Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Hereditary peculiarities in individual responses to environmental chemicals are a common occurrence in human populations. Genetic variation in glutathione S-transferase, CYP1A2, N-acetyltransferase, and paraoxonase exemplify the relationship of metabolic variation to individual susceptibility to cancer and other toxicants of environmental origin. Heritable receptor protein variants, a subset of proteins of enormous pharmacogenetic potential that have not thus far been extensively explored from the pharmacogenetic standpoint, are also considered. Examples of interest that are considered include receptor variants associated with retinoic acid resistance in acute promyelocytic leukemia, with paradoxical responses to antiandrogens in prostate cancer, and with retinitis pigmentosa. Additional heritable protein variants of pharmacogenetic interest that result in antibiotic-induced deafness, glucocorticoid-remediable aldosteronism and hypertension, the long-QT syndrome, and beryllium-induced lung disease are also discussed. These traits demonstrate how knowledge of the molecular basis and mechanism of the variant response may contribute to its prevention in sensitive persons as well as to improved therapy for genetically conditioned disorders that arise from environmental chemicals.
Environ Mol Mutagen 1995
PMID:Influence of heredity on human sensitivity to environmental chemicals. 778 56

The subcellular localization and different biochemical properties of a human hepatic microsomal enzyme that hydrolyses paraoxon (paraoxonase, PON1) were studied and compared to the paraoxon hydrolase activity found in human plasma as well as in rat liver and plasma. Having evaluated the influence of the postmortem interval by a parallel experiment performed in rats, we conclude that the paraoxonase activity was preferentially localized in the microsomal fraction. The enzyme reaction was optimized according to temperature, pH, buffer, ionic strength, substrate concentration, and enzyme protein concentration. The characterization of human liver paraoxonase included the study of optimum pH, pH stability, heat inactivation assays, and kinetic parameters (K(m) and Vmax). In addition, the enzyme activity showed an absolute requirement for exogenous calcium. The activity was lost after incubation with EDTA and partially restored by the addition of calcium; however, other metals assayed were not able to activate the human liver enzyme as did calcium. Our results support the possible identity between human plasma and liver paraoxonases. In spite of the technical difficulties of this study and the possible interference of the postmortem changes in the results, this article represents the first systematic approach to the characterization of human liver paraoxonase.
J Biochem Mol Toxicol 1998
PMID:Human liver paraoxonase (PON1): subcellular distribution and characterization. 941 88

Oxidized LDL is highly atherogenic as it stimulates macrophage cholesterol accumulation and foam cell formation, it is cytotoxic to cells of the arterial wall and it stimulates inflammatory and thrombotic processes. LDL oxidation can lead to its subsequent aggregation, which further increases cellular cholesterol accumulation. All major cells in the arterial wall including endothelial cells, smooth muscle cells and monocyte derived macrophages can oxidize LDL. Macrophage-mediated oxidation of LDL is probably a hallmark in early atherosclerosis, and it depends on the oxidative state of the LDL and that of the macrophages. The LDL oxidative state is elevated by increased ratio of poly/mono unsaturated fatty acids, and it is reduced by elevation of LDL-associated antioxidants such as vitamin E, beta-carotene, lycopene, and polyphenolic flavonoids. The macrophage oxidative state depends on the balance between cellular NADPH-oxidase and the glutathione system. LDL-associated polyphenolic flavonoids which inhibit its oxidation, can also reduce macrophage oxidative state, and subsequently the cell-mediated oxidation of LDL. Oxidation of the macrophage lipids, which occurs under oxidative stress, can lead to cell-mediated oxidation of LDL even in the absence of transition metal ions, and may be operable in vivo. Finally, elimination of Ox-LDL from extracellular spaces, after it was formed under excessive oxidative stress, can possibly be achieved by the hydrolytic action of HDL-associated paraoxonase on lipoprotein's lipid peroxides. The present review article summarizes the above issues with an emphasis on our own data.
Mol Cell Biochem 1998 Nov
PMID:LDL oxidation by arterial wall macrophages depends on the oxidative status in the lipoprotein and in the cells: role of prooxidants vs. antioxidants. 982 20

