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)

To determine the active site residue, human milk bile-salt stimulated lipase (BSSL) was labelled with [3H]diisopropyl fluorophosphate (DFP). Partial sequence analysis of cyanogen bromide fragments (a total of 146 residues from 6 peptides) revealed 84% sequence identity with a putative rat lysophospholipase. Sequence analysis of a [3H]DFP-labelled peptide indicated that the active site serine was contained in the sequence Gly-Glu-Ser-Ala-Gly. In addition to similarity with rat lysophospholipase, this sequence showed homology with regions of human butyrylcholinesterase and electric ray acetylcholinesterase (68% identity). It is concluded that these proteins are members of a new supergene family.
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PMID:Human milk bile-salt stimulated lipase. Sequence similarity with rat lysophospholipase and homology with the active site region of cholinesterases. 199 11

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

The delayed neurotoxic organophosphate [3H]diisopropylfluorophosphate ([3H]DFP) binds with high affinity to membrane-bound proteins from the chicken spinal cord. The DFP binding proteins were solubilized from membrane preparations, using a detergent (CHAPS). The protein(s) sites that labeled with a low concentration of [3H]DFP, e.g. 10(-10)-10(-9) M, were defined as the high-affinity binding sites. The density (or concentration) of the high-affinity binding sites in protein(s) was determined by the difference between total and non-specific binding. The high-affinity binding sites were saturable, and the maximal amount of binding sites was estimated at 400 fmol/mg protein. [3H]DFP binding to solubilized proteins was not completely reversible. Concentration-dependent curves suggested that the [3H]DFP binding sites differ from the active sites of acetylcholinesterase, butyrylcholinesterase, and neuropathy target esterase, as well as from muscarinic acetylcholine receptors. The amount of DFP binding sites after a neurotoxic dose of tri-o-cresyl phosphate (TOCP) decreased markedly in membrane preparations from the chicken spinal cord. These results indicate that a TOCP metabolite(s) interacts with the DFP binding sites in vivo. Gel filtration chromatography of the solubilized membranes indicated at least two major high-affinity DFP binding proteins with apparent molecular weights of 300 and 110 kDa. The DFP binding sites corresponding to the 110 kDa protein were insensitive to eserine, a potent anti-cholinesterase agent.
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PMID:Characterization of high-affinity binding sites for diisopropylfluorophosphate (DFP) from chicken spinal cord membranes. 780 97

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.
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PMID:Studies on the delayed neuropathic and anticholinesterase potential of quinalphos (diethyl 2-quinoxalyl phosphorothionate) in hens. 825 30

It has been thought that the phosphorus-enzyme bond in inhibited esterases inhibited by such agents as mipafox (N,N'-di-iso-propylphosphorodiamidate) was refractory to reactivating agents either because an 'aging' reaction occurs soon after inhibition or because the bond was intrinsically very strong. We have found that both acetylcholinesterase (AChE) and neuropathy target esterase (NTE) which had been inhibited with either mipafox or with a di-n-butylphosphorodiamidate could be reactivated by prolonged treatment with aqueous potassium fluoride (KF): the reaction proceeded with first-order kinetics. Furthermore there was no time-dependent loss of reactivatability (aging). Di-isopropylphosphoro-butyrylcholinesterase could be fully reactivated by this treatment but after 18 h to allow aging the monoisopropyl phosphoro-enzyme was totally refractory to KF. We conclude that it is likely that the mipafox-enzyme bond in inhibited NTE and AChE is relatively strong but that aging has not occurred. The local disturbance around the active site of NTE caused by attachment of the phosphorodiamidate molecule appears to be sufficient to initiate delayed neuropathy without necessity for an 'aging' reaction.
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PMID:Reactivation of phosphorodiamidated acetylcholinesterase and neuropathy target esterase by treatment of inhibited enzyme with potassium fluoride. 834 98

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.
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PMID:Subacute neurotoxicity induced in mice by potent organophosphorus neuropathy target esterase inhibitors. 868 3

Carbamyl sulfonate (CS) compounds are a novel class of carbamates derived from amino acid methyl esters. They have the general structure RCH(COOCH3)NH(CO)SO-3K+, where R is the sidechain of the parent amino acid. These compounds were developed as active site-directed inhibitors of human leukocyte elastase (HLE). The purpose of this study was to characterize the inhibition of hen brain neurotoxic esterase (neuropathy target esterase, NTE), horse serum butyrylcholinesterase (BuChE), and bovine erythrocyte acetylcholinesterase (AChE) by CS analogs derived from the methyl esters of L-ala, D-norval, L-norval, L-phe, L-val, L-norleu, D-met, and L-met. Bimolecular rate constants of inhibition (ki) for NTE ranged from 0.571 for L-ala-CS to 17.7 mM-1 min-1 for L-norleu-CS (10-min I50 values of 123 and 3.92 microM, respectively). Potency against NTE increased with chain length for straight-chain R-groups of L-CS compounds. Unlike HLE, NTE was only weakly stereoselective for CS compound enantiomers. The L-isomers were weaker inhibitors of BuChE than NTE (10-min I50 range of 742 to 35.6 microM). In contrast to the L-enantiomers, the I50 plots of D-met-CS and D-norval-CS were not linear for BuChE, suggesting a possible stereospecific mechanistic shift for inhibition of this enzyme, AChE was not effectively inhibited by any of the CS compounds (I50 values > 750 microM). The specificity and charged nature of CS compounds give these unusual NTE inhibitors potential advantages for mechanistic studies of organophosphorus compound-induced delayed neurotoxicity (OPIDN) and its protection or potentiation.
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PMID:Inhibition of neurotoxic esterase in vitro by novel carbamates. 907 5

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

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


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