Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.5 (neuropathy target esterase)
1,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have observed that the oral administration of a single dose of a mixture of oleyl and linoleylanilides (80 mg/kg) in adult hens determines the apparition of delayed muscular neuropathy, which we have compared to that induced by metamidophos as a model of organophosphate-induced delayed neuropathy (OPIDN). We have compared the modifications produced by each of the 2 treatments on the enzymatic activity of neuropathy target esterase (NTE) measured in nervous tissue homogenates of brain, medulla and sciatic nerve. In addition we determined total esterases (TE), acetylcholine esterase (AchE) and serum creatine phosphate kinase (CPK). The organophosphate compound (OP) induced an initial reduction in the activity of NTE, TE and AchE which was reestablished 48 h later, except for brain TE which increased slowly during the latency period. This behaviour was accompanied by a permanent increase in the activity of serum CPK. Anilides induced a strong activation of AchE, NTE and TE (except brain TE) in the first 24-36 h. Normal levels were relatively quickly reestablished in brain (by 48 h) and slowly in medulla and sciatic nerve. But the AchE activity remained high throughout the whole period of latency. This activity level coincided with the AchE level observed at the onset of signs in animals dosed with OPs. CPK was also increased in sciatic nerve at 15 d but was depressed in serum throughout the whole latency period. Substances with chemical characteristics very different from OPs can induce a delayed neuropathy with modification of the activity of NTE.
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PMID:Study of delayed neurotoxicity caused by fatty acid anilides in hens. 223 37

The complete amino acid sequence of a mammalian acetylcholinesterase from fetal bovine serum (FBS AChE) is presented. This enzyme has a high degree of sequence identity with other cholinesterases, liver carboxyesterases, esterase-6, lysophospholipase, and thyroglobulin. The locations of 191 amino acids in 10 regions of the FBS enzyme were compared with corresponding sequences of Torpedo, human, and Drosophila AChEs and human serum butyrylcholinesterase (BChE). In one region there is a marked difference in both the number of amino acids and their sequence between mammalian AChE and other AChEs and the human serum BChE. The amino acid sequence of FBS AChE showed overall homologies of 90% with human AChE, 60% with T. california AChE, 50% with human serum BChE, and 39% with Drosophila AChE in these regions.
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PMID:Complete amino acid sequence of fetal bovine serum acetylcholinesterase and its comparison in various regions with other cholinesterases. 236 60

Carbaryl and aldicarb, two carbamate pesticides used extensively throughout the United States, are known to act as acetylcholinesterase inhibitors. We have demonstrated previously that exposure to carbaryl and aldicarb in young chicks caused persistent locomotion alterations with no correlation to esterase inhibition. In this study, we investigated the effects of these carbamates when injected in ovo to chick embryos, at two time periods (days 5 and 15) during incubation. Carbaryl dosed at 45 mg kg-1 egg weight was extremely toxic to the embryos on day 5 of incubation. Hatchability was reduced to 0% as compared to 80% when carbaryl was injected on day 15 of incubation. Aldicarb at 1.5 mg kg-1 egg weight had no major effect on hatchability when injected either on day 5 or day 15 of incubation (hatchability = 90 and 100%, respectively). Plasma, liver and brain esterases were measured in the chick at different time points during incubation and after hatching. Brain acetylcholinesterase (AChE) and liver cholinesterase (ChE) were inhibited significantly during incubation in embryos dosed on day 15 with both carbaryl and aldicarb. Liver carboxylesterase was inhibited significantly during incubation with only the carbaryl treatment. All esterase enzyme activities returned to normal after hatching. Plasma ChE and carboxylesterase levels were not affected with either carbaryl or aldicarb treatment from 8 until 47 days after hatching. Neither carbamate had any effect on brain neuropathy target esterase (NTE) activity either during incubation or after hatching. The locomotion of chicks was affected in both treatment groups until 47 days after hatching. This study indicates that carbaryl and aldicarb may cause long-term delayed alterations in the chicks.
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PMID:Effects of in ovo injection of carbamates on chick embryo hatchability, esterase enzyme activity and locomotion of chicks. 238 Apr 82