Paraoxon, the active metabolite of parathion, can be detoxified through a noncatalytic pathway by carboxylesterases and a catalytic pathway by calcium-dependent A-esterases, producing p-nitrophenol as a common metabolite. The detoxication patterns of carboxylesterases and A-esterases were investigated in vitro in the present study with a high tissue concentration (75 mg/mL rat liver homogenate or 50% rat serum solution) to more closely reflect enzyme concentrations in intact tissues. A final paraoxon concentration of 3.75 microM was used to incubate with liver homogenates or serum solutions for 5 seconds or 3, 5, 15, or 25 minutes; also 0.625, 1.25, 2.5, 3.125, 3.75, or 5.0 microM paraoxon (final concentration) was incubated with liver homogenates or serum solutions for 15 minutes. Phenyl saligenin cyclic phosphate and EDTA were used to inhibit carboxylesterases and A-esterases, respectively. Significant amounts of p-nitrophenol were generated with or without either inhibitor during a 15 minute incubation with paraoxon from low (0.625 microM) to high (5.0 microM) concentrations. The amount of p-nitrophenol generated via carboxylesterase phosphorylation was greater than via A-esterase-mediated hydrolysis in the initial period of incubation or when incubating with a low concentration of paraoxon. Plateau shape curves of p-nitrophenol concentration versus time or paraoxon concentration indicated that carboxylesterase phosphorylation was saturable. When incubated for long time intervals or with high concentrations of paraoxon, more p-nitrophenol was generated via A-esterase-mediated hydrolysis than from carboxylesterase phosphorylation. The ratio of paraoxon concentration to tissue amount used in in vitro assays of this study was equivalent to dosing a rat with toxicologically relevant dosages. These in vitro data suggest that both carboxylesterases and A-esterases detoxify paraoxon in vivo; carboxylesterases may be an important mode of paraoxon detoxication in initial exposures to paraoxon or parathion before they become saturated, whereas A-esterases may contribute to paraoxon detoxication in repeated exposures to paraoxon or parathion because they will not become inhibited and will remain catalytically active unlike the carboxylesterases. The importance of carboxylesterases in detoxication of paraoxon was verified by an in vivo study. In rats pretreated with tri-o-tolyl phosphate, an in vivo carboxylesterase inhibitor, brain acetylcholinesterase was significantly inhibited after intravenous exposure to parathion. No significant inhibition of brain acetylcholinesterase was observed in rats pretreated with corn oil.
J Biochem Mol Toxicol 1999
PMID:Detoxication of paraoxon by rat liver homogenate and serum carboxylesterases and A-esterases. 1040 60

Human serum paraoxonase (PON1) is an esterase that is bound to high-density lipoproteins (HDLs). It can hydrolyze organophosphates and its activity is inversely related to atherosclerosis. Some studies also suggest that a relationship exists between polymorphisms of the gene that encodes paraoxonase and coronary heart disease (CHD), whereas other studies, in different populations, have not found such an association. One mechanism by which certain PON1 allozymes might protect against atherosclerosis is by inhibition of the oxidation of HDL and low-density lipoprotein (LDL). Experimental studies suggest that this protection is associated with the ability of PON1 to hydrolyze specific lipid peroxides in oxidized lipoproteins. Interventions that preserve or enhance PON1 activity, as well as manipulations of PON1 polymorphisms, might help delay the onset of CHD.
Mol Med Today 1999 Sep
PMID:Does paraoxonase play a role in susceptibility to cardiovascular disease? 1046 49

We investigated 190 healthy, unrelated and randomly selected, north-west Indian Punjabis (M:102; F:88) for paraoxonase (PON1) polymorphism by dual substrate method and also determined lipid variables i.e., total cholesterol (TC), high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL) and triglycerides (TG) in them to determine any relationship between PON1 activity, PON1 phenotypes and lipids. The basal plasma paraoxonase (PON) activity, and PON activity in presence of 1 Mol NaCl (salt activated paraoxonase i.e., SAP) were estimated by using paraoxon as substrate whereas the, phenyl acetate esterase (A) activity was estimated by using phenylacetate as substrate. Based on the ratio of SAP/A activity, three distinct phenotypes of PON1 could be determined with gene frequencies of PON*A (low activity) and PON*B (high activity) allele being 0.847 and 0.153 respectively. In the whole population on partial correlation after normalising the variables and after adjusting the lipids for age and body mass index (BMI), a significant negative correlation was observed between SAP/A ratio and TC (r = -0.290; P < 0.01) and LDL (r = -0.154; P < 0.05). However, on analysis of covariance (ANCOVA) after normalizing the lipid variables and adjusting these for age and body mass index (BMI), no significant difference could be observed in lipid profile of these three phenotypes. The lack of a significant relationship between lipids and PON1 phenotypes, suggests that PON phenotype does not significantly influence the lipid profile in north-west Indian Punjabis. However, a significant negative correlation between the PON activity and TC and LDL suggests that low PON activity could be a risk factor for atherosclerosis in these subjects.
 ...
PMID:Paraoxonase (PON1) polymorphism & its relation with lipids in north west Indian Punjabis. 1064 1

Whole body homogenates from azinphosmethyl-resistant fifth instars of the tufted apple bud moth demonstrated 11.8-fold elevated phosphoric triester hydrolase (methyl paraoxonase) activity as compared to susceptible insects of the same species. Elevated phosphoric triester hydrolase (PTEH) activity associated with resistance was also found in the Colorado potato beetle but not in the German cockroach or tobacco budworm. Phosphoric triester hydrolase activity in the tufted apple bud moth was minimal in resistant and susceptible third instars and in adult males and females and was highest in whole body homogenates and in the alimentary canal of resistant fifth instars. A microtiterplate assay was developed, which successfully diagnosed resistance in individual fifth instars based on increased phosphoric triester hydrolase (methyl paraoxonase) activity. Phosphoric triester hydrolase was purified 289-fold from fifth instars of resistant bud moths, but any additional resolution resulted in the loss of enzyme activity. Phosphoric triester hydrolase demonstrated an apparent molecular weight of 41,000 with an isoelectric point of 5.28. Methyl paraoxonase activity was increased by calcium, cobalt, manganese, and octylthio-1,1,1-trifluoro-2-propanone and decreased by mercury, phosphate ions, tin, and ethylenediaminetetraacetic acid. Iron, potassium chloride, lithium, magnesium, sodium chloride, and lead had no effect.
J Biochem Mol Toxicol 2001
PMID:Purification and characterization of a phosphoric triester hydrolase from the tufted apple bud moth, Platynota idaeusalis (Walker). 1117 Mar 16

