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

---

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

2-Substituted-4H-1,3,2-benzodioxaphosphorin 2-oxides (2-substituted-BDPOs) are known to be potent neuropathy target esterase (NTE) inhibitors (I50s for the racemates of 0.2-3 nM) when the 2-substituents are n-alkyl (C5-C12), N-alkoxy (C7-C10), or p-n-alkylbenzyl (C3 and C4). The list of potent inhibitors (I50s < 3 nM) is expanded by the new n-alkylamino (C9) and n-alkylthio (C5, C7, and C9) analogs reported here. The optimal chain length of the 2-substituent is about 10 atoms in the alkylamino and alkylthio series as in our previous study on alkyl and alkoxy moieties. In contrast, an I50 of 60 nM is reported for o-methylphenoxy-BDPO, the neuropathic metabolite of tri-o-cresyl phosphate (TOCP). In addition to substituent effects, each of these compounds contains two enantiomers of unknown stereospecificity as NTE inhibitors. Separation by chiral HPLC with the CHIRALCEL OC column and hexane-2-propanol eluent gives individual enantiomers of > 98% e.e. and a stereospecificity for NTE inhibition depending on the type and chain length of the 2-substituent; e.g., the ratio for inhibitory potency of the individual enantiomers is 1.7-fold for nonylthio, 1255-fold for nonylamino, and 9-fold for the TOCP metabolite. In comparing enantiomeric pairs of BDPOs with alkyl, alkoxy, alkylamino, alkylthio, benzyl, p-butylbenzyl, o-methylphenoxy, or phenyl as the 2-substituent, the more retained enantiomer in HPLC is always the better NTE inhibitor (in a series of twenty-two pairs) and housefly toxicant (based on two pairs) than the less retained one.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Neuropathy target esterase inhibitors: enantiomeric separation and stereospecificity of 2-substituted-4H-1,3,2-benzodioxaphosphorin 2-oxides. 815 29

Incidence of numerous human poisonings by quinalphos (Ekalux, Bayrusil) in agricultural areas near Belgrade initiated this study on the ability of the compound to inhibit hen brain neuropathy target esterase, acetylcholinesterase and plasma butyrylcholinesterase in vivo. Hens were treated with a single oral dose ranging from 25 to 600 mg kg-1 quinalphos (LD50 = 72 mg kg-1) or 500 mg kg-1 triorthocresyl phosphate (positive control), sacrificed 24-96 h later for enzyme assays and monitored for 25 days for evaluation of walking impairments. High inhibition (> 80%) of both cholinesterases was obtained with 25 and 50 mg kg-1 quinalphos. Doses of 200 and 600 mg kg-1 of the agent inhibited up to 23 and 28% of hen brain neuropathy target esterase activity, respectively. Clinical signs of neuropathy were not seen. Quinalphos was slowly absorbed from the gastrointestinal tract, as indicated by the severity of the cholinergic symptoms and the inhibition of neuropathy target esterase, which reached its maximum 72 and 96 h after poisoning. The results suggest that quinalphos, at doses tested, has no ability to cause delayed neuropathy in hens without showing signs of severe cholinergic intoxication.
...
PMID:Studies on the delayed neuropathic and anticholinesterase potential of quinalphos (diethyl 2-quinoxalyl phosphorothionate) in hens. 825 30

The mouse is considered to be insensitive and the hen sensitive to clinical expression of organophosphorus-induced delayed neuropathy (OPIDN) which is associated with inhibition of neuropathy target esterase (NTE). This species difference is reevaluated with two optimized inhibitors of hen brain NTE by examining them for potential neurotoxic effects in mice. 2-Octyl-4H-1,3,2-benzodioxaphosphorin 2-oxide (OBDPO) and ethyl octylphosphonofluoridate (EOPF) inhibit mouse brain NTE in vitro by 50% at 0.12 and 0.02 nM and induce neurotoxic signs in mice at 10 and 5 mg/kg, respectively. The action of these compounds in both l- and 6-month-old mice, sometimes after early transient cholinergic signs, involves ataxia, paralysis, and death in 1 to 3 days and is accordingly referred to as subacute neurotoxicity. The neurotoxic signs are associated with brain edema and severe vacuolation in the grey matter of the brain and spinal cord, particularly the neuropile. Subacute neurotoxic signs are always associated with at least 80% inhibition of brain NTE activity 16-24 hr after treatment. Acetylcholinesterase and butyrylcholinesterase are much less sensitive than NTE to inhibition by OBDPO and EOPF both in vitro and in vivo. Selected carbamates, thiocarbamates, phosphinates, and sulfanyl fluorides are prophylactic agents and dipentyl 2,2-dichlorovinyl phosphate is a promoter for OBDPO-induced subacute neurotoxicity. Although this type of neurotoxicity in mice is similar to OPIDN in the correlation with NTE inhibition and the prophylactic action of reversible NTE inhibitors, it differs from OPIDN in the delay time prior to onset, the sensitivity of both young and old animals, and the high incidence of fatality. A full neuropathological study is desirable to further characterize this subacute neurotoxicity.
...
PMID:Subacute neurotoxicity induced in mice by potent organophosphorus neuropathy target esterase inhibitors. 868 3

A Ca2+-independent phospholipase A2 (PLA2) maximally active at pH 4 and specifically inhibited by the transition-state analogue 1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol (MJ33) was isolated from rat lungs. The sequence for three internal peptides (35 amino acids) was used to identify a 1653-base pair cDNA clone (HA0683) from a human myeloblast cell line. The deduced protein sequence of 224 amino acids contained a putative motif (GXSXG) for the catalytic site of a serine hydrolase, but showed no significant homology to known phospholipases. Translation of mRNA produced from this clone in both a wheat germ system and Xenopus oocytes showed expression of PLA2 activity with properties similar to the rat lung enzyme. Apparent kinetic constants for PLA2 with dipalmitoylphosphatidylcholine as substrate were Km = 0.25 mM and Vmax = 1.89 nmol/h. Activity with alkyl ether phosphatidylcholine as substrate was decreased significantly compared with diacylphosphatidylcholine. Significant lysophospholipase, phospholipase A1, or 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine acetylhydrolase activity was not observed. Enzyme activity was insensitive to p-bromophenacyl bromide, bromoenol lactone, trifluoromethylarachidonoyl ketone, mercaptoethanol, and ATP, but was inhibited by MJ33 and diethyl p-nitrophenyl phosphate, a serine protease inhibitor. SDS-polyacrylamide gel electrophoresis with autoradiography of the translated [35S]methionine-labeled protein confirmed a molecular mass of 25.8 kDa, in good agreement with the enzyme isolated from rat lung. By Northern blot analysis, mRNA corresponding to this clone was present in both rat lung and isolated rat granular pneumocytes. These results represent the first molecular cloning of a cDNA for the lysosomal type Ca2+-independent phospholipase A2 group of enzymes.
...
PMID:Identification of a human cDNA clone for lysosomal type Ca2+-independent phospholipase A2 and properties of the expressed protein. 899 71

The differential inhibition of the target esterases acetylcholinesterase (AChE) and neuropathy target esterase (NTE, neurotoxic esterase) by organophosphorus compounds (OPs) is followed by distinct neurological consequences in exposed subjects. The present study demonstrates that neuroblastoma cell lines (human SH-SY5Y and murine NB41A3) can be used to differentiate between neuropathic OPs (i.e., those inhibiting NTE and causing organophosphorus-induced delayed neuropathy) and acutely neurotoxic OPs (i.e., those highly capable of inhibiting AChE). In these experiments, concentration-response data indicated that the capability to inhibit AChE was over 100x greater than the capability to inhibit NTE for acutely toxic, nonneuropathic OPs (e.g., paraoxon and malaoxon) in both cell lines. Inhibition of AChE was greater than inhibition of NTE, without overlap of the concentration-response curves, for OPs which are more likely to cause acute, rather than delayed, neurotoxic effects in vivo (e.g., chlorpyrifos-oxon, dichlorvos, and trichlorfon). In contrast, concentrations inhibiting AChE and NTE overlapped for neuropathy-causing OPs. For example, apparent IC50 values for NTE inhibition were less than 9.6-fold the apparent IC50 values for AChE inhibition when cells were exposed to the neuropathy-inducing OPs diisopropyl phosphorofluoridate, cyclic tolyl saligenin phosphate, phenyl saligenin phosphate, mipafox, dibutyl dichlorovinyl phosphate, and di-octyl-dichlorovinyl phosphate. In all cases, esterase inhibition occurred at lower concentrations than those needed for cytoxicity. These results suggest that either mouse or human neuroblastoma cell lines can be considered useful in vitro models to distinguish esterase-inhibiting OP neurotoxicants.
...
PMID:Acetylcholinesterase and neuropathy target esterase inhibitions in neuroblastoma cells to distinguish organophosphorus compounds causing acute and delayed neurotoxicity. 926 5

This study compares two direct-acting neuropathy target esterase (NTE) inhibitors (mipafox and 2-octyl-4H-1,3,2-benzodioxophosphorin 2-oxide (OBDPO)), a metabolic precursor to an NTE inhibitor (tri-o-cresyl phosphate or TOCP) and a potent acetylcholinesterase inhibitor (chlorpyrifos oxon or CPO) for their effects on outgrowth of neurite-like and cell processes and on viability in differentiated cultured cells (rat adrenal pheochromocytoma (PC-12) and brain glial tumor (C6)). The direct-acting NTE inhibitors block process outgrowth by 50% or more at 50-100 microM for OBDPO and 100-200 microM for mipafox, well below their cytotoxic levels (EC50 values, 445-474 microM for OBDPO and 1021-1613 microM for mipafox). In contrast, the effects on process development for TOCP and CPO parallel their cytotoxicity. These findings suggest that inhibition of neurite-like and cell process outgrowth by OBDPO and mipafox may be associated with NTE inhibition.
...
PMID:Organophosphorus neuropathy target esterase inhibitors selectively block outgrowth of neurite-like and cell processes in cultured cells. 978 82

Delayed neuropathy and inhibition of soluble neuropathy target esterase (NTE) and acetylcholinesterase (AChE) activities in different regions of brain and spinal cord of adult hens were studied after the intravenous administration of leptophos (30 mg/kg), tri-o-cresyl phosphate (TOCP 40 mg/kg) or dipterex (200 mg/kg). The level of NTE activity varied according to the regions of the central nervous system (CNS) of the control (normal) hen, being higher in the cerebrum (74.1 micromol of phenyl valerate hydrolyzed/10 minutes/mg protein) and in the cerebellum (68.7), and lower in the spinal cord (44.5 in cervical, 55.6 in thoracic and 50.0 in lumbar cord). Hens given leptophos and TOCP demonstrated delayed neuropathy with obvious inhibition of NTE, but the times of onset and the degrees of peak inhibition of NTE activity were different: 6-24 hours after dosing and 73-82% of normal activity for leptophos, and 24-48 hours and 45-80% for TOCP, respectively. Furthermore, the average inhibition of NTE during 6-48 hours after dosing, (called here 'period average inhibition') was also significantly different between the leptophos group (63-73%) and TOCP group (40-64%). Hens given dipterex did not demonstrate delayed neuropathy, and had the least peak inhibition and period average inhibition of NTE activity among the 3 groups. Ratios of NTE inhibition/AChE inhibition were higher in the leptophos group (0.91-1.24) and TOCP group (1.13-2.45) than in the dipterex group (0.25-0.79). These results indicate that the distribution of NTE in the soluble fraction of membrane proteins is different in different regions of the CNS, and that the degree of peak inhibition of NTE activity and the time of onset of peak inhibition induced by organophosphorus compounds (OPs) also differ for different OPs. Thus, practical and useful NTE measurements should identify the peak inhibition and period inhibition in several nervous tissue regions.
...
PMID:Delayed neuropathy and inhibition of soluble neuropathy target esterase following the administration of organophosphorus compounds to hens. 982 77

Mucolipidosis (ML) II and III are rare autosomal recessively inherited diseases characterized by deficiency of multiple lysosomal enzymes and, as a result, a generalized storage of macromolecules in lysosomes of cells of mesenchymal origin. In ML II and ML III fibroblasts, most, but not all, newly synthesized lysosomal enzymes are secreted into the medium instead of being targeted correctly to lysosomes. Defects in the enzyme UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase underlie this effect. It is unknown how lysosomal phospholipases are targeted to the lysosomes of fibroblasts. In the present study lysosomal phospholipase activity was determined in delipidated fibroblast homogenates and plasma from ML II and ML III patients and controls using a [3H]choline-labeled phosphatidylcholine. After incubation, residual phosphatidylcholine and its labeled degradation products (lysophosphatidylcholine, glycerophosphorylcholine and choline phosphate) were quantified. We found that ML II and ML III fibroblasts are deficient in lysosomal phospholipase A and C activity. These enzymes were present in elevated amounts in plasma of ML II and ML III patients. These data indicate that phospholipases, like most other lysosomal enzymes in these diseases, are secreted into the blood instead of being targeted specifically to lysosomes. Thus, the mannose-6-phosphate receptor pathway is needed for proper delivery of lysosomal phospholipases to lysosomes. We also found that production of labeled choline phosphate was mainly due to the activity of acid sphingomyelinase instead of phospholipase C under the assay conditions used. Other active lipolytic enzymes were phospholipase A and lysophospholipase. No evidence for phospholipase D activity was found.
...
PMID:Lysosomal phospholipase activity is decreased in mucolipidosis II and III fibroblasts. 998 67

The ability of bromine and rat liver microsomes (RLM) to convert organophosphorus (OP) protoxicants to esterase inhibitors was determined by measuring acetylcholinesterase (AChE) and neuropathy target esterase (NTE) inhibition. Species specific differences in susceptibility to esterase inhibition were determined by comparing the extent of esterase inhibition observed in human neuroblastoma cells and hen, bovine, and rodent brain homogenates. OP protoxicants examined included tri-o-tolyl phosphate (TOTP), O-ethyl O-p-nitrophenyl phenylphosphonothioate (EPN), leptophos, fenitrothion, fenthion, and malathion. Bromine activation resulted in greater AChE inhibition than that produced by RLM activation for equivalent concentrations of fenitrothion, malathion, and EPN. For EPN and leptophos, bromine activation resulted in greater inhibition of NTE than RLM. Only preincubation with RLM activated TOTP; resultant inhibition of AChE was less in hen brain (13 +/- 3%) than in neuroblastoma cells (73 +/- 1%) at 10(-6) M. In contrast, 10(-6) M RLM-activated TOTP produced more inhibition of hen brain NTE (89 +/- 6%) than NTE of human neuroblastoma cells (72 +/- 7%). Human neuroblastoma cells and brain homogenates from hens, the accepted animal model for study of OP-induced neurotoxicity, were relatively similar in sensitivity to esterase inhibition. Homogenates from hens were more sensitive to NTE inhibition induced by phenyl saligenin phosphate (PSP), an active congener of TOTP, than were homogenates from less susceptible species (mouse, rat, bovine). AChE of hen brain homogenates was also more sensitive than homogenates from other species to malaoxon, the active form of malathion.
...
PMID:Comparative effectiveness of organophosphorus protoxicant activating systems in neuroblastoma cells and brain homogenates. 1032 2

Neural carboxylesterases can be discriminated by differential inhibition assays with organophosphorus compounds (OPs), paraoxon (O,O'-diethyl p-nitrophenyl phosphate) and mipafox (N,N'-diisopropyl phosphorodiamidofluoridate) being the ones used to discriminate esterases that should be either irrelevant or candidates as targets of the mechanism of induction of the organophosphorus-induced delayed polyneuropathy (OPIDP). The brain membrane-bound phenyl valerate esterase (PVase) defined by Dr Johnson in 1969 as neuropathy target esterase (NTE) and recently cloned by Dr Glynn and coworkers is termed here as particulate NTE due to its association to the membrane particulate fraction. It is considered as the target of OPIDP and is the activity measured in standard NTE assays and toxicity tests. Following the same operational criteria in the soluble fraction of sciatic nerve a paraoxon-resistant but mipafox-sensitive PVase activity was described and termed as S-NTE, with an apparent lower sensitivity to some inhibitors than particulate NTE. Two isoforms (S-NTE1 and S-NTE2) were subsequently separated by gel filtration chromatography. In a partly purified S-NTE2 preparation polypeptides were identified in western blots by labelling with S9B [1-(saligenin cyclic phospho)-9-biotinyldiaminononane], the same biotinylated OP used to label and isolate particulate NTE, but not with anti-particulate NTE antibodies. From sequential inhibition protocols, inhibitor washing-out and time course inhibition studies it is deduced that reversibility of inhibition is a new factor introducing a higher complexity in the identification of the esterases that could be candidates as targets of the mechanisms of induction and/or promotion of neuropathy. We have evidences that in sciatic nerve soluble fraction a high proportion (about 70%) of the activity that is inhibited by paraoxon in the usual concurrent assay is quickly reactivated after removing paraoxon and it is permanently inhibited by mipafox. Under this improved sequential paraoxon/mipafox inhibition procedure S-NTE represents about 50% of total PVases while in the usual concurrent assay it was only apparently about 1-2%. Moreover with such criteria, S-NTE2 isoform(s) represents about 97-99% of total S-NTE, and S-NTE1 is only a marginal amount probably resulting of a partial solubilization from particulate NTE. Fixed time inhibiton curves with variable mipafox concentration failed to discriminate more than one component. However kinetic behaviour of the time progressive inhibition cannot be explained by a simple model with a single exponential mathematical component, indicating that either the possibility of more than one component or a more complex mechanistic model should be considered. Consequently both particulate NTE and S-NTE assay protocols and their role in induction and promotion of neuropathies will need to be reviewed. Data published by Drs Lotti, Moretto and coworkers suggest that particulate NTE cannot be the target of promotion of axonopathies. The proposal that S-NTE2 could be such a target is suggestive and under collaborative biochemical and toxicological studies.
...
PMID:NTE soluble isoforms: new perspectives for targets of neuropathy inducers and promoters. 1042 92


<< Previous 1 2 3 4 5 6 7 8 9 Next >>

---