Neurotoxic esterase (neuropathy target enzyme, NTE) is an enzyme whose irreversible inhibition is the apparent first step in the induction of organophosphorus-induced delayed neuropathy. NTE is an integral membrane protein and thus must be solubilized before isolation can be attempted. This study describes solubilization of active chicken brain NTE with the nondenaturing detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) and characterization of the detergent-solubilized enzyme by gel exclusion chromatography. When detergent-solubilized membranes were chromatographed on Sepharose gel exclusion media, NTE activity eluted with an apparent molecular weight of 880-970 kD. When [3H]diisopropylphosphorofluoridate-radiolabeled membranes and unlabeled microsomal membranes were CHAPS-solubilized, combined and chromatographed on Sepharose 4B, NTE activity coeluted with two radiolabeled proteins (Mr = 148 kD and Mr = 112 kD using sodium dodecyl sulfate-polyacrylamide gel electrophoresis with reducing conditions). Another radiolabeled protein (Mr = 92 kD) coeluted exclusively with inhibitor-resistant esterase activity. This study provides strong evidence that the 148 and 112 kD proteins are subunits of a multicomponent NTE complex.
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PMID:Chromatographic characterization of neurotoxic esterase. 291 Feb 99

Brain neuropathy target esterase is identified as a paraoxon-resistant, mipafox-sensitive esterase that can be labelled with [3H]diisopropyl phosphorofluoridate. During "aging" of the labelled (inhibited) esterase, half the label (one isopropyl group) is transferred to a site (of the same molecular weight in sodium dodecyl sulphate) whence it may be released in volatile form by treatment with alkali. Our previously published procedure for complete extraction in a form suitable for scintillation counting of tritium-labelled proteins from polyacrylamide gels includes treatment of part-solubilised gels with alkali. Particles from brain of the hen, pig, sheep, guinea-pig, and rat were preincubated with paraoxon with or without mipafox, treated with [3H]diisopropyl phosphorofluoridate, and solubilised in sodium dodecyl sulphate. Labelled polypeptides (except from the rat) were separated by electrophoresis. Both mipafox-sensitive labelling and "volatilisable counts" were located principally in the 155-kilodalton region, with the residues dispersed throughout the gels. The quantities of paraoxon-resistant, mipafox-sensitive labelling sites and of "volatilisable counts" (in pmol/particles from 1 g) were, respectively, 12.2 and 8.65 in hen brain, 9.80 and 6.82 in pig, 8.48 and 5.46 in sheep, 4.46 and 4.01 in guinea-pig, and 4.91 and 2.08 in rat. The "volatilisable count" assay seems more specific for neuropathy target esterase and is easier and more precise than assays based on differences in labelling of two samples, each subjected to much processing. Hydrolytic activity of particles taken before labelling was measured against phenyl valerate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Species distribution of paraoxon-resistant brain polypeptides radiolabelled with diisopropyl phosphorofluoridate ([3H]DiPF): electrophoretic assay for the aged polypeptide of [3H]DiPF-labelled neuropathy target esterase. 292 99