Escherichia coli thioesterase/protease I (TEP-I) is a member of a novel subclass of the lipolytic enzymes with a distinctive GDSLS motif. In addition to possessing thioesterase and protease activities, TEP-I also exhibits arylesterase activity. We have determined the (15)N nuclear magnetic spin relaxation rates, R(1) and R(2), and the steady state (1)H-(15)N heteronuclear Overhauser effect, measured at both 11.74 T and 14.09 T, of (u-(15)N) TEP-I. These data were analyzed using model-free formalism (with axially symmetric rotational diffusion anisotropy) to extract the backbone dynamics of TEP-I. The results reveal that the core structure of the central beta-sheet and the long alpha-helices are rigid, while the binding pocket appears to be rather flexible. The rigid core serves as a scaffold to anchor the essential loops, which form the binding pocket. The most flexible residues display large amplitude fast (ps/ns time-scale) motion and lie on one stripe whose orientation is presumed to be the ligand-binding orientation. We also detected the presence of several residues displaying slow (microseconds/ms time-scale) conformational exchanging processes. These residues lie around the binding pocket and are oriented perpendicularly to the orientation of the flexible stripe. Two of the putative catalytic triads, Ser10 and His157, and their neighbors show motion on the microseconds/ms time-scale, suggesting that their slow motion may have a role in catalysis, in addition to their possible roles in ligand binding. The presence of a flexible substrate-binding pocket may also facilitate binding to a wide range of substrates and confer the versatile functional property of this protein.
J Mol Biol 2001 Apr 06
PMID:Backbone dynamics of Escherichia coli thioesterase/protease I: evidence of a flexible active-site environment for a serine protease. 1128 57

Nitrogen-fixing Sinorhizobium meliloti cells depend upon dicarboxylic acids as carbon and energy sources. The metabolism of these intermediate compounds of the trichloroacetic acid cycle is dependent upon the availability of acetyl-coenzyme A (CoA). In bacteroids, the combined activities of malic enzymes and pyruvate dehydrogenase (PDH) have been proposed to be responsible for the anaplerotic synthesis of acetyl-CoA. We obtained a S. meliloti mutant strain, PD3, in which a Tn5 insertion led to a significant decrease in the overall PDH activity. The genetic characterization of this mutant revealed that the transposon is located at the 3' end of a gene (ada) encoding a putative arylesterase. The mutant PD3 is deficient in nitrogen fixation, which strengthens the physiological importance of PDH activity in the symbiosis of S. meliloti with alfalfa plants.
Mol Plant Microbe Interact 2001 Jun
PMID:The disruption of a gene encoding a putative arylesterase impairs pyruvate dehydrogenase complex activity and nitrogen fixation in Sinorhizobium meliloti. 1138 77

This study examined the relationships between paraoxonase genotypes, coronary artery reactivity, and indices of low-density lipoprotein oxidation in healthy men. Impairment in coronary flow reserve, as assessed by positron emission tomography, is associated with lipoprotein oxidation, which is affected by high-density lipoprotein bound enzyme, paraoxonase. Paraoxonase has two common polymorphisms (M/L55 and R/Q192) that change the activity of the enzyme. Forty-nine healthy men (mean age 35 +/- 4 years) were divided by paraoxonase genotype into low (Q192/Q192, or M55/M55, M55/L55) and high-active (R192/Q192, R192/R192, or L55/L55) groups and related to the myocardial blood flow, to the susceptibility of low-density lipoprotein to oxidation, and the autoantibody titer against oxidized low-density lipoprotein. The blood flow was measured by positron emission tomography at rest and during adenosine infusion. The low-active Q192/Q192 genotype was associated with higher resting blood flow corrected for rate-pressure product compared to the high-active R192/R192 and R192/Q192 genotypes (P=0.011). The blood flow stimulated by adenosine was not significantly different in the low- and high-active genotype groups. Paraoxonase genotypes had no effect on low-density lipoprotein susceptibility to oxidation or autoantibody formation against oxidized low-density lipoprotein. Genotypes of paraoxonase may not clearly contribute to the early changes in coronary reactivity. Coronary vasomotor tone at rest appears to be modulated by paraoxonase R/Q192 polymorphism through mechanism(s) unrelated to low-density lipoprotein oxidation.
J Mol Med (Berl) 2001 Aug
PMID:Paraoxonase gene polymorphisms and coronary reactivity in young healthy men. 1151 70


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