{{Short description|Protein-coding gene in the species Homo sapiens}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox_gene}} '''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.<ref name="pmid8661009">{{cite journal | vauthors = Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN | title = The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family | journal = Genomics | volume = 33 | issue = 3 | pages = 498–507 | date = May 1996 | pmid = 8661009 | doi = 10.1006/geno.1996.0225 }}</ref> Paraoxonase 1 has esterase and more specifically paraoxonase activity.<ref name="pmid16517986">{{cite journal | vauthors = van Himbergen TM, van Tits LJ, Roest M, Stalenhoef AF | title = The story of PON1: how an organophosphate-hydrolysing enzyme is becoming a player in cardiovascular medicine | journal = The Netherlands Journal of Medicine | volume = 64 | issue = 2 | pages = 34–8 | date = Feb 2006 | pmid = 16517986 | url = http://www.zuidencomm.nl/njm/getarticle.php?v=64&i=2&p=34 }}</ref> ''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.<ref name="pmid36732521">{{cite journal | vauthors = Kumar S, Maniya N, Wang C, Satyajyoti S, Chang HC | title = Quantifying PON1 on HDL with nanoparticle-gated electrokinetic membrane sensor for accurate cardiovascular risk assessment | journal = Nature Communications | volume = 14| issue = 557 | date = Feb 2023| page = 557 | doi = 10.1038/s41467-023-36258-w | pmid = 36732521 | pmc = 9895453 | bibcode = 2023NatCo..14..557K }}</ref>
== 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) 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.<ref name="pmid15098021">{{cite journal | vauthors = 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 | title = Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes | journal = Nature Structural & Molecular Biology | volume = 11 | issue = 5 | pages = 412–9 | date = May 2004 | pmid = 15098021 | doi = 10.1038/nsmb767 | s2cid = 52874893 }}</ref><ref name=PMID9703197>{{cite journal | vauthors = Mackness B, Durrington PN, Mackness MI | title = Human serum paraoxonase | journal = General Pharmacology | volume = 31 | issue = 3 | pages = 329–36 | date = Sep 1998 | pmid = 9703197 | doi=10.1016/s0306-3623(98)00028-7}}</ref><ref name=PMID15265000>{{cite journal | vauthors = Deakin SP, James RW | title = Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1 | journal = Clinical Science | volume = 107 | issue = 5 | pages = 435–47 | date = Nov 2004 | pmid = 15265000 | doi = 10.1042/CS20040187 | s2cid = 18754293 }}</ref>
== Function == PON1 is responsible for hydrolysing organophosphate pesticides and nerve gases. Polymorphisms in the PON1 gene significantly affect the catalytic ability of the enzyme.<ref name="pmid15653099">{{cite journal | vauthors = Costa LG, Cole TB, Vitalone A, Furlong CE | title = Measurement of paraoxonase (PON1) status as a potential biomarker of susceptibility to organophosphate toxicity | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 352 | issue = 1–2 | pages = 37–47 | date = Feb 2005 | pmid = 15653099 | doi = 10.1016/j.cccn.2004.09.019 }}</ref>
PON1 (paraoxonase 1) is also a major anti-atherosclerotic component of high-density lipoprotein (HDL).<ref name="PON1_HDL1">{{cite journal | vauthors = Getz GS, Reardon CA | title = Paraoxonase, a cardioprotective enzyme: continuing issues | journal = Current Opinion in Lipidology | volume = 15 | issue = 3 | pages = 261–7 | date = Jun 2004 | pmid = 15166781 | doi = 10.1097/00041433-200406000-00005 | s2cid = 23497678 }}</ref><ref name="PON1_HDL2"> {{cite journal | vauthors = Mackness M, Mackness B | title = Paraoxonase 1 and atherosclerosis: is the gene or the protein more important? | journal = Free Radical Biology & Medicine | volume = 37 | issue = 9 | pages = 1317–23 | date = Nov 2004 | pmid = 15454272 | doi = 10.1016/j.freeradbiomed.2004.07.034 }}</ref> The PON1 gene is activated by PPAR-γ, which increases synthesis and release of paraoxonase 1 enzyme from the liver, reducing atherosclerosis.<ref name="pmid19783251">{{cite journal | vauthors = Khateeb J, Gantman A, Kreitenberg AJ, Aviram M, Fuhrman B | title = Paraoxonase 1 (PON1) expression in hepatocytes is upregulated by pomegranate polyphenols: a role for PPAR-gamma pathway | journal = Atherosclerosis | volume = 208 | issue = 1 | pages = 119–25 | date = Jan 2010 | pmid = 19783251 | doi = 10.1016/j.atherosclerosis.2009.08.051 }}</ref>
