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:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro inhibition of goat cerebellar acetylcholinesterase by pure and commercial anticholinesterase pesticides clearly indicates a remarkably high inhibitory effect of commercial carbamate and organophosphate pesticides containing a lower percentage of the respective active ingredients comparable to that of the known anticholinesterase agents such as DFP and physostigmine. It may be presumed that injudicious use of commercial formulations conduce severe toxicity in the nontarget mammalian species, namely, goat, and this response of the brain acetylcholinesterase may be utilized as a reliable bioindicator of pesticidal contamination of the terrestrial environment.
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PMID:In vitro inhibition of goat brain acetylcholinesterase by pure and commercial anticholinesterase pesticides. 271 16

Rats were given glycyl-L-glutamine (Gly-Gln) by intraaortic infusion with Alzet osmotic pumps during the 48-hr period following the intraaortic administration of diisopropyl phosphorofluoridate (DFP) (10 mumol/kg). The infusion of 1.2 mumol of Gly-Gln per 24 hr resulted in a significant increase in the acetylcholinesterase (AcChoEase; acetylcholine acetylhydrolase, EC 3.1.1.7) activity of the gastrocnemius muscles over that of rats that received DFP only. At a total dose of 3.6 mumol per 24 hr, a diminished result was obtained; at 0.36 mumol per 24 hr, no effect was detectable. These findings, together with earlier ones, suggest that the neurotrophic effect of Gly-Gln or a similar endogenous factor on AcChoEase synthesis is a general phenomenon at sites of cholinergic transmission.
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PMID:Effect of glycyl-L-glutamine on the rate of regeneration of acetylcholinesterase in the rat gastrocnemius muscle after diisopropyl phosphorofluoridate administration. 272 74

1-Bromo-2-[14C]pinacolone, (CH3)3C14COCH2Br [( 14C]BrPin), was prepared from [1-14C]acetyl chloride and tert-butylmagnesium chloride with cuprous chloride catalyst, followed by bromination. It was examined as an active-site directed label for acetylcholinesterase (acetylcholine acetylhydrolase, EC 3.1.1.7) (AcChE). AcChE, isolated from Torpedo nobiliana, has k(cat) = (4.00 +/- 0.04).10(3) s-1, Km = 0.055 +/- 0.008 mM in hydrolysis of acetylthiocholine, and k(cat) = (5.6 +/- 0.2).10(3) s-1, Km = 0.051 +/- 0.003 mM in hydrolysis of acetylcholine. BrPin, binding in the trimethyl cavity, acts initially as a reversible competitive inhibitor, Ki = 0.20 +/- 0.09 mM, and, with time, as an irreversible covalently bound inactivator. Introduction of 14C from [14C]BrPin into Torpedo AcChE at pH 7.0 was followed by SDS-PAGE, autoradiography and scintillation counting, in the absence and presence of 5-trimethylammonio-2-pentanone (TAP), a competitive inhibitor (Ki = 0.075 +/- 0.001 mM) isosteric with acetylcholine; 1.8-1.9 14C was incorporated per inactivated enzyme unit at 50% inactivation. TAP retarded inactivation by [14C]BrPin, and prevented introduction of 0.9-1.1 14C per unit of enzyme protected. Prior inactivation of AcChE by BrPin prevents reaction with [3H]diisopropyl fluorophosphate [( 3H]DFP). Prior inactivation by DFP or [3H]DFP does not prevent reaction with [14C]BrPin, and this subsequent reaction with BrPin does not displace the [3H] moiety. [14C]BrPin alkylates a nucleophile in the active site, and this reaction does not alkylate or utilize the serine-hydroxyl.
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PMID:Reactions of 1-bromo-2-[14C]pinacolone with acetylcholinesterase from Torpedo nobiliana. Effects of 5-trimethylammonio-2-pentanone and diisopropyl fluorophosphate. 276 53

