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)

Biochemical events in the initiation of organophosphorus induced delayed neurotoxicity (OPIDN) are not well understood. To find new putative target(s) for OPIDN, we investigated the biochemical and pharmacological characteristics of [3H] diisopropyl phosphorofluoridate (DFP) binding to membrane and cytosol preparations from the brain and spinal cord of hens in vitro. [3H]DFP binding to both preparations was determined by the specific binding obtained by subtracting non-specific binding from total binding. The specific binding sites of [3H]DFP were found not only on membrane but also in cytosol. Kd values were higher and Bmax values were lower in cytosol than in membrane. Moreover, the Kd values in both membrane and cytosol preparations from spinal cord were lower than those of brain. The Bmax values in membrane and cytosol were similar between brain and spinal cord. The specific binding to both preparations was markedly displaced by unlabeled DFP. The specific binding of DFP to the membrane was highly or partly displaced by organophosphorus compounds (OPs) or a carbamate, respectively. However, both the OPs and the carbamate had considerably weaker blocking effects on the specific binding of DFP to cytosol. None of the compounds known to interact with neuropathy target esterase (NTE) had a strong blocking effect on the specific binding of DFP to either membrane or cytosol. These results show that the specific binding of DFP to the membrane may be binding with cholinesterase (ChE). However, cytosol, especially in spinal cord, may have DFP binding sites other than ChE and NTE.
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PMID:A comparative study of binding sites for diisopropyl phosphorofluoridate in membrane and cytosol preparations from spinal cord and brain of hens. 1140 51

To find new putative target(s) for organophosphorus induced delayed neurotoxicity (OPIDN), we investigated the biochemical and pharmacological characteristics of [3H] diisopropyl phosphorofluoridate (DFP) binding to membrane and cytosol preparations from the brain and spinal cord of hens. Specific [3H]DFP binding was determined by subtracting non-specific binding from total binding. The binding sites of [3H]DFP, an organophosphate that induces OPIDN, were found not only on membrane but also in cytosol. Reduction of subsequent ex vivo specific [3H]DFP binding by in vivo pretreatment with unlabeled DFP was found in cytosol, not membrane. The reduced binding lasted to the onset of OPIDN, especially in spinal cord. These results suggest that the specific DFP binding sites in cytosol, rather than on membrane, are the most important with regard to the initiation of OPIDN. Inhibitors of cholinesterase (ChE) and neuropathy target esterase (NTE) other than DFP did not affect specific [3H]DFP binding to either membranes or cytosol in vivo. Additionally, inhibition of the activities of these esterases by these compounds was not consistent with either the degree of inhibition of the [3H]DFP binding or a time-dependent manner of OPIDN. These results suggest that DFP binding site(s) involved in the initiation of OPIDN may be different from the active sites of ChE and NTE.
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PMID:Correlation of binding sites for diisopropyl phosphorofluoridate with cholinesterase and neuropathy target esterase in membrane and cytosol preparations from hen. 1140 52

Occupational exposure to organophosphorus insecticides (OPs), such as chlorpyrifos, may be monitored by the measurement of the activity of peripheral cholinesterase (ChE) enzymes, including erythrocyte acetylcholinesterase (EAChE) and serum cholinesterase (SChE). Lymphocyte neuropathy target esterase (NTE) is thought to have potential as a predictor of organophosphate-induced delayed neuropathy (OPIDN). This paper describes work performed in 39 Australian pest control operators (PCOs) exposed to a termiticide containing chlorpyrifos, and 34 unexposed control subjects. EAChE activities in PCOs did not differ from those of unexposed control workers. Mean NTE activity was slightly higher in PCOs than in controls and mean SChE was 52% of control activity. These results indicate that exposure of Australian PCOs to termiticides containing chlorpyrifos may be monitored using SChE but not EAChE or NTE, and that workers in this industry have sufficiently high OP exposure to significantly depress SChE activity. SChE inhibition of 70-80% may be associated with symptoms. Although no current symptoms were reported to be associated with occupational OP exposure, these workers may be at increased risk of acute effects following inadvertent spills or self-contamination due to their background level of exposure to OPs. While it is preferable to compare ChE enzyme activities between pre- and post-exposure periods to evaluate OP-related effects in individuals, in some cases there is an absence of pre-exposure data. The results of this study suggest that a screening value for SChE of 550 nmol/min/ml in a single blood sample may be useful to identify potentially OP-exposed individuals in the Australian population. Australian control subjects were similar with respect to EAChE, but displayed activities of NTE and SChE approximately 50 and 23% lower than an unexposed UK reference group. While these comparisons are presently speculative, they suggest that there may be differences in SChE and NTE activities in control populations of the two countries. The routine treatment of Australian homes with termiticides containing OPs, or differences in the availability and use of domestic OP-containing insecticides may explain these population differences. Further work is required to examine whether these differences are real, and if so their likely cause.
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PMID:Peripheral cholinesterase inhibition by occupational chlorpyrifos exposure in Australian termiticide applicators. 1171 58

