Serum paraoxonase and 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. Paraoxonase 1 has esterase and more specifically paraoxonase activity. 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, 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. Function PON1 is responsible for hydrolysing organophosphate pesticides and nerve gasses. Polymorphisms in the PON1 gene significantly affect the catalytic ability of the enzyme. PON1 (paraoxonase 1) is also a major anti-atherosclerotic component of high-density lipoprotein (HDL). The PON1 gene is activated by PPAR-γ, which increases synthesis and release of paraoxonase 1 enzyme from the liver, reducing atherosclerosis. The "natural" substrates for PON1 appear to be lactones. 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. Although many nutritional, life-style and pharmaceutical modulators of PON1 are known., by far the biggest effect on PON1 activity levels, which can vary by over 40 fold between individuals, is through PON1 genetic polymorphisms. 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. 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