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)

Phenyl di-n-pentylphosphinate (PPP) is a potent inhibitor of neuropathy target esterase (NTE) with negligible effect on acetylcholinesterase: I50S at 37 degrees C for 20 min and pH 8, respectively are 0.2 microM and > 2mM. PPP is not neuropathic. This is compatible with the fact that inhibited NTE is autopsy material from hens dosed with PPP can always be reactivated in vitro, presumably because no 'aging' reaction has occurred. PPP (10 mg/kg s.c.) given to hens up to 4 days before severely neuropathic doses (1.7 mg/kg) of diisopropylphosphorofluoridate (DFP) prevented neuropathic but not cholinergic effects of DFP. Hens given PPP 3 days after a sub-neuropathic dose of DFP (0.4 mg/kg) developed severe clinical neuropathy (clinical scores of 7 and 5 compared with DFP-plus-solvent scores 0,1,3). These prophylactic and promoting effects are similar to those exerted by phenylmethanesulphonyl fluoride (PMSF) at doses which inhibit NTE. In 3 out of 4 birds a pre-dose with PMSF (15 mg/kg) prevented the promoting effect of 120 mg/kg PMSF given after DFP.
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PMID:Prophylaxis against and promotion of organophosphate-induced delayed neuropathy by phenyl di-n-pentylphosphinate. 834 2

Certain esterase inhibitors (such as phenylmethanesulfonyl fluoride, PMSF) enhance the clinical and morphological signs of organophosphate-induced delayed polyneuropathy (OPIDP) in hens. This is called promotion of OPIDP. The target of promotion is unknown, but it is likely to be different from neuropathy target esterase (NTE), the target of OPIDP, NTE is a neural phenyl valerate (PV) esterase, operationally defined by selective inhibition with organophosphates. This study was aimed to ascertain whether the target for promotion is a PV esterase other than NTE. Brain and sciatic nerve PV esterases of hens were incubated with diisopropylphosphorofluoridate (DFP; 5 microM) or N,N-diisopropyl phosphorodiamidofluoridate (mipafox; 50 microM) to inhibit NTE and other esterases thought not to be relevant to promotion. Remaining activities, quantitatively similar after either inhibition, were titrated with PMSF (up to 500 microM) and analysis of time course of inhibition showed first-order kinetics. Mipafox (50 microM)-resistant PMSF (500 microM)-sensitive activity (about 80% of mipafox-resistant ones) was tested both in vitro and in vivo with several inhibitors. No correlation was found between inhibition of mipafox-resistant PMSF-sensitive activity and the capability of several inhibitors to promote OPIDP. We conclude that the target of promotion is unlikely to be a PV esterase resistant to mipafox (50 microM).
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PMID:Phenyl valerate esterases other than neuropathy target esterase and the promotion of organophosphate polyneuropathy. 930 88

Carboxylesterases are enzymes present in neural and other tissues that are sensitive to organophosphorus compounds. The esterase activity in particulate forms, resistant to paraoxon and sensitive to mipafox have been implicated in the initiation of organophosphorus-induced delayed polyneuropathy (OPIDP) and is called neuropathy target esterase (P-NTE). Certain esterases inhibitors such as phenylmethylsulfonyl fluoride (PMSF), can also irreversibly inhibit P-NTE and by this mechanism PMSF 'protects' from further effect of neuropathic OPs. However, if PMSF is dosed after a low non-neuropathic dose of a neuropathic OP, its neurotoxicity is 'promoted', causing severe neuropathy. The molecular target of promotion has not yet been identified and it has been shown that it is unlikely to be the P-NTE. In order to discriminate the different esterases, we used non-neuropathic (paraoxon), and neuropathic organophosphorus compounds (mipafox, DFP) and a neuropathy promoter (PMSF). They were used alone or in concurrent inhibition to study particulate and soluble fractions of brain, spinal cord and sciatic nerve of chicken. From the experimental data, a matrix was constructed and equations deduced to estimate the proportions of the different potential activity fractions that can be discriminated by their sensitivity to the tested inhibitors. It was deduced that only combinations of up to three inhibitors can be used for the analysis with consistent results. In all tissues, inside the paraoxon sensitive activity, most of the activity was sensitive either to mipafox, to PMSF or both. In all fractions, except brain soluble fractions, within the paraoxon resistant activity, a mipafox sensitive component was detected that is operationally considered NTE (P-NTE and S-NTE in particulate and soluble fractions, respectively). Most of this activity was also sensitive to PMSF, and this should be considered the target of organophosphorus inducing neuropathy and of PMSF protective effect. Either in brain and spinal cord, a significant amount of the activity resistant to 40 microM paraoxon and 250 microM mipafox (usually called 'C' activity) is sensitive to PMSF. It could be a good candidate to contain the target of the promotion effect of PMSF as well as the S-NTE activity that is also PMSF sensitive.
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PMID:Discrimination of carboxylesterases of chicken neural tissue by inhibition with a neuropathic, non-neuropathic organophosphorus compounds and neuropathy promoter. 941 46