Measurements of plasma cholinesterase (pl.ChE), brain cholinesterase (Br.ChE) and brain Neuropathy Target Esterase (Br.NTE) were made in three different lineages of chickens. All birds received toxicants through gavage in a single oral dose between 08:00 and 09:00 h, after overnight fast. Babcock chickens were treated with 800 mg/kg tri-ortho-cresyl phosphate (TOCP) or 80 mg/kg trichlorfon. The TOCP group had 82% Br.NTE inhibition, when compared to the control group, and no birds displayed symptoms of clinical organophosphate-induced delayed neuropathy (OPIDN). Hy-line w36 lineage chickens were given 1600 mg/kg TOCP and despite this higher dose, Br.NTE inhibition was similar that presented by Babcock chickens. Isabrown chickens were given 1600 mg/kg TOCP or 80 mg/kg trichlorfon. At 36 h all trichlorfon treated birds had from 80 to 90% inhibition of Pl.ChE and Br.ChE, when compared to controls. However, Br.NTE was inhibited less than 20%, and there were no clinical signs of OPIDN. All TOCP treated isabrown chickens had more than 80% Br.NTE inhibition while one of them exhibited just light signs of OPIDN, two chickens became totally paralyzed. This finding suggested that chicken strain was important in the appearance of OPIDN. In addition, 70-80% of NTE inhibition was necessary but was not sufficient to produce OPIDN in chickens, since babcock and hy-line w36 chickens exhibited NTE inhibition in the range of 70-80% without clinical signs of OPIDN.
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PMID:Organophosphate induced delayed neuropathy in genetically dissimilar chickens: studies with tri-ortho-cresyl phosphate (TOCP) and trichlorfon. 1242 64

Arachidonylsulfonyl fluoride (3), reported here for the first time, is similar in potency to its known methyl arachidonylfluorophosphonate (2) analogue as an inhibitor of mouse brain fatty acid amide hydrolase activity (IC(50) 0.1 nM) and cannabinoid CB1 agonist [3H]CP 55,940 binding (IC(50) 304-530 nM). Interestingly, 3 is much more selective than 2 as an inhibitor for fatty acid amide hydrolase relative to acetylcholinesterase, butyrylcholinesterase and neuropathy target esterase. N-(2-Hydroxyethyl)arachidonylsulfonamide (4) is at least 2500-fold less potent than N-(2-hydroxyethyl)arachidonamide (anandamide) (1) at the CB1 agonist site.
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PMID:Arachidonylsulfonyl derivatives as cannabinoid CB1 receptor and fatty acid amide hydrolase inhibitors. 1295 Nov 14

An animal (rat) model of chronic stress (corticosterone in the drinking water) was used to study the interaction of stress and the organophosphorus (OP) neurotoxicants chlorpyrifos (60 mg/kg subcutaneously in a single dose) and tri-ortho-tolyl phosphate (TOTP, at 75, 150, or 300 mg/kg given 7 times orally in a 2-wk period). Adult male Long-Evans rats were provided with corticosterone in drinking water (400 microg/ml, w/v) for a total of 28 d, which led to significantly decreased weight and decreased cellularity of the thymus and spleen. Seven days after initiation of corticosterone treatment, half of the rats were given chlorpyrifos, and an additional 7 d later the 2-wk, 7-dose treatment of TOTP was initiated. During the 28-d test period, behavior of rats was evaluated using a functional observational battery (FOB), motor activity, and passive avoidance. Reductions in body weight, grip strength, and ambulatory movements occurred as a result of corticosterone treatment. Decreased body weight and grip strength were also elicited by TOTP, and the interactions of corticosterone and TOTP enhanced the effects on body weight and grip strength. Blood cholinesterase levels were obtained during the 28-d study period and found useful for monitoring OP exposure. At the end of the 28-d testing period, rats were sacrificed and activities of cholinesterase, neurotoxic esterase (neuropathy target esterase), and/or carboxylesterase were evaluated in blood, liver, and/or brain regions (basal forebrain, caudate putamen, cerebral cortex, hippocampus). All these esterases in brain were inhibited in a dose-related manner by TOTP, with some enhancement in rats drinking corticosterone-containing water. In addition, choline acetyltransferase, glial acidic fibrillary protein (GFAP), glutathione peroxidase, and superoxide dismutase were evaluated in one or more of the brain regions already identified. Choline acetyltransferase, glutathione peroxidase, and superoxide dismutase activities were unaffected by treatments. However, GFAP was elevated above control levels in the cerebral cortex of rats by all treatments (corticosterone, chlorpyrifos, TOTP). Neuropathological examination revealed early stages of dose-related increased distal myelinated fiber axonal degeneration seen in the medullary fasciculus gracilis at only the highest dose of TOTP (300 mg/kg).
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PMID:Neurologic and immunologic effects of exposure to corticosterone, chlorpyrifos, and multiple doses of tri-ortho-tolyl phosphate over a 28-day period in rats. 1471 79

Acetylcholinesterase (AChE) is one of several hundred serine hydrolases in people potentially exposed to about 80 organophosphorus (OP) compounds important as insecticides or chemical warfare agents. The toxicology of OPs was interpreted until recently almost solely on the basis of AChE inhibition. It is assumed that each serine hydrolase has a specific function and proposed that every OP compound has a unique inhibitory profile. This review considers the progress in sifting the expanding list of potential serine hydrolase toxicological targets. About 50 serine hydrolase targets have been recognized but only a few studied thoroughly. The toxicological relevance of known secondary OP targets is established mainly from observations with humans (butyrylcholinesterase and neuropathy target esterase-lysophospholipase) and studies with mice (cannabinoid CB1 receptor, carboxylesterase, lysophospholipase and platelet activating factor acetylhydrolase) and hen eggs (arylformamidase or kynurenine formamidase). Pesticides most commonly shown to inhibit these targets in experimental vertebrates are chlorpyrifos and tribufos. Generally the levels of environmental and occupational OP pesticide exposure are well below those causing in vivo inhibition of secondary serine hydrolase targets. Although exposure to OP insecticides is decreasing from stricter regulations and the development of resistant pest strains, it will continue to some degree for decades in the future. Only two OPs are used as pharmaceuticals, i.e. echothiophate as an ophthalmic for treatment of glaucoma and metrifonate as an anthelmintic for Schistosoma (and formerly as a candidate drug for improved cognitive function in Alzheimer's disease). In safety evaluations, knowledge on known OP targets must be balanced against major gaps in current understanding since more than 75% of the serine hydrolases are essentially unknown as to OP targeting and relevance, i.e. it is not clear if they play a role in OP toxicology.
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PMID:Serine hydrolase targets of organophosphorus toxicants. 1624 4

Elucidating mechanisms of aging of esterases inhibited by organophosphorus (OP) compounds is important for understanding toxicity and developing biomarkers of exposure to these agents. Aging has classically been thought to involve net loss of a single side group from the OP moiety of phosphylated esterases, rendering the enzyme refractory to reactivation. However, recent evidence has shown that acetylcholinesterase (AChE) and the catalytic domain of human neuropathy target esterase (NEST) undergo aging by alternative mechanisms following their inhibition with N,N'-diisopropylphosphorodiamidofluoridate (mipafox, MIP). This study was performed to determine whether MIP-inhibited butyrylcholinesterase (BChE) ages conventionally, by net loss of a single side group, or by an alternate route, e.g., reversible deprotonation or displacement of both isopropylamine groups, as recently observed for MIP-inhibited NEST and AChE, respectively. Diisopropylphosphorofluoridate (DFP), the phosphate analogue of the phosphoroamidate MIP, was used for comparison. Kinetic values for MIP against BChE were as follows: ki = (1.28 +/- 0.053) x 10(6) M-1 min-1; k3 = 0.004,15 +/- 0.000,27 min-1; k4 = 0.008,49 +/- 0.000,99 min-1. Kinetic values for DFP against BChE were as follows: ki = (1.83 +/- 0.18) x 10(6) M-1 min-1; k3 = 0.004,88 +/- 0.000,24 min-1; k4 = 0.0121 +/- 0.0028 min-1. Mass spectrometric studies revealed a mass shift of 123.4 +/- 0.7 Da for the active-site peptide peak of aged DFP-inhibited BChE, corresponding to a monoisopropylphosphate adduct. Similarly, the analogous mass shift for aged MIP-inhibited BChE was 122.4 +/- 0.7 Da, corresponding to a monoisopropylphosphoroamido adduct. Therefore, we conclude that the MIP-BChE conjugate ages by loss of a single isopropylamine group, in contrast to MIP-inhibited AChE or NEST.
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PMID:Mechanism of aging of mipafox-inhibited butyrylcholinesterase. 1732 78

