Interplay between amino acid residues at positions 192 and 115 in modulating hydrolytic activities of human paraoxonase 1

Bajaj, Priyanka; Aggarwal, Geetika; Tripathy, Rajan K.; Pande, Abhay H.

doi:10.1016/j.biochi.2014.07.024

Cited by 10 publications

(20 citation statements)

References 48 publications

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“…Construction of pET23a(+) plasmid containing a gene encoding rh-PON1 (H115W,R192) has been described in our previous report [ 28 ]. This plasmid was used to generate mutants of rh-PON1 in which the amino acid residue at position 192 was substituted by other amino acid residues.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, the crystal structures of a variant of chimeric PON1 (Chi-PON1) has been elucidated [ 23 , 24 ]. Although, this variant of chi-PON1 (G2E6) shares ~ 85% sequence similarity with h-PON1 (at amino acid level), there is a considerable difference in the catalytic activities of these enzymes [ 25 – 28 ]. On the basis of the information gained from in silico analysis and enzymatic characterization of h-PON1 and Chi-PON1 different mechanisms explaining various hydrolytic activities of h-PON1 have been proposed [ 24 , 27 – 28 , 29 – 32 ].…”

Section: Introductionmentioning

confidence: 99%

“…Although, this variant of chi-PON1 (G2E6) shares ~ 85% sequence similarity with h-PON1 (at amino acid level), there is a considerable difference in the catalytic activities of these enzymes [ 25 – 28 ]. On the basis of the information gained from in silico analysis and enzymatic characterization of h-PON1 and Chi-PON1 different mechanisms explaining various hydrolytic activities of h-PON1 have been proposed [ 24 , 27 – 28 , 29 – 32 ]. It has been proposed that the His residue at position 115 (H115) plays a pivotal role in carrying out the lactonase/arylesterase activities of the enzyme, and the replacement of H with W at position 115 causes significant decrease in these activities of the enzyme [ 25 , 28 , 31 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

“…On the basis of the information gained from in silico analysis and enzymatic characterization of h-PON1 and Chi-PON1 different mechanisms explaining various hydrolytic activities of h-PON1 have been proposed [ 24 , 27 – 28 , 29 – 32 ]. It has been proposed that the His residue at position 115 (H115) plays a pivotal role in carrying out the lactonase/arylesterase activities of the enzyme, and the replacement of H with W at position 115 causes significant decrease in these activities of the enzyme [ 25 , 28 , 31 , 33 ]. However, results from our earlier studies have shown that H115 residue of h-PON1 may not always be required for mediating the lactonase/arylesterase activities of the enzyme [ 27 – 28 ].…”

Section: Introductionmentioning

confidence: 99%

“…It has been proposed that the His residue at position 115 (H115) plays a pivotal role in carrying out the lactonase/arylesterase activities of the enzyme, and the replacement of H with W at position 115 causes significant decrease in these activities of the enzyme [ 25 , 28 , 31 , 33 ]. However, results from our earlier studies have shown that H115 residue of h-PON1 may not always be required for mediating the lactonase/arylesterase activities of the enzyme [ 27 – 28 ].…”

Section: Introductionmentioning

confidence: 99%

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Toward Understanding the Catalytic Mechanism of Human Paraoxonase 1: Site-Specific Mutagenesis at Position 192

et al. 2016

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Human paraoxonase 1 (h-PON1) is a serum enzyme that can hydrolyze a variety of substrates. The enzyme exhibits anti-inflammatory, anti-oxidative, anti-atherogenic, anti-diabetic, anti-microbial and organophosphate-hydrolyzing activities. Thus, h-PON1 is a strong candidate for the development of therapeutic intervention against a variety conditions in human. However, the crystal structure of h-PON1 is not solved and the molecular details of how the enzyme hydrolyzes different substrates are not clear yet. Understanding the catalytic mechanism(s) of h-PON1 is important in developing the enzyme for therapeutic use. Literature suggests that R/Q polymorphism at position 192 in h-PON1 dramatically modulates the substrate specificity of the enzyme. In order to understand the role of the amino acid residue at position 192 of h-PON1 in its various hydrolytic activities, site-specific mutagenesis at position 192 was done in this study. The mutant enzymes were produced using Escherichia coli expression system and their hydrolytic activities were compared against a panel of substrates. Molecular dynamics simulation studies were employed on selected recombinant h-PON1 (rh-PON1) mutants to understand the effect of amino acid substitutions at position 192 on the structural features of the active site of the enzyme. Our results suggest that, depending on the type of substrate, presence of a particular amino acid residue at position 192 differentially alters the micro-environment of the active site of the enzyme resulting in the engagement of different subsets of amino acid residues in the binding and the processing of substrates. The result advances our understanding of the catalytic mechanism of h-PON1.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Toward Understanding the Catalytic Mechanism of Human Paraoxonase 1: Site-Specific Mutagenesis at Position 192

et al. 2016

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Role of paraoxonase 1 in organophosphate G-series nerve agent poisoning and future therapeutic strategies

Tripathy,

Khandave,

Bzdrenga

et al. 2024

Arch Toxicol

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Paraoxonases: metabolic role and pharmacological projection

Moya

Máñez

2018

Naunyn-Schmiedeberg's Arch Pharmacol

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Atherosclerosis is one of the leading causes of death in Western countries, with high-density lipoproteins (HDL) playing an important protective role due to their ability to inhibit oxidation of low-density lipoproteins (LDL), thus relieving vascular subendothelial damage. One of the proteins constituting HDL particles is paraoxonase-1 (PON1), an enzyme able to hydrolyze aryl esters, lactones, and organophosphates. Other closely related paraoxonases are designated as PON2, which is a protein localized inside many different kinds of cells, and PON3, not only present in HDL but also in mitochondria and endoplasmic reticulum, as well. Given that the amount and the activity of PON1 in human serum are significantly lower in people suffering from cardiovascular diseases, enhancing both parameters might contribute to their treatment and prevention. One of the physiologically interesting substrates for the abovementioned hydrolytic cleavage is homocysteine thiolactone (HTL), an atherothrombotic active form of homocysteine. Although it was therefore postulated that PON1 would participate in preventing the HTL-mediated lipid peroxidation, some attention is recently paid to other enzymes, like biphenyl hydrolase-like protein, that seem to more selectively involved in lowering this risk factor. The aim of this paper is to elucidate the role of paraoxonases, especially PON1, by reviewing the latest studies in order to understand both its physiological role and modulation by drugs, nutrients, and plant extracts.

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Interplay between amino acid residues at positions 192 and 115 in modulating hydrolytic activities of human paraoxonase 1

Cited by 10 publications

References 48 publications

Toward Understanding the Catalytic Mechanism of Human Paraoxonase 1: Site-Specific Mutagenesis at Position 192

Toward Understanding the Catalytic Mechanism of Human Paraoxonase 1: Site-Specific Mutagenesis at Position 192

Role of paraoxonase 1 in organophosphate G-series nerve agent poisoning and future therapeutic strategies

Paraoxonases: metabolic role and pharmacological projection

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