PON1

Paraoxonase 1

Rendering of 1V04​
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PON1 ; ESA; MVCD5; PON
External IDs OMIM: 168820 MGI: 103295 HomoloGene: 68058 ChEMBL: 3167 GeneCards: PON1 Gene
EC number 3.1.1.2, 3.1.1.81, 3.1.8.1
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 5444 18979
Ensembl ENSG00000005421 ENSMUSG00000002588
UniProt P27169 P52430
RefSeq (mRNA) NM_000446 NM_011134
RefSeq (protein) NP_000437 NP_035264
Location (UCSC) Chr 7:
95.3 – 95.32 Mb		 Chr 6:
5.17 – 5.19 Mb
PubMed search

Serum paraoxonase/arylesterase 1 (PON1) also known as A esterase , homocysteine thiolactonase or serum aryldialkylphosphatase 1 is an enzyme that in humans is encoded by the PON1 gene.[1] Paraoxonase 1 has esterase and more specifically paraoxonase activity.[2] Serum PON1 is found in all mammalian species studied so far but is not present in the serum of birds, fish and reptiles or in insects. PON1 is the first discovered member of a multigene family also containing PON2 and PON3, the genes for which are located adjacent to each other on chromosome 7.

Structure

Human PON1 is a glycoprotein composed of 354 amino acids and has a molecular weight of 43000 Daltons which associates with high-density lipoprotein (HDL, "good cholesterol") in the circulation. Serum PON1 is secreted mainly by the liver although local synthesis occurs in several tissues and PON1 protein is found in almost all tissues. X-ray crystallography has revealed the structure of PON1 to be a 6 bladed propeller with a unique lid structure covering the active site passage and which allows association with HDL. The structure contains 2 calcium ions which are essential for catalytic activity and enzyme stability.[3][4][5]

Its 3D structure was determined in 2004 and revealed that it is a six-bladed beta-propeller with a unique active site lid that is also involved in HDL binding.[3]

Function

PON1 is responsible for hydrolysing organophosphate pesticides and nerve gasses. Polymorphisms in the PON1 gene significantly affect the catalytic ability of the enzyme.[6]

PON1 (paraoxonase 1) is also a major anti-atherosclerotic component of high-density lipoprotein (HDL).[7][8] The PON1 gene is activated by PPAR-γ, which increases synthesis and release of paraoxonase 1 enzyme from the liver, reducing atherosclerosis.[9]

The "natural" substrates for PON1 appear to be lactones.[10] However, PON1 has evolved to be a highly promiscuous enzyme capable of hydrolysing a wide variety of substrates such as lactones (including a number of important pharmaceutical agents such as statins), glucuronide drugs, thiolactones, arylesters, cyclic carbonates, organophosphorus pesticides and nerve gases such as sarin, soman and VX, oestrogen esters and lipid-peroxides(oxidised lipids).

Genetics

PON1 in humans is encoded by the PON1 gene which is located on the long arm of chromosome 7.[11] Although many nutritional, life-style and pharmaceutical modulators of PON1 are known.,[12][13] by far the biggest effect on PON1 activity levels, which can vary by over 40 fold between individuals, is through PON1 genetic polymorphisms.[4] The coding region PON1-Q192R polymorphism determines a substrate dependent effect on activity. Some substrates e.g. paraoxon are hydrolysed faster by the R- isoform while others such as diazoxon and lipid-peroxides are hydrolysed more rapidly by the Q- isoform.[4] Both the coding region PON1-L55M and the promoter region PON1-T-108C polymorphisms are associated with different serum concentrations and therefore activities. The 55L allele results in significantly higher PON1 mRNA and serum protein levels and therefore activity compared to the 55M allele.[12][13] The -108C allele has greater promoter activity than the -108T allele which results in different serum activities.[12][13] It is worth noting that the distribution of the PON1 polymorphisms varies with ethnicity. The frequency of the PON1-192R allele increases the further from Europe a population originates, the frequency in Caucasians of 15-30% increases to 70-90% in Far Eastern Oriental and Sub-Saharan African populations.[14] In the southern USA African-Americans are 5 times more likely to be RR than Caucasians.[15] In contrast the PON1-55M allele is much less frequent in Oriental and black African populations compared to Caucasians and are extremely rare/absent in some populations e.g. Thais. These ethnic differences in SNP distribution can lead to large activity differences between populations.[14]