Using a microtiter plate spectrophotometric system, an assay procedure was developed for the following toxic organophosphorus compounds: 1,2,2-trimethylpropyl ester of methylphosphonofluoridic acid (1, soman); ethyl N,N-dimethylphosphoramidocyanidate (3, tabun); O-ethyl S-[2-[bis(1-methylethyl)amino]ethyl]- methylphosphonothiolate (4, VX); the diethyl 4-nitrophenyl ester of phosphoric acid (5, paraoxon); and bis(1-methylethyl) phosphorofluoridate (6, DFP). The procedure, based on the Ellman assay method, uses inhibition of eel acetylcholinesterase (0.01 unit per well) to carry out the determination of inhibitor concentrations for both a standard curve and the unknown samples on a single 96-well microtiter plate. On a typical plate, samples of both unknowns and standards (a minimum of six concentrations were used per standard curve) were assayed five times per sample, with three control (uninhibited) enzyme activity points included for each sample. The time required for carrying out a single plate was approx 30 min. Sensitivity for the most potent acetylcholinesterase inhibitor tested was 0.4 nM under the conditions used for a typical assay. It should be noted, however, that no attempt was made to optimize the assay procedure for sensitivity.
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PMID:A microassay-based procedure for measuring low levels of toxic organophosphorus compounds through acetylcholinesterase inhibition. 281 69

The organophosphorus compounds diisopropylphosphorofluoridate (DFP) and isopropylmethylphosphonofluoridate (sarin) depressed the monosynaptic reflex (MSR) in spinal cords from 7- to 9-day-old male rats. The concentrations of DFP and sarin which depressed the MSR by nearly 50% were 100 microM and 100 nM, respectively. Simultaneous superfusion of the cords with thyrotropin-releasing hormone (TRH) with either DFP or sarin resulted in a reversal of the depression. The depression caused by DFP was reversed to 95% of control by 100 nM TRH whereas similar reversal of sarin-induced depression required a 10-fold greater concentration of TRH. The potentiating effect of TRH was not affected by atropine even at a high concentration (1 microM) although atropine easily reversed organophosphorus-induced depression of the MSR. It appears that reversal of organophosphorus-induced depression by TRH might occur through a noncholinergic, TRH-sensitive receptor mechanism and may be unrelated to acetylcholinesterase activity. This action represents a possible utility of TRH as an adjunct in organophosphorus toxicity.
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PMID:Segmental synaptic depression caused by diisopropylphosphorofluoridate and sarin is reversed by thyrotropin-releasing hormone in the neonatal rat spinal cord. 284 64

An enzyme that hydrolyzes soman (1,2,2-trimethylpropyl methylphosphonofluoridate) and two other phosphonofluoridates, but does not hydrolyze DFP (diisopropylphosphorofluoridate), has been partially purified from a rod-shaped spore-forming gram-positive OT (obligate thermophilic) bacterium. The enzyme shows a marked Mn2+ stimulation, and in this and its substrate preference does not resemble the organophosphorus acid anhydrolase (sometimes termed DFPase) found in squid. Like the squid enzyme, it is not inhibited by mipafox (N,N'-diisopropylphosphordiamidofluoridate), is not inactivated by ammonium sulfate, and does hydrolyze the acetylcholinesterase-inhibitory pair of diastereoisomers of soman as well as the relatively noninhibitory pair, thus detoxifying soman. In these three properties the OT enzyme does not resemble the ubiquitous organophosphorus acid anhydrolase often purified from mammalian and bacterial sources by cold ethanol fractionation. Thus this phosphono-specific OT enzyme may have a natural substrate and a physiological role distinct from other organophosphorus acid anhydrolases.
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PMID:Soman-hydrolyzing and -detoxifying properties of an enzyme from a thermophilic bacterium. 285 72

The protective action of eseroline--(3aS,8aR)-1,2,3,3a,8,8a-hexahydro-1,3 a, 8-trimethyl-pyrrolo[2,3-b]indol-5-ol--salicylate against (DFP) diisopropyl fluorophosphate and carbamate poisoning of cholinesterases (ChEs) has been examined in-vitro with human erythrocytes and purified preparations of electric eel acetylcholinesterase (AChE) and of horse serum butyrylcholinesterase (BuChE), and in-vivo using mice. Eseroline afforded 50% protection (ED 50) of erythrocyte AChE against inactivation by 1 microM DFP, physostigmine or neostigmine, at concentrations of 4.3, 22 and 23.5 microM, respectively, while for eel AChE protection against 10 and 30 microM DFP, 0.3 and 1 microM physostigmine and 1 microM neostigmine the eseroline ED 50 values were 0.3, 0.4, 0.7, 1.9 and 5.6 microM, respectively. On the other hand, up to 0.3 mM eseroline did not appreciably affect the inhibitory action of the same drugs on horse serum BuChE. Eseroline concentrations in the range 0.1-1 mM were able to reactivate 20-42% of erythrocyte AChE previously inhibited by 100 microM physostigmine, but failed to reactivate the DFP (10 microM)-pretreated enzyme to any extent. Finally, eseroline salicylate injected into mice (10 mg kg-1 s.c.) protected an average of 82 and 26% of the animals against lethal doses of DFP (7 mg kg-1 s.c.) and physostigmine sulphate (1 mg kg-1 i.p.) respectively, which were administered 15 min later. These results indicate that the protective activity of eseroline correlates well with its own anti-ChE profile, and that the effectiveness of the protection depends largely on the rate of AChE inhibition by the agents used to inactivate the enzyme.
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PMID:In-vitro and in-vivo protection of acetylcholinesterase by eseroline against inactivation by diisopropyl fluorophosphate and carbamates. 285 26