Assay of neuropathy target esterase (NTE) which accounts for about 70% of paraoxon-resistant phenyl valerate (PV) esterase activity of hen brain depends on the fact that it is selectively inhibited by mipafox. A previous study of structure/activity relationships (Biochem. Pharmac. 24, 797, 1975) has been extended. Among 14 potential substrates NTE hydrolysed phenyl phenoxyacetate and phenyl thiophenoxyacetate faster (1.5-1.7X) than PV, but selectivity of these substrates for NTE among the paraoxon-resistant esterases was only 35-52%. Seventy-seven other potential inhibitors (organophosphates, phosphonates, phosphoramidates, phosphinates and carbamates) were examined to determine I50NTE and effects on both NTE and "non-NTE" at 3-4 x I50NTE (I 85-95) and, where possible, at 6-20 X I50NTE. Hydrophophic inhibitors with small/flexible leaving groups were generally very inhibitory: several 2,2-dichlorovinyl phosphates and fluorides were active at low nanomolar concentrations. In the dichlorovinyl phosphate series increasing dialkyl chain length beyond n-pentyl decreased inhibitory power, presumably due to steric hindrance since the methyl/n-decyl ester was 15X more active than di-n-decyl. Chloro-substitution of both ortho-positions of a phenyl leaving group for benzylcarbamates reduced inhibitory power more than 20X but had little effect in a phenyl leaving group of methyl phenylphosphonates where the acyl-leaving group bond is longer and less subject to steric hindrance. N-phenylbenzohydroxamyl benzylcarbamate is 10X more potent than any previously described carbamate against NTE. Among stereo-isomers differences of activity ranged from less than 2- to 15-fold. Only diphenylphosphinyl fluoride appeared to be virtually specific for NTE: at 0.5-1 microM it inhibited ca.92% of NTE and 10-13% of "non-NTE" which is similar to the specificity found for 2,6-dichlorophenyl methyl phenylphosphonate which has been claimed to be specific. Diphenylphosphinyl fluoride has an advantage in that it is easily synthesized and should be protective rather than neuropathic, but it is not stable in store. We cannot repeat experiments purporting to show a substantial proportion of a second isozyme of NTE. However, according to first-order kinetics, concentrations of inhibitor greater than 6 X I50 should inhibit NTE greater than 98% and for 19 out of 26 compounds a residue greater than 3% (limit of precision) was found under these conditions: in nearly every case the quantity was 3-5%. This quantity may not be "true NTE" but it cannot be the target for organophosphate-induced delayed neuropathy since it is resistant to various neuropathic and protective compounds.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sensitivity and selectivity of compounds interacting with neuropathy target esterase. Further structure-activity studies. 319 Jul 48

Organophosphorus-induced delayed polyneuropathy (OPIDP) is thought to result from organophosphorylation of neuropathy target esterase (NTE; formerly known as neurotoxic esterase), followed by an "aging" of the phosphorylated NTE. Protection against OPIDP should thus be achieved by production of an inhibited but "nonaging" NTE. Inhibited NTE produced in vitro by interaction with any of the four resolved isomers of soman aged negligibly (M. K. Johnson, D. J. Read, and H. P. Benschop, 1985a, Biochem. Pharmacol., 34, 1945-1951). Therefore both unresolved soman and the most inhibitory isomer (C(-)P(+)) were tested in adult hens for effects on NTE and for ability to produce OPIDP. With improved prophylaxis and therapy of acute intoxication, birds survived greater than 100 X LD50 of unresolved soman and did not develop OPIDP. One day after dosing, about half of brain and spinal cord NTE was in an unmodified (unaged) inhibited form; at this time eight survivors were challenged with a neuropathic dose of diisopropyl phosphorofluoridate (DFP). No neuropathy developed in four out of eight birds and mild to moderate signs were seen in the other four. Nine challenge control birds receiving DFP after solvent all developed severe neuropathy. Partial protection was seen in three out of three birds dosed prior to DFP challenge with sufficient C(-)P(+) isomer of soman (1.2 mg/kg sc) to convert about half of the spinal cord NTE to unaged inhibited form. Protection was not related to cholinergic shock. Two birds which survived out of eight pretreated with tabun (12 mg/kg sc) had about as much NTE inhibited as after soman administration but it was all in the modified (aged) inhibited form; these birds were not protected against DFP-induced neuropathy. A limited histopathologic examination showed that typical neurodegenerative lesions were seen only in birds with clear clinical neuropathy.
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PMID:High doses of soman protect against organophosphorus-induced delayed polyneuropathy but tabun does not. 334 Oct 26