Clinical significance

PON1 was first discovered through its ability to hydrolyse and therefore detoxify organophosphorus compounds which are widely used as pesticides and nerve gases. Despite decades of research it is only now becoming clear that PON1 protects humans from the acute and chronic harmful effects of these compounds[16][17] Low PON1 activity found in children may increase their susceptibility to organophosphates. Oxidised-lipids are the major cause of inflammation and are responsible for the initiation and/or propagation of several inflammatory diseases including atherosclerosis (heart disease and stroke), diabetes, liver and kidney diseases, rheumatic diseases, eye diseases (macular degeneration), cancer and HIV infection. Because of its ability to destroy oxidised-lipids PON1 appears to play some role in all these diseases. However, the greatest research interest has been the role of PON1 in atherosclerosis, where, because of its ability to remove harmful oxidised-lipids, PON1 protects against the development of atherosclerosis[18] PON1 also protects against bacterial infection by destroying the bacterial signalling molecules that cause gram negative bacteria to invade human tissue and form colonies, thus PON1 contributes to the bodies innate immunity[19] Recently it has been suggested that PON1 has a role in healthy aging, however, the mechanism is currently unknown[20]

PON1 activity is low in infants compared to adults. A study of Mexican-American children showed that PON1 activity increased 3.5 times between birth and age seven.[21] An association between PON1 gene polymorphism and susceptibility to Parkinson's disease was not found in a Chinese population.[22]

References

  1. ↑ Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN (May 1996). "The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family". Genomics 33 (3): 498–507. doi:10.1006/geno.1996.0225. PMID 8661009.
  2. ↑ van Himbergen TM, van Tits LJ, Roest M, Stalenhoef AF (Feb 2006). "The story of PON1: how an organophosphate-hydrolysing enzyme is becoming a player in cardiovascular medicine". The Netherlands Journal of Medicine 64 (2): 34–8. PMID 16517986.
  3. 1 2 Harel M, Aharoni A, Gaidukov L, Brumshtein B, Khersonsky O, Meged R, Dvir H, Ravelli RB, McCarthy A, Toker L, Silman I, Sussman JL, Tawfik DS (May 2004). "Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes". Nature Structural & Molecular Biology 11 (5): 412–9. doi:10.1038/nsmb767. PMID 15098021.
  4. 1 2 3 Mackness B, Durrington PN, Mackness MI (Sep 1998). "Human serum paraoxonase". General Pharmacology 31 (3): 329–36. doi:10.1016/s0306-3623(98)00028-7. PMID 9703197.
  5. ↑ Deakin SP, James RW (Nov 2004). "Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1". Clinical Science 107 (5): 435–47. doi:10.1042/CS20040187. PMID 15265000.
  6. ↑ Costa LG, Cole TB, Vitalone A, Furlong CE (Feb 2005). "Measurement of paraoxonase (PON1) status as a potential biomarker of susceptibility to organophosphate toxicity". Clinica Chimica Acta; International Journal of Clinical Chemistry 352 (1-2): 37–47. doi:10.1016/j.cccn.2004.09.019. PMID 15653099.
  7. ↑ Getz GS, Reardon CA (Jun 2004). "Paraoxonase, a cardioprotective enzyme: continuing issues". Current Opinion in Lipidology 15 (3): 261–7. doi:10.1097/00041433-200406000-00005. PMID 15166781.
  8. ↑ Mackness M, Mackness B (Nov 2004). "Paraoxonase 1 and atherosclerosis: is the gene or the protein more important?". Free Radical Biology & Medicine 37 (9): 1317–23. doi:10.1016/j.freeradbiomed.2004.07.034. PMID 15454272.
  9. ↑ Khateeb J, Gantman A, Kreitenberg AJ, Aviram M, Fuhrman B (Jan 2010). "Paraoxonase 1 (PON1) expression in hepatocytes is upregulated by pomegranate polyphenols: a role for PPAR-gamma pathway". Atherosclerosis 208 (1): 119–25. doi:10.1016/j.atherosclerosis.2009.08.051. PMID 19783251.
  10. ↑ Khersonsky O, Tawfik DS (Apr 2005). "Structure-reactivity studies of serum paraoxonase PON1 suggest that its native activity is lactonase". Biochemistry 44 (16): 6371–82. doi:10.1021/bi047440d. PMID 15835926.
  11. ↑ Clendenning JB, Humbert R, Green ED, Wood C, Traver D, Furlong CE (Aug 1996). "Structural organization of the human PON1 gene". Genomics 35 (3): 586–9. doi:10.1006/geno.1996.0401. PMID 8812495.
  12. 1 2 3 Costa LG, Vitalone A, Cole TB, Furlong CE (Feb 2005). "Modulation of paraoxonase (PON1) activity". Biochemical Pharmacology 69 (4): 541–50. doi:10.1016/j.bcp.2004.08.027. PMID 15670573.
  13. 1 2 3 Schrader C, Graeser AC, Huebbe P, Wagner AE, Rimbach G (Feb 2012). "Allyl isothiocyanate as a potential inducer of paraoxonase-1--studies in cultured hepatocytes and in mice". IUBMB Life 64 (2): 162–8. doi:10.1002/iub.587. PMID 22131196.
  14. 1 2 La Du BN (1992). "Human serum paraoxonase/arylesterase". In Kalow W. Pharmacogenetics of Drug Metabolism. New York: Pergamon Press. pp. 51–91.
  15. ↑ McDaniel CY, Dail MB, Wills RW, Chambers HW, Chambers JE (Dec 2014). "Paraoxonase 1 polymorphisms within a Mississippi USA population as possible biomarkers of enzyme activities associated with disease susceptibility". Biochemical Genetics 52 (11-12): 509–23. doi:10.1007/s10528-014-9663-8. PMID 25027835.
  16. ↑ Costa LG, Giordano G, Cole TB, Marsillach J, Furlong CE (May 2013). "Paraoxonase 1 (PON1) as a genetic determinant of susceptibility to organophosphate toxicity". Toxicology 307: 115–22. doi:10.1016/j.tox.2012.07.011. PMC 3516631. PMID 22884923.
  17. ↑ Mackness M, Mackness B (2014). "Current aspects of paraoxonase-1 research". In Komoda T. The HDL handbook : biological functions and clinical implications (Second edition. ed.). Amsterdam: Academic Press. ISBN 978-0-12-407867-3.
  18. ↑ Costa LG, Cole TB, Jarvik GP, Furlong CE (2003). "Functional genomic of the paraoxonase (PON1) polymorphisms: effects on pesticide sensitivity, cardiovascular disease, and drug metabolism". Annual Review of Medicine 54: 371–92. doi:10.1146/annurev.med.54.101601.152421. PMID 12525679.
  19. ↑ Camps J, Pujol I, Ballester F, Joven J, Simó JM (Apr 2011). "Paraoxonases as potential antibiofilm agents: their relationship with quorum-sensing signals in Gram-negative bacteria". Antimicrobial Agents and Chemotherapy 55 (4): 1325–31. doi:10.1128/AAC.01502-10. PMID 21199929.
  20. ↑ Lee YS, Park CO, Noh JY, Jin S, Lee NR, Noh S, Lee JH, Lee KH (Sep 2012). "Knockdown of paraoxonase 1 expression influences the ageing of human dermal microvascular endothelial cells". Experimental Dermatology 21 (9): 682–7. doi:10.1111/j.1600-0625.2012.01555.x. PMID 22897574.
  21. ↑ Huen K, Harley K, Bradman A, Eskenazi B, Holland N (Apr 2010). "Longitudinal changes in PON1 enzymatic activities in Mexican-American mothers and children with different genotypes and haplotypes". Toxicology and Applied Pharmacology 244 (2): 181–9. doi:10.1016/j.taap.2009.12.031. PMC 2846980. PMID 20045427.
  22. ↑ Wang J, Liu Z (Nov 2000). "No association between paraoxonase 1 (PON1) gene polymorphisms and susceptibility to Parkinson's disease in a Chinese population". Movement Disorders 15 (6): 1265–7. doi:10.1002/1531-8257(200011)15:6<1265::AID-MDS1034>3.0.CO;2-0. PMID 11104219.