The effect of excitatory amino acid antagonists on antagonist on neuropeptide Y (NPY) and cholinergic neurons in the striatum of the rat was studied by means of NPY immunocytochemistry, DFP histochemistry for acetylcholinesterase (AChE), and biochemical determinations of choline acetyltransferase (ChAT). Intrastriatal infusion of drugs revealed that striatal neurons containing NPY are more sensitive than cholinergic neurons to the neurotoxic actions of kainic acid (KA), quinolinic acid (QA) and L-glutamic acid (GA); all 3 compounds produced a marked loss of NPY neurons, but only a moderate decrease in the number of AChE neurons or ChAT activity. Co-injection experiments showed that the neurotoxicity of QA and GA, but not that of KA, can be antagonized by the specific N-methyl-D-aspartate (NMDA) receptor antagonist 3-((+/-)-2-(carboxypiperazine-4-yl))-propyl-1-phosphonic acid (CPP). Destruction of the glutamatergic corticostriatal projection by cerebral decortication protected striatal NPY and cholinergic neurons against KA neurotoxicity. These results indicate that striatal NPY and cholinergic neurons receive prominent cortical amino acid afferents, and that the neurotoxic effect of QA and GA on these neurons is mediated through NMDA receptors.
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PMID:The response of striatal neuropeptide Y and cholinergic neurons to excitatory amino acid agonists. 290 50

1. The bivalve Rangia cuneata can enzymatically detoxify the organophosphorus acetylcholinesterase inhibitors DFP and soman. 2. Digestive gland homogenates contained Mazur-type DFPases based on response to Mn2+ ions, and relative rates of DFP: soman hydrolysis. Squid-type DFPase contributed little to the total organophosphate acid (OPA) anhydrase activity of these preparations. 3. The natural substrate(s) and physiological role(s) of OPA anhydrase in R. cuneata has yet to be determined; however, DFPase specific activity was pronounced in the digestive gland, the primary organ involved in bioconcentration and biotransformation of xenobiotics, and in the gills, which are in continuous contact with water-borne chemicals.
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PMID:Organofluorophosphate-hydrolyzing activity in an estuarine clam, Rangia cuneata. 290 72

The properties of a rat liver enzyme that hydrolyzes organophosphorus (OP) inhibitors of cholinesterases were studied. The rates of hydrolysis of OP inhibitors were determined by continuous titration of released hydrogen ions, using a pH stat method. Centrifugation of homogenates at 205,000 g for 30 min demonstrated that the activity was in the soluble fraction. Hydrolysis of sarin, soman, and diisopropyl phosphorofluoridate (DFP), but not of tabun, was stimulated by the addition of Mn2+ and Mg2+. Hydrolysis of sarin greater than soman greater than tabun greater than DFP. Unlike other OP hydrolases that preferentially hydrolyze the non-toxic isomers of soman, this enzyme hydrolyzed all four soman isomers at approximately the same rate. This result was obtained in vitro by gas chromatographic analysis of enzyme-catalyzed soman hydrolysis and confirmed in vivo by demonstrating reduced toxicity in mice of soman partially hydrolyzed by this enzyme. Km and Vmax were determined by fitting V vs [S] to a hyperbolic function using regression analysis. Km values ranged from 1.1 mM for soman to 8.9 mM for tabun. Vmax values ranged from 54 nmol/min/mg protein for DