Polymorphism of Human Serum Paraoxonase

Mallinckrodt, M. Geldmacher-von

doi:10.1007/978-3-642-67179-1_9

Cited by 7 publications

(3 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, these authors demonstrated that, in Caucasian (British) and Indian subjects, the frequency distribution of PON activity displayed bimodality with approximately comparable frequencies of the low-and high-activity alleles. However, some non-Caucasian populations display markedly different patterns of activity, with a unimodal distribution of PON activity and a higher median value than in Caucasians (29). In contrast, Malay, Chinese and African subjects failed to show bimodality.…”

Section: Polymorphism Of Paraoxonase Activitymentioning

confidence: 87%

Paraoxonase as a Risk Marker for Cardiovascular Disease: Facts and Hypotheses

Laplaud¹,

Dantoine²,

Chapman³

1998

CCLM

View full text Add to dashboard Cite

Paraoxonase (PON1) is a Ca2+-dependent enzyme whose mechanism of action is incompletely elucidated. PON1 was originally found to be responsible for the hydrolysis of paraoxon, a catabolite of the insecticide parathion, but this enzyme is equally able to hydrolyze other substrates such as phenyl acetate. PON1 exhibits two sequence polymorphisms, Arg-->Gln 192 and Met-->Leu 55, respectively, of which the former is responsible for the distinct catalytic activity of the two corresponding allozymes against paraoxon. The PON1 gene is a member of a family of at least three related genes. Although the physiologic substrate of PON1 is unknown, a protective role against the oxidative degradation of serum lipoproteins has been attributed to this enzyme. Indeed, PON1 is a component of a spectrum of circulating high density lipoprotein particles and can hydrolyze oxidized phospholipids and cholesteryl ester hydroperoxides. Studies have been conducted to evaluate the possible "protective" role of PON, and especially the influence of the Arg-->Gln 192 polymorphism, in coronary artery disease. Results from these investigations are conflicting, and recent data suggest a complex pattern with influences from other polymorphisms in either the PON1 and/or the PON2 and PON3 genes, or even another region of the gene cluster. A number of related factors, which include the heterogeneity of the high density lipoprotein particles incorporating PON(s), the metabolism of associated apolipoproteins such as apoJ/clusterin, the respective roles of PON(s) and other high density lipoprotein-associated enzymes such as platelet-activating-factor acetyl-hydrolase and lecithin-cholesterol acyltransferase, modifications of high density lipoprotein composition and activity under acute-phase conditions, the dietary and environmental regulation of PON(s), and the actual in situ availability of PON in the atherosclerotic artery wall, must equally be taken into account.

show abstract

Section: Polymorphism Of Paraoxonase Activitymentioning

confidence: 87%

Paraoxonase as a Risk Marker for Cardiovascular Disease: Facts and Hypotheses

Laplaud¹,

Dantoine²,

Chapman³

1998

CCLM

View full text Add to dashboard Cite

show abstract

“…It has been established that the in vitro toxicity of highly purified parathion is relatively low (Diggle and Gage 1951) and that parathion is oxidized in vivo to paraoxone via metabolism in the liver (Davison 1957;Neal 1967a, b), a process in which parathion becomes toxic (for review see O'Brien 1960;Koelle 1963;Schrader 1963;Geldmacher-von Mallinckrodt 1975, 1978. Our in vitro experiments demonstrating very weak blocking activity for parathion dissolved in glycerin and in blood confirmed these observations.…”

Section: Discussionmentioning

confidence: 99%

Forensic significance of acetylcholine esterase histochemistry in organophosphate intoxication

Oehmichen

Besserer

1982

Z Rechtsmed

View full text Add to dashboard Cite

The reduction of acetylcholine esterase (AChE) activity or the complete blocking of AChE to be observed by histochemical demonstration of AChE in tissue after experimental and spontaneous (human) organophosphate intoxication (especially paraoxone = E600 and parathion = E605) should be interpreted as an indication of an in vivo inhibition of the cholinergic system. In animal experiments, a relationship was demonstrated between AChE activity and the applied dose of organophosphorous compounds. In addition, enzyme inhibition was observed in in vitro systems using AChE-containing mouse tissue sections pretreated with organophosphate solutions or with body fluids containing organophosphates. Examination of the concentration dependency indicated that the inhibiting solution must contain at least 0.15 microgram/ml paraoxone or 5 mg/ml parathion to block AChE in the section. Using the same in vitro system, a half-life of 6-7 min was established for the paraoxone inactivating enzyme in blood. The in vivo and in vitro inhibited AChE was reactivated by consecutive treatment of blocked sections with toxogonin. This possibility of reactivation therefore allows qualitative classifications of the AChE-inhibiting toxin to the alkylphosphates. The postmortem persistence of the AChE inhibitory effect was demonstrable for about a 2-month interval. Since the histochemically demonstrable activity of the enzyme AChE is more or less constant during a postmortem interval of at least 70h, the model of histochemical demonstration is a method which provides a morphological equivalent for acute organophosphate intoxication.

show abstract

“…We then examined whether any of the mutations were in the vicinity of any of the other 44 mutations present in G2E6, and we found a single case wherein Lys192 made a hydrogen bond to Ser166. Position 192 is an interesting site because it is a site of human polymorphism, where Gln and Arg are common [32]. Also, of all 59 mutations in G2E6, only five positions are within 9 Å of the active-site His115 residue, and of those only the side chains of Ser166 and Lys192 point toward the active site.…”

Section: Resultsmentioning

confidence: 99%

Solubilization and Humanization of Paraoxonase-1

et al. 2012

View full text Add to dashboard Cite

Paraoxonase-1 (PON1) is a serum protein, the activity of which is related to susceptibility to cardiovascular disease and intoxication by organophosphorus (OP) compounds. It may also be involved in innate immunity, and it is a possible lead molecule in the development of a catalytic bioscavenger of OP pesticides and nerve agents. Human PON1 expressed in E. coli is mostly found in the insoluble fraction, which motivated the engineering of soluble variants, such as G2E6, with more than 50 mutations from huPON1. We examined the effect on the solubility, activity, and stability of three sets of mutations designed to solubilize huPON1 with fewer overall changes: deletion of the N-terminal leader, polar mutations in the putative HDL binding site, and selection of the subset of residues that became more polar in going from huPON1 to G2E6. All three sets of mutations increase the solubility of huPON1; the HDL-binding mutant has the largest effect on solubility, but it also decreases the activity and stability the most. Based on the G2E6 polar mutations, we “humanized” an engineered variant of PON1 with high activity against cyclosarin (GF) and found that it was still very active against GF with much greater similarity to the human sequence.

show abstract

Polymorphism of Human Serum Paraoxonase

Cited by 7 publications

References 7 publications

Paraoxonase as a Risk Marker for Cardiovascular Disease: Facts and Hypotheses

Paraoxonase as a Risk Marker for Cardiovascular Disease: Facts and Hypotheses

Forensic significance of acetylcholine esterase histochemistry in organophosphate intoxication

Solubilization and Humanization of Paraoxonase-1

Contact Info

Product

Resources

About