Further reading

  • Furlong CE, Costa LG, Hassett C, Richter RJ, Sundstrom JA, Adler DA, Disteche CM, Omiecinski CJ, Chapline C, Crabb JW (Jun 1993). "Human and rabbit paraoxonases: purification, cloning, sequencing, mapping and role of polymorphism in organophosphate detoxification". Chemico-Biological Interactions 87 (1-3): 35–48. doi:10.1016/0009-2797(93)90023-R. PMID 8393745. 
  • Furlong CE, Cole TB, Jarvik GP, Costa LG (May 2002). "Pharmacogenomic considerations of the paraoxonase polymorphisms". Pharmacogenomics 3 (3): 341–8. doi:10.1517/14622416.3.3.341. PMID 12052142. 
  • Mackness B, Durrington PN, Mackness MI (Aug 2002). "The paraoxonase gene family and coronary heart disease". Current Opinion in Lipidology 13 (4): 357–62. doi:10.1097/00041433-200208000-00002. PMID 12151850. 
  • Costa LG, Cole TB, Furlong CE (2003). "Polymorphisms of paraoxonase (PON1) and their significance in clinical toxicology of organophosphates". Journal of Toxicology. Clinical Toxicology 41 (1): 37–45. doi:10.1081/CLT-120018269. PMID 12645966. 
  • Furlong CE, Cole TB, Jarvik GP, Pettan-Brewer C, Geiss GK, Richter RJ, Shih DM, Tward AD, Lusis AJ, Costa LG (Aug 2005). "Role of paraoxonase (PON1) status in pesticide sensitivity: genetic and temporal determinants". Neurotoxicology 26 (4): 651–9. doi:10.1016/j.neuro.2004.08.002. PMID 16112327. 
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