Paraoxonase 1 (PON1) also known as Serum paraoxonase and arylesterase 1, A esterase, homocysteine thiolactonase or serum aryldialkylphosphatase 1, is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that in humans is encoded by the ''PON1''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. Paraoxonase 1 has

esterase In biochemistry, an esterase is a class of enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis (and as such, it is a type of hydrolase). A wide range of different esterases exist that differ ...

and more specifically

paraoxonase Paraoxonases are a protein family, family of mammalian enzymes with aryldialkylphosphatase activity. There are three paraoxonase isozymes, which were originally discovered for their involvement in the hydrolysis of organophosphates. Research ...

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. PON1 on HDL (different from soluble PON1) is responsible for significant atheroprotection rendered by the HDL.

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 High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are t ...

(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 X-ray crystallography is the experimental science of determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to Diffraction, diffract in specific directions. By measuring th ...

has revealed the structure of PON1 to be a 6 bladed propeller with a unique lid structure covering the

active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate, the ''binding s ...

passage which allows association with HDL.

Function

PON1 is responsible for hydrolysing

organophosphate In organic chemistry, organophosphates (also known as phosphate esters, or OPEs) are a class of organophosphorus compounds with the general structure , a central phosphate molecule with alkyl or aromatic substituents. They can be considered ...

pesticides and

nerve gas Nerve agents, sometimes also called nerve gases, are a class of organic chemicals that disrupt the mechanisms by which nerves transfer messages to organs. The disruption is caused by the blocking of acetylcholinesterase (AChE), an enzyme that ...

ses. Polymorphisms in the PON1 gene significantly affect the catalytic ability of the enzyme. PON1 (

1) is also a major anti-

atherosclerotic Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by elev ...

component of

(HDL). The PON1 gene is activated by

PPAR-γ In the field of molecular biology, the peroxisome proliferator–activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating gene expression. PPARs play essential roles in regulating cel ...

, which increases synthesis and release of paraoxonase 1 enzyme from the liver, reducing

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...

. PON1 is a highly promiscuous enzyme capable of hydrolysing a wide variety of substrates, such as

lactones Lactones are cyclic carboxylic esters. They are derived from the corresponding hydroxycarboxylic acids by esterification. They can be saturated or unsaturated. Lactones are formed by lactonization, the intramolecular esterification of the corre ...

, 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 Lipid peroxidation, or lipid oxidation, is a complex chemical process that leads to oxidative degradation of lipids, resulting in the formation of peroxide and hydroperoxide derivatives.{{Cite journal , last1=Ayala , first1=Antonio , last2=Muñoz ...

(

oxidized Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

lipids). Oxidized polyunsaturated fatty acids (notably in oxidized

low-density lipoprotein Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall density ...

) form lactone-like structures that are PON substrates.

Genetics

PON1 in humans is encoded by the PON1 gene, which is located on the long arm of chromosome 7. 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. The coding region PON1-Q192R polymorphism determines a substrate dependent effect on activity. Many organophosphates used in pesticides, such as

paraoxon Paraoxon is a parasympathomimetic drug which acts as an cholinesterase inhibitor. It is an organophosphate oxon, and the active metabolite of the insecticide parathion. It is also used as an ophthalmological drug against glaucoma. Paraoxon is o ...

, are hydrolysed faster by the PON1-R

allozyme Alloenzymes (or also called allozymes) are variant forms of an enzyme which differ structurally but not functionally from other allozymes coded for by different alleles at the same locus. These are opposed to isozymes, which are enzymes that p ...

. 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. In the southern US, African-Americans are five times more likely to be RR than Caucasians. 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 compound Organophosphorus chemistry is the scientific study of the synthesis and properties of organophosphorus compounds, which are organic compounds containing phosphorus. They are used primarily in pest control as an alternative to chlorinated hydrocarbo ...

s which are widely used as pesticides and nerve gases. PON1 protects humans from the acute and chronic harmful effects of these compounds. 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. 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. 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. Recently it has been suggested that PON1 has a role in healthy aging, however, the mechanism is currently unknown. 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. An association between PON1 gene polymorphism and susceptibility to Parkinson's disease was not found in a Chinese population.

Structure

Function

Genetics

Clinical significance

Notes

References

Further reading