Certain esterase inhibitors such as O-(2-chloro-2,3,3-trifluorocyclobutyl) O-ethyl S-propyl phosphorothioate (KBR-2822) and phenylmethanesulfonyl fluoride (PMSF) cause exacerbation (promotion) of toxic and traumatic axonopathies. Although these chemicals are capable of inhibiting neuropathy target esterase (NTE), which is the target for organophosphate induced delayed neuropathy, the target for promotion is unlikely to be NTE. Experiments were aimed to ascertain if neuropathy is caused by repeated dosing with a promoter not causing NTE inhibition and in the absence of deliberate injury to axons. Hens were treated with KBR-2822 (0.2 or 0.4 mg/kg per day) by gavage for 90 days and observed for clinical signs up to 21-23 days after treatment when histopathological examination was carried out. NTE and acetylcholinesterase (AChE) were measured at intervals and mean percentages of inhibition at steady state of inhibition/resynthesis (on day 20) were as follows: mean inhibition NTE was < or = 8% in the 0.2 mg/kg group and between 15 and 18% in the 0.4 mg/kg group in brain, spinal cord and peripheral nerve; mean AChE inhibition in brain was 31 and 57% in the two experimental groups, respectively. Controls treated with paraoxon (not neuropathic or a promoter and given at 0.05 mg/kg per day by gavage) showed 45% mean AChE inhibition and no NTE inhibition. Neither clinical nor morphological signs of neuropathy were observed in any group. To ascertain whether subclinical lesions were produced by the repeated treatment with KBR-2822, hens were given KBR-2822 (0.2 mg/kg per day) for 21 days by gavage followed by PMSF (120 mg/kg s.c. 24 h after the last dose of KBR-2822). A control group of hens was treated with the neuropathic DFP (0.03 mg/kg s.c. daily for 21 days causing 40-50% NTE inhibition) followed by PMSF (120 mg/kg s.c.). After PMSF, the KBR-2822 treated hens did not develop neuropathy whereas DFP treated hens did. Lack of neuropathy after repeated treatment with KBR-2822 indicates that a continuous promoting 'pressure' on hen axons is harmless in the absence of a concurrent biochemical or neurotoxic injury.
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PMID:Repeated low doses of O-(2-chloro-2,3,3 trifluorocyclobutyl) O-ethyl S-propyl phosphorothioate (KBR-2822) do not cause neuropathy in hens. 945 80

This study was aimed to investigate the possibility of modifying the rate of aging of diisopropylfluorophosphate-inhibited neuropathy target esterase (NTE) of hen brain. This reaction on NTE occurs with a half-time of 7.4 min. Atropine was effective in decreasing the rate of aging on DFP-inhibited NTE and this effect was time- and concentration-dependent. Atropine was also a weak but progressive inhibitor of NTE activity (I50 = 80 mM) and this reaction appears to be reversible at lower atropine concentrations. Among compounds containing oxime functional groups only OPAB, having longer methylene chain and being more lipophylic than other oximes usually used in acetylcholinesterase (AChE) reactivation studies, was effective in decreasing the rate of aging on DFP-inhibited NTE. However, when atropine and oximes were used together we have obtained a potentiating and/or synergistic effect which was most significant with combination of atropine and TMB-4 giving up to a 15-fold decrease in the rate of aging reaction. The efficacy of this particular combination was concentration-dependent. We have also discussed similarities and differences in aging reaction occurring on NTE and AChE.
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PMID:Modification of the rate of aging of diisopropylfluorophosphate-inhibited neuropathy target esterase of hen brain. 963 12

Neuropathy target esterase (neurotoxic esterase, NTE), a protein thought to be involved in the production of organophosphorus compound-induced delayed neurotoxicity (OPIDN), has been postulated to be a component of endogenous neuronal protein phosphorylation systems. The purpose of this work was to test this hypothesis as well as to investigate further the role of endogenous protein phosphorylation in toxic neuropathies. White Leghorn hens were dosed with the neuropathic compounds di-1-butyl-2,2-dichlorovinyl phosphate (dibutyl dichlorvos, DBDCV), tri-o-cresyl phosphate (TOCP), or acrylamide, and regions from brain were fractionated into axolemmal, synaptosomal, and microsomal preparations. Radiolabeling of NTE or endogenously phosphorylated proteins was carried out by incubation with [14C]-DFP or gamma-[32P]-ATP, respectively. Radiolabeled proteins were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and visualized by autoradiography. Relative amounts of phosphoproteins were quantified by densitometry of the autoradiographs. Changes in endogenous phosphorylation of a protein exhibiting the characteristics of NTE were not observed in these experiments. However, levels of a [32P]-labeled 50-kDa brainstem axolemmal protein were decreased significantly on d 15, but not on d 1, 3, 7, or 10 after dosing with 2.8 mg/kg DBDCV. Clinical signs of ataxia and histopathological findings of axonal degeneration in the spinocerebellar tracts of the brainstem were evident on d 10-15, and hens were unable to perch on a horizontal wooden rod from d 12 after dosing with DBDCV. The decrease in the 50-kDa phosphoprotein was not observed on d 15 after the production of clinically evident neuropathy with either 14 daily doses of 50 mg/kg acrylamide or with a single dose of 500 mg/kg TOCP. These results suggest that NTE is not an endogenously phosphorylated protein under the conditions of these experiments. However, an effect on endogenous phosphorylation limited to a 50-kDa axolemmal protein was selectively produced by treatment with a neuropathic dose of DBDCV that was in evidence only after clinical signs and histopathological findings of axonopathy were apparent.
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PMID:Brainstem axolemmal protein phosphorylation in vitro in hens dosed with di-1-butyl-2,2-dichlorovinyl phosphate. 1070 44

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

Gulf War veterans were given pyridostigmine bromide (PB) tablets to enhance the therapeutic effect of antidotes to nerve agents in the event of exposure. The goal of this research is to examine whether combined exposure to PB and sarin (agent GB) is more neurotoxic to sensitive surrogate animals, mice and chickens, than if given separately. Scoping trials were performed to establish appropriate dose-response ranges for sarin and control chemicals. IC50 values were determined in chickens and mice for in vitro inhibition of acetylcholinesterase (AChE) and neuropathy target esterase (NTE). The results indicated PB neither inhibits NTE nor does it spare sarin's inhibition of AChE. Chick embryo nerve cells in vitro showed more inhibition of AChE activity and no faster recovery when PB treatment was followed by DFP treatment than the other way around. Experiments on chickens also indicated that PB treatment did not inhibit NTE and that it crossed the blood brain barrier inhibiting brain AChE although to a lesser extent than it inhibited blood cholinesterases. Other experiments determined multiple dose levels in chickens for sarin and DFP that inhibited > 80% of NTE, considered a threshold for triggering organophosphate-induced delayed neuropathy.
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PMID:Actions of pyridostigmine and organophosphate agents on chick cells, mice, and chickens. 1202 98

Aging of organophosphorus (OP)-compound-inhibited neuropathy target esterase (NTE) is the critical event that initiates OP-compound-induced delayed neurotoxicity (OPIDN). Aging has classically been considered to involve side-group loss from phosphylated NTE, rendering the enzyme refractory to reactivation. N,N'-Diisopropylphosphorodiamidofluoridate (mipafox, MIP)-inhibited NTE has been thought to age quickly; however, it can be reactivated under acidic conditions. The present study was undertaken to determine whether MIP-inhibited human recombinant NTE esterase domain (NEST) ages classically by isopropylamine loss. Diisopropylphosphorofluoridate (DFP), the oxygen analogue of MIP, was used for comparison. Kinetic values for DFP against NEST were as follows: k(i) = 17 200 +/- 180 M(-1) min(-1); reactivation t(1/2) approximately 90 min at pH 8.0 and approximately 60 min at pH 5.2; k(4) = 0.108 +/- 0.041 min(-1) at pH 8.0 and 0.181 +/- 0.034 min(-1) at pH 5.2. Kinetic values for MIP against NEST were as follows: k(i) = 1880 +/- 61 M(-1) min(-1); reactivation t(1/2) = 0 min at pH 8.0 and approximately 60 min at pH 5.2; aging was complete at all time points tested at pH 8.0, but no aging occurred at pH 5.2. Mass spectrometry revealed a mass shift of 123.0 +/- 0.6 Da for the active site peptide peak of aged DFP-inhibited NEST, corresponding to a monoisopropyl phosphate adduct. In contrast, the analogous mass shift for aged MIP-inhibited NEST was 162.8 +/- 0.6 Da, corresponding to the intact N,N'-diisopropylphosphorodiamido adduct. Thus, MIP-inhibited NEST does not age by isopropylamine loss. However, because kinetically aged MIP-inhibited NEST yields an intact adduct capable of reversible deprotonation, aging could occur by proton loss. Indeed, MIP-inhibited NEST does not age at pH 5.2 but ages immediately and completely at pH 8.0. Therefore, we conclude that the MIP-NEST conjugate ages by deprotonation rather than classical side-group loss.
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PMID:The mipafox-inhibited catalytic domain of human neuropathy target esterase ages by reversible proton loss. 1503 42


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