoto B, Pappas K, Tripepi G, Georgiou I, Tselepis A, Elisaf M, Tsakiris D, Zoccali C, Siamopoulos K. A Genetic Biomarker of Oxidative Stress, the Paraoxonase-1 Q192R Gene Variant, Associates with Cardiomyopathy in CKD: A Longitudinal Study. Oxid Med Cell Longev. 2016;2016:1507270. doi:10.1155/2016/1507270
Mackness B, Turkie W, Mackness M. Paraoxonase-1 (PON1) promoter region polymorphisms, serum PON1 status and coronary heart disease. Arch Med Sci. 2013;9(1):8–13. doi:10.5114/aoms.2013.33189
Eckerson HW, Wyte CM, La Du BN. The human serum paraoxonase/arylesterase polymorphism. Am J Hum Genet. 1983;35(6):1126–1138.
Jakubowski H, Ambrosius WT, Pratt JH. Genetic determinants of homocysteine thiolactonase activity in humans: implications for atherosclerosis. FEBS Lett. 2001;491(1-2):35–39. doi:10.1016/s0014-5793(01)02143-3
Jakubowski H, Zhang L, Bardeguez A, Aviv A. Homocysteine thiolactone and protein homocysteinylation in human endothelial cells: implications for atherosclerosis. Circ Res. 2000;87(1):45–51. doi:10.1161/01.res.87.1.45
Eckerson HW, Wyte CM, La Du BN. The human serum paraoxonase/arylesterase polymorphism. Am J Hum Genet. 1983;35(6):1126–1138.
Zargari M, Sharafeddin F, Mahrooz A, Alizadeh A, Masoumi P. The common variant Q192R at the paraoxonase 1 (PON1) gene and its activity are responsible for a portion of the altered antioxidant status in type 2 diabetes. Exp Biol Med. 2016;241(14):1489–1496.