This paper reviews previously published data and presents new results to address the hypothesis that fluorinated aminophosphonates (FAPs), (RO)(2)P(O)C(CF(3))(2)NHS(O)(2)C(6)H(5), R=alkyl, inhibit serine esterases by scission of the P-C bond. Kinetics studies demonstrated that FAPs are progressive irreversible inhibitors of acetylcholinesterase (AChE, EC 3.1.1.7.), butyrylcholinesterase (BChE, EC 3.1.1.8.), carboxylesterase (CaE, EC 3.1.1.1.), and neuropathy target esterase (NTE, EC 3.1.1.5.), consistent with P-C bond breakage. Chemical reactivity experiments showed that diMe-FAP and diEt-FAP react with water to yield the corresponding dialkylphosphates and (CF(3))(2)CHNHS(O)(2)C(6)H(5), indicating lability of the P-C bond. X-ray crystallography of diEt-FAP revealed an elongated (and therefore weaker) P-C bond (1.8797 (13)A) compared to P-C bonds in dialkylphosphonates lacking alpha-CF(3) groups (1.805-1.822A). Semi-empirical and non-empirical molecular modeling of diEt-FAP and (EtO)(2)P(O)C(CH(3))(2)NHS(O)(2)C(6)H(5) (diEt-AP), which lacks CF(3) groups, indicated lengthening and destabilization of the P-C bond in diEt-FAP compared to diEt-AP. Active site peptide adducts formed by reacting diEt-FAP with BChE and diBu-FAP with NTE catalytic domain (NEST) were identified using peptide mass mapping with mass spectrometry (MS). Mass shifts (mean+/-SE, average mass) for peaks corresponding to active site peptides with diethylphosphoryl and monoethylphosphoryl adducts on BChE were 136.1+/-0.1 and 108.0+/-0.1Da, respectively. Corresponding mass shifts for dibutylphosphoryl and monobutylphosphoryl adducts on NEST were 191.8+/-0.2 and 135.5+/-0.1Da, respectively. Each of these values was statistically identical to the theoretical mass shift for each dialkylphosphoryl and monoalkylphosphoryl species. The MS results demonstrate that inhibition of BChE and NEST by FAPs yields dialkylphosphoryl and monoalkylphosphoryl adducts, consistent with phosphorylation via P-C bond cleavage and aging by net dealkylation. Taken together, predictions from enzyme kinetics, chemical reactivity, X-ray crystallography, and molecular modeling were confirmed by MS and support the hypothesis that FAPs inhibit serine esterases via scission of the P-C bond.
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PMID:Kinetics and mechanism of inhibition of serine esterases by fluorinated aminophosphonates. 2003 29

This paper reviews our previously published data and presents new results on biosensor assay of blood esterases. Tyrosinase and choline oxidase biosensors based on nanostructured polyelectrolyte films were developed for these purposes. Experiments were performed on the quantitative determination of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carboxylesterase (CaE), and neuropathy target esterase (NTE) in samples of whole blood of rats, mice, and humans. Good agreement was found between biosensor and spectrophotometric assays for AChE, BChE, and CaE. No direct comparison could be made for NTE because its activity cannot be measured spectrophotometrically in whole blood. A new method of simultaneous quantitative determination of AChE and BChE in test mixtures is also described. This method represents a bifunctional biosensor for the simultaneous analysis of choline and phenol based on integration of individual sensors. Algorithms for calculation of separate concentrations of AChE and BChE in the mixture were developed. The mean error of calculated component concentrations was approximately 6% for binary test mixtures. The present work provides a foundation for building multiplexed systems for the simultaneous determination of multiple esterases with applications to biomonitoring for exposures to organophosphorus compounds.
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PMID:Biosensor analysis of blood esterases for organophosphorus compounds exposure assessment: approaches to simultaneous determination of several esterases. 2009 86


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