PON1 is a highly promiscuous enzyme capable of hydrolysing a wide variety of substrates, such as lactones,<ref name="Mack10">{{cite journal |vauthors=Khersonsky O, Tawfik DS |date=Apr 2005 |title=Structure-reactivity studies of serum paraoxonase PON1 suggest that its native activity is lactonase |journal=Biochemistry |volume=44 |issue=16 |pages=6371–82 |doi=10.1021/bi047440d |pmid=15835926}}</ref> 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.<ref name="pmid27771368">{{cite journal |vauthors=Chistiakov DA, Melnichenko AA, Orekhov AN, Bobryshev YV |year=2017 |title=Paraoxonase and atherosclerosis-related cardiovascular diseases |journal=Biochimie |volume=132 |pages=19–27 |doi=10.1016/j.biochi.2016.10.010 |pmid=27771368}}</ref>
== Genetics == PON1 in humans is encoded by the PON1 gene, which is located on the long arm of chromosome 7.<ref name=Mack5>{{cite journal | vauthors = Clendenning JB, Humbert R, Green ED, Wood C, Traver D, Furlong CE | title = Structural organization of the human PON1 gene | journal = Genomics | volume = 35 | issue = 3 | pages = 586–9 | date = Aug 1996 | pmid = 8812495 | doi = 10.1006/geno.1996.0401 }}</ref> PON1 activity can vary by over 40 fold between individuals. The biggest effect on PON1 activity levels is through PON1 genetic polymorphisms.<ref name="PMID9703197" /> Many nutritional, life-style and pharmaceutical modulators of PON1 are also known.<ref name=Mack6>{{cite journal | vauthors = Costa LG, Vitalone A, Cole TB, Furlong CE | title = Modulation of paraoxonase (PON1) activity | journal = Biochemical Pharmacology | volume = 69 | issue = 4 | pages = 541–50 | date = Feb 2005 | pmid = 15670573 | doi = 10.1016/j.bcp.2004.08.027 }}</ref><ref name=Mack7>{{cite journal | vauthors = Schrader C, Graeser AC, Huebbe P, Wagner AE, Rimbach G | title = Allyl isothiocyanate as a potential inducer of paraoxonase-1--studies in cultured hepatocytes and in mice | journal = IUBMB Life | volume = 64 | issue = 2 | pages = 162–8 | date = Feb 2012 | pmid = 22131196 | doi = 10.1002/iub.587 | s2cid = 26735383 | doi-access = free }}</ref>
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.<ref name="PMID9703197" />
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.<ref name="Mack6" /><ref name="Mack7" /> The -108C allele has greater promoter activity than the -108T allele which results in different serum activities.<ref name="Mack6" /><ref name="Mack7" />
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.<ref name="Mack8">{{cite book| vauthors = La Du BN | veditors = Kalow W |title=Pharmacogenetics of Drug Metabolism|date=1992|publisher=Pergamon Press|location=New York|pages=51–91|chapter=Human serum paraoxonase/arylesterase }}</ref> In the southern US, African-Americans are five times more likely to be RR than Caucasians.<ref name="Mack9">{{cite journal | vauthors = McDaniel CY, Dail MB, Wills RW, Chambers HW, Chambers JE | title = Paraoxonase 1 polymorphisms within a Mississippi USA population as possible biomarkers of enzyme activities associated with disease susceptibility | journal = Biochemical Genetics | volume = 52 | issue = 11–12 | pages = 509–23 | date = Dec 2014 | pmid = 25027835 | doi = 10.1007/s10528-014-9663-8 | s2cid = 16649798 }}</ref> 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.<ref name="Mack8" />
== 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.<ref name=Mack11>{{cite journal | vauthors = Costa LG, Giordano G, Cole TB, Marsillach J, Furlong CE | title = Paraoxonase 1 (PON1) as a genetic determinant of susceptibility to organophosphate toxicity | journal = Toxicology | volume = 307 | pages = 115–122 | date = May 2013 | pmid = 22884923 | pmc = 3516631 | doi = 10.1016/j.tox.2012.07.011 }}</ref><ref name=Mack12>{{cite book| vauthors = Mackness M, Mackness B | veditors = Komoda T |title=The HDL handbook : biological functions and clinical implications|date=2014|publisher=Academic Press|location=Amsterdam|isbn=978-0-12-407867-3|edition=Second|chapter=Current aspects of paraoxonase-1 research }}</ref> 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.<ref>{{cite journal | vauthors = Haley RW, Kramer G, Xiao J, Dever JA, Teiber JF | title = Evaluation of a Gene-Environment Interaction of <i>PON1</i> 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 | journal = Environmental Health Perspectives | volume = 130 | issue = 5 | pages = 57001 | date = May 2022 | pmid = 35543525 | pmc = 9093163 | doi = 10.1289/EHP9009 }}</ref> 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.<ref name=Mack13>{{cite journal | vauthors = Costa LG, Cole TB, Jarvik GP, Furlong CE | title = Functional genomic of the paraoxonase (PON1) polymorphisms: effects on pesticide sensitivity, cardiovascular disease, and drug metabolism | journal = Annual Review of Medicine | volume = 54 | pages = 371–92 | date = 2003 | pmid = 12525679 | doi = 10.1146/annurev.med.54.101601.152421 }}</ref>