The inhibitory power of organophosphorus compounds in vitro was compared against neurotoxic esterase (also known as neuropathy target esterase, NTE), acetylcholinesterase and carboxylesterase activities in brains from chickens, turkeys, quail and rats. Brains from the species most susceptible to clinical signs of organophosphorus-induced delayed neuropathy (chicken, turkey) contained more NTE than did rat and quail. Higher concentrations of organophosphorus compounds were required to inhibit rat NTE and quail acetylcholinesterase than were necessary for inhibition of these enzymes in chicken and turkey brains. Total carboxylesterase and acetylcholinesterase activities were less in rats than in the avian species.
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PMID:Comparative sensitivities of avian neural esterases to in vitro inhibition by organophosphorus compounds. 357 51

For the purpose of assessing the neurotoxic potential of organophosphorus compounds, it has been determined that paraoxon-preinhibited hen brain has both neurotoxicant (mipafox)-sensitive (neurotoxic esterase; NTE) and -insensitive esterase components. Several experiments designed to investigate the kinetic parameters governing the reaction of these esterases with two substrates and one organophosphorus inhibitor are presented. First, kinetic parameters for the hydrolysis of phenyl valerate and phenyl phenylacetate were measured. At 37 degrees C, the Km values of NTE for phenyl valerate and phenyl phenylacetate were found to be about 1.4 X 10(-3) and 1.6 X 10(-4) M respectively. At 25 degrees C, the Km of NTE for phenyl valerate was determined to be about 2.4 X 10(-3) M. Secondly, the kinetic constants of NTE for mipafox were measured at both 25 degrees C and 37 degrees C. With either phenyl valerate or phenyl phenylacetate as substrate, the Km at 37 degrees C was determined to be about 1.8 X 10(-4) M, and the phosphorylation constant (k2) was about 1.1 min-1. For phenyl valerate only, the Km at 25 degrees C was found to be about 6 X 10(-4) M, and the k2 was about 0.7 min-1. The data obtained at 25 degrees C were analysed by using a two-component model without formation of Michaelis complex, a two-component model with formation of Michaelis complex on the second component (NTE), or a three-component model without formation of Michaelis complex. The fact that the Michaelis model fit the data significantly better than either of the other two models indicates that the higher apparent Ki values that occur with low concentrations of mipafox are due to formation of Michaelis complex at high concentrations, rather than because of the presence of two NTE isoenzymes, as has been suggested by other investigators.
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PMID:Kinetics of substrate hydrolysis and inhibition by mipafox of paraoxon-preinhibited hen brain esterase activity. 375 63

The target enzyme in organophosphorous-induced delayed neuropathy (OPIDN) has been designated neuropathy target esterase or neurotoxic esterase (NTE). NTE activity can be measured in blood lymphocytes and platelets, which could be of use as biomonitors in man at risk for the development of OPIDN. Separation of lymphocytes and platelets from whole blood, recovery, purity, storage and expression of data were examined. A substantial amount of the NTE activity of a human lymphocyte preparation made using Ficoll/Pacque was due to contamination by platelets; further purification was achieved by sucrose-gradient centrifugation. In an easily prepared sample of human platelets less than 10% of NTE was associated with contaminating white cells. We were unable to preserve NTE activity of platelets or lymphocytes at -80 degrees C either 'dry' or with added buffer and glycerol. In 68 male subjects, NTE activity in platelets averaged 8.36 +/- 1.54 nmol min-1 mg protein-1 and NTE activity in lymphocytes, obtained from blood after removal of platelets, 13.34 +/- 2.42 nmol min-1 mg protein-1. A good correlation was found between platelet and lymphocyte NTE activity. NTE activity in platelets may be a preferable method for measuring exposure to axonopathic organophosphorous compounds because of the ease and purity of separation. No correlation with other neuropathic risk factors such as age, smoking and alcohol intake was noted.
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PMID:Neuropathy target esterase in human lymphocytes and platelets. 395 22


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