The Human Serum Paraoxonase/Arylesterase Gene (PON1) Is One Member of a Multigene Family

doi:10.1006/geno.1996.0225

Genomics

Volume 33, Issue 3, 1 May 1996, Pages 498-507

https://doi.org/10.1006/geno.1996.0225 Get rights and content

Abstract

A physiological role for paraoxonase (PON1) is still uncertain, but it catalyzes the hydrolysis of toxic organophosphates. Evidence that the human genome contains twoPON1-like genes, designatedPON2andPON3,is presented here. HumanPON1andPON2each have nine exons, and the exon/intron junctions occur at equivalent positions.PON1andPON2genes are both on chromosome 7 in human and on chromosome 6 in the mouse. Turkey and chicken, like most birds, lack paraoxonase activity and are very susceptible to organophosphates. However, they have aPON-like gene with ∼70% identity with humanPON1, PON2,andPON3.Another unexpected finding is that the deduced amino acid sequences of PON2 in human, mouse, dog, turkey, and chicken and of human PON3 are all missing the amino acid residue 105, which is lysine in human PON1. The expanded number ofPONgenes will have important implications for future experiments designed to discover the individual functions, catalytic properties, and physiological roles of the paraoxonases.

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Enhancement in the production of recombinant human paraoxonase 1 in Escherichia coli: A comprehensive approach of cellular engineering and optimization of protein folding process in vitro
2022, International Journal of Biological Macromolecules
Human paraoxonase 1(hPON1) belongs to the paraoxonase (PON) family. It is a calcium-dependent enzyme with a size of ∼43 kDa and is composed of 6 bladed beta-barrel structures with two calcium ions in its active site. In humans, it is synthesized in the liver and remains bound with the high-density lipoproteins (HDL) within the blood. It has immense potential to tackle the poisoning associated with the use of organophosphates (OPs) and their derivatives, such as nerve agents, due to role in their degradation. Therefore, hPON1 serves as a potential bio-scavenger that can be used as an antidote or as a surface decontaminating agent in OPs poisoning. However, present systems prove insufficient to produce it in sufficient quantity to make it industrially relevant. Here, our efforts involve producing it recombinantly in an E. coli system with enhanced expression levels by altering cellular and environmental conditions. This has been further improved by the development of in-vitro refolding process for the denatured recombinant hPON1 (rhPON1) protein. This methodology resulted in approximately 200 mg of the enzymatically functional protein from 1 l of E. coli culture. Proper refolding of rhPON1 was confirmed by comparing its enzymatic activity and conformation with serum purified hPON1.
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Several studies in recent years have shown that lipid overload causes lipotoxic damage to the kidney, and oxidative stress, inflammation, and autophagic arrest are all important mechanisms of renal lipotoxicity. However, effective measures with therapeutic effects on renal lipotoxicity are limited. The present study indicated the protective effect of the paraoxonase 1 (PON1) against renal lipotoxicity in high-fat diet–fed scavenger receptor class B type I–deficient (SR-BI^−/−) mice. The results showed that SR-BI^−/− mice exhibited significant renal pathologic characteristics, such as oxidative stress, inflammation, and fibrosis, under a normal chow diet, and were accompanied by dyslipidemia and reduced plasma PON1 activity and renal PON1 levels. PON1 overexpression significantly attenuated the above pathologic changes in the kidneys of SR-BI^−/− mice fed with a high-fat diet. Mechanistically, PON1 may ameliorate renal oxidative stress by reducing reactive oxygen species production, reduce renal lipid accumulation by inhibiting AKT/mechanistic target of rapamycin kinase pathway to activate lipophagy, and reduce the occurrence of inflammation and cell death by inhibiting Nod-like receptor family protein 3 inflammasome-mediated pyroptosis. The present study is the first to show that PON1 overexpression can effectively alleviate renal lipotoxicity injury, and PON1 may be a promising therapeutic strategy for the treatment of renal lipotoxicity-related diseases.
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Paraoxonases (PON) 1–3 are lactonases with antioxidant and atheroprotective properties. The best known single nucleotide polymorphisms (SNPs) within the PON family, include: Q192R (rs662), L55M (rs854560) in the PON1 gene and C311S (rs7493) in the PON2 gene. Their influence on the occurrence and course of coronary artery disease (CAD) is unclear. The aim of this study was to assess the association between the most common PON1 and PON2 genetic variants with the presence of CAD, as well as their relation to coronary lesion complexity in accordance with the ACC/AHA standard.
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We found no association between the analyzed SNPs and symptomatic CAD. However, in patients with diagnosed CAD, the PON311S allele was independently associated with the risk of the most complex type C coronary lesion occurrence.
Our study is the first report of an association between PON2 311S SNP and the type of coronary atherosclerotic lesions in humans.
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Regular ArticleThe Human Serum Paraoxonase/Arylesterase Gene (PON1) Is One Member of a Multigene Family

Abstract

Regular Article
The Human Serum Paraoxonase/Arylesterase Gene (PON1) Is One Member of a Multigene Family