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.<ref name=Mack14>{{cite journal | vauthors = Camps J, Pujol I, Ballester F, Joven J, Simó JM | title = Paraoxonases as potential antibiofilm agents: their relationship with quorum-sensing signals in Gram-negative bacteria | journal = Antimicrobial Agents and Chemotherapy | volume = 55 | issue = 4 | pages = 1325–31 | date = Apr 2011 | pmid = 21199929 | doi = 10.1128/AAC.01502-10 | pmc=3067127}}</ref>
Recently it has been suggested that PON1 has a role in healthy aging, however, the mechanism is currently unknown.<ref name=MAck15>{{cite journal | vauthors = Lee YS, Park CO, Noh JY, Jin S, Lee NR, Noh S, Lee JH, Lee KH | title = Knockdown of paraoxonase 1 expression influences the ageing of human dermal microvascular endothelial cells | journal = Experimental Dermatology | volume = 21 | issue = 9 | pages = 682–7 | date = Sep 2012 | pmid = 22897574 | doi = 10.1111/j.1600-0625.2012.01555.x | s2cid = 12440057 }}</ref>
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.<ref name="pmid20045427">{{cite journal | vauthors = Huen K, Harley K, Bradman A, Eskenazi B, Holland N | title = Longitudinal changes in PON1 enzymatic activities in Mexican-American mothers and children with different genotypes and haplotypes | journal = Toxicology and Applied Pharmacology | volume = 244 | issue = 2 | pages = 181–9 | date = Apr 2010 | pmid = 20045427 | pmc = 2846980 | doi = 10.1016/j.taap.2009.12.031 }}</ref>
An association between PON1 gene polymorphism and susceptibility to Parkinson's disease was not found in a Chinese population.<ref name="Wang J, Liu Z. 2000">{{cite journal | vauthors = Wang J, Liu Z | title = No association between paraoxonase 1 (PON1) gene polymorphisms and susceptibility to Parkinson's disease in a Chinese population | journal = Movement Disorders | volume = 15 | issue = 6 | pages = 1265–7 | date = Nov 2000 | pmid = 11104219 | doi = 10.1002/1531-8257(200011)15:6<1265::AID-MDS1034>3.0.CO;2-0 | s2cid = 35775326 }}</ref>
==Notes== {{Academic-written review|Q=Q28395898}}
== References == {{Reflist|33em}}
== Further reading == {{refbegin|33em}} * {{cite journal | vauthors = Furlong CE, Costa LG, Hassett C, Richter RJ, Sundstrom JA, Adler DA, Disteche CM, Omiecinski CJ, Chapline C, Crabb JW | title = Human and rabbit paraoxonases: purification, cloning, sequencing, mapping and role of polymorphism in organophosphate detoxification | journal = Chemico-Biological Interactions | volume = 87 | issue = 1–3 | pages = 35–48 | date = Jun 1993 | pmid = 8393745 | doi = 10.1016/0009-2797(93)90023-R | bibcode = 1993CBI....87...35F }} * {{cite journal | vauthors = Furlong CE, Cole TB, Jarvik GP, Costa LG | title = Pharmacogenomic considerations of the paraoxonase polymorphisms | journal = Pharmacogenomics | volume = 3 | issue = 3 | pages = 341–8 | date = May 2002 | pmid = 12052142 | doi = 10.1517/14622416.3.3.341 }} * {{cite journal | vauthors = Mackness B, Durrington PN, Mackness MI | title = The paraoxonase gene family and coronary heart disease | journal = Current Opinion in Lipidology | volume = 13 | issue = 4 | pages = 357–62 | date = Aug 2002 | pmid = 12151850 | doi = 10.1097/00041433-200208000-00002 | s2cid = 22912885 }} * {{cite journal | vauthors = Costa LG, Cole TB, Furlong CE | title = Polymorphisms of paraoxonase (PON1) and their significance in clinical toxicology of organophosphates | journal = Journal of Toxicology. Clinical Toxicology | volume = 41 | issue = 1 | pages = 37–45 | year = 2003 | pmid = 12645966 | doi = 10.1081/CLT-120018269 | s2cid = 46233526 }} * {{cite journal | vauthors = Furlong CE, Cole TB, Jarvik GP, Pettan-Brewer C, Geiss GK, Richter RJ, Shih DM, Tward AD, Lusis AJ, Costa LG | title = Role of paraoxonase (PON1) status in pesticide sensitivity: genetic and temporal determinants | journal = Neurotoxicology | volume = 26 | issue = 4 | pages = 651–9 | date = Aug 2005 | pmid = 16112327 | doi = 10.1016/j.neuro.2004.08.002 }} {{refend}}