PON1 explained

Paraoxonase 1 (PON1) also known as Serum paraoxonase and arylesterase 1, 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] 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. PON1 on HDL (different from soluble PON1) is responsible for significant atheroprotection rendered by the HDL.[3]

Structure

Human PON1 is a glycoprotein composed of 354 amino acids and has a molecular weight of 43,000 daltons which associates with high-density lipoprotein (HDL, 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 which allows association with HDL.[4] [5] [6]

Function

PON1 is responsible for hydrolysing organophosphate pesticides and nerve gasses. Polymorphisms in the PON1 gene significantly affect the catalytic ability of the enzyme.[7]

PON1 (paraoxonase 1) is also a major anti-atherosclerotic component of high-density lipoprotein (HDL).[8] [9] The PON1 gene is activated by PPAR-γ, which increases synthesis and release of paraoxonase 1 enzyme from the liver, reducing atherosclerosis.[10]

PON1 is a highly promiscuous enzyme capable of hydrolysing a wide variety of substrates, such as lactones,[11] including thiolactones and pharmaceutical agents such as statins. PON1 substrates also include glucuronide drugs, arylesters, cyclic carbonates, organophosphorus pesticides and nerve gases such as sarin, soman and VX, oestrogen esters and lipid peroxides (oxidized lipids). Oxidized polyunsaturated fatty acids (notably in oxidized low-density lipoprotein) form lactone-like structures that are PON substrates.[12]

Genetics

PON1 in humans is encoded by the PON1 gene, which is located on the long arm of chromosome 7.[13] PON1 activity can vary by over 40 fold between individuals. The biggest effect on PON1 activity levels is through PON1 genetic polymorphisms. Many nutritional, life-style and pharmaceutical modulators of PON1 are also known.[14] [15]

The coding region PON1-Q192R polymorphism determines a substrate dependent effect on activity. Many organophosphates used in pesticides, such as paraoxon, are hydrolysed faster by the PON1-R allozyme. Other substrates such as diazoxon, lipid-peroxides and sarin are hydrolysed more rapidly by the PON1-Q allozyme.

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. The -108C allele has greater promoter activity than the -108T allele which results in different serum activities.

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.[16] In the southern US, African-Americans are five times more likely to be RR than Caucasians.[17] In contrast, the PON1-55M allele is much less frequent in Oriental and black African populations compared to Caucasians and are extremely rare or absent in some populations e.g. Thais. These ethnic differences in SNP distribution can lead to large activity differences between populations.

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. PON1 protects humans from the acute and chronic harmful effects of these compounds.[18] [19] Low PON1 activity found in children may increase their susceptibility to organophosphates. Because PON1-Q is more protective against sarin than PON1-R, the PON1-R allele and low PON1-Q activity levels are associated with Gulf War Illness.[20] 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.[21]

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.[22]

Recently it has been suggested that PON1 has a role in healthy aging, however, the mechanism is currently unknown.[23]

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.[24]

An association between PON1 gene polymorphism and susceptibility to Parkinson's disease was not found in a Chinese population.[25]

Further reading

Notes and References

  1. Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN . The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family . Genomics . 33 . 3 . 498–507 . May 1996 . 8661009 . 10.1006/geno.1996.0225 .
  2. van Himbergen TM, van Tits LJ, Roest M, Stalenhoef AF . 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 . Feb 2006 . 16517986 .
  3. Kumar S, Maniya N, Wang C, Satyajyoti S, Chang HC . Quantifying PON1 on HDL with nanoparticle-gated electrokinetic membrane sensor for accurate cardiovascular risk assessment . Nature Communications . 14. 557 . Feb 2023. 557 . 10.1038/s41467-023-36258-w . 36732521 . 9895453 . 2023NatCo..14..557K .
  4. 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 . Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes . Nature Structural & Molecular Biology . 11 . 5 . 412–9 . May 2004 . 15098021 . 10.1038/nsmb767 . 52874893 .
  5. Mackness B, Durrington PN, Mackness MI . Human serum paraoxonase . General Pharmacology . 31 . 3 . 329–36 . Sep 1998 . 9703197 . 10.1016/s0306-3623(98)00028-7.
  6. Deakin SP, James RW . Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1 . Clinical Science . 107 . 5 . 435–47 . Nov 2004 . 15265000 . 10.1042/CS20040187 . 18754293 .
  7. Costa LG, Cole TB, Vitalone A, Furlong CE . 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 . Feb 2005 . 15653099 . 10.1016/j.cccn.2004.09.019 .
  8. Getz GS, Reardon CA . Paraoxonase, a cardioprotective enzyme: continuing issues . Current Opinion in Lipidology . 15 . 3 . 261–7 . Jun 2004 . 15166781 . 10.1097/00041433-200406000-00005 . 23497678 .
  9. Mackness M, Mackness B . Paraoxonase 1 and atherosclerosis: is the gene or the protein more important? . Free Radical Biology & Medicine . 37 . 9 . 1317–23 . Nov 2004 . 15454272 . 10.1016/j.freeradbiomed.2004.07.034 .
  10. Khateeb J, Gantman A, Kreitenberg AJ, Aviram M, Fuhrman B . Paraoxonase 1 (PON1) expression in hepatocytes is upregulated by pomegranate polyphenols: a role for PPAR-gamma pathway . Atherosclerosis . 208 . 1 . 119–25 . Jan 2010 . 19783251 . 10.1016/j.atherosclerosis.2009.08.051 .
  11. 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 . 10.1021/bi047440d . 15835926.
  12. Chistiakov DA, Melnichenko AA, Orekhov AN, Bobryshev YV . 2017 . Paraoxonase and atherosclerosis-related cardiovascular diseases . . 132 . 19–27 . 10.1016/j.biochi.2016.10.010 . 27771368.
  13. Clendenning JB, Humbert R, Green ED, Wood C, Traver D, Furlong CE . Structural organization of the human PON1 gene . Genomics . 35 . 3 . 586–9 . Aug 1996 . 8812495 . 10.1006/geno.1996.0401 .
  14. Costa LG, Vitalone A, Cole TB, Furlong CE . Modulation of paraoxonase (PON1) activity . Biochemical Pharmacology . 69 . 4 . 541–50 . Feb 2005 . 15670573 . 10.1016/j.bcp.2004.08.027 .
  15. Schrader C, Graeser AC, Huebbe P, Wagner AE, Rimbach G . Allyl isothiocyanate as a potential inducer of paraoxonase-1--studies in cultured hepatocytes and in mice . IUBMB Life . 64 . 2 . 162–8 . Feb 2012 . 22131196 . 10.1002/iub.587 . 26735383 . free .
  16. Book: La Du BN . Kalow W . Pharmacogenetics of Drug Metabolism. 1992. Pergamon Press. New York. 51–91. Human serum paraoxonase/arylesterase .
  17. McDaniel CY, Dail MB, Wills RW, Chambers HW, Chambers JE . 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 . Dec 2014 . 25027835 . 10.1007/s10528-014-9663-8 . 16649798 .
  18. Costa LG, Giordano G, Cole TB, Marsillach J, Furlong CE . Paraoxonase 1 (PON1) as a genetic determinant of susceptibility to organophosphate toxicity . Toxicology . 307 . 115–122 . May 2013 . 22884923 . 3516631 . 10.1016/j.tox.2012.07.011 .
  19. Book: Mackness M, Mackness B . Komoda T . The HDL handbook : biological functions and clinical implications. 2014. Academic Press. Amsterdam. 978-0-12-407867-3. Second. Current aspects of paraoxonase-1 research .
  20. Haley RW, Kramer G, Xiao J, Dever JA, Teiber JF . Evaluation of a Gene-Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness: A Prevalence Case-Control Study Drawn from the U.S. Military Health Survey's National Population Sample . Environmental Health Perspectives . 130 . 5 . 57001 . May 2022 . 35543525 . 9093163 . 10.1289/EHP9009 .
  21. Costa LG, Cole TB, Jarvik GP, Furlong CE . Functional genomic of the paraoxonase (PON1) polymorphisms: effects on pesticide sensitivity, cardiovascular disease, and drug metabolism . Annual Review of Medicine . 54 . 371–92 . 2003 . 12525679 . 10.1146/annurev.med.54.101601.152421 .
  22. Camps J, Pujol I, Ballester F, Joven J, Simó JM . Paraoxonases as potential antibiofilm agents: their relationship with quorum-sensing signals in Gram-negative bacteria . Antimicrobial Agents and Chemotherapy . 55 . 4 . 1325–31 . Apr 2011 . 21199929 . 10.1128/AAC.01502-10 . 3067127.
  23. Lee YS, Park CO, Noh JY, Jin S, Lee NR, Noh S, Lee JH, Lee KH . Knockdown of paraoxonase 1 expression influences the ageing of human dermal microvascular endothelial cells . Experimental Dermatology . 21 . 9 . 682–7 . Sep 2012 . 22897574 . 10.1111/j.1600-0625.2012.01555.x . 12440057 .
  24. Huen K, Harley K, Bradman A, Eskenazi B, Holland N . 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 . Apr 2010 . 20045427 . 2846980 . 10.1016/j.taap.2009.12.031 .
  25. Wang J, Liu Z . No association between paraoxonase 1 (PON1) gene polymorphisms and susceptibility to Parkinson's disease in a Chinese population . Movement Disorders . 15 . 6 . 1265–7 . Nov 2000 . 11104219 . 10.1002/1531-8257(200011)15:6<1265::AID-MDS1034>3.0.CO;2-0 . 35775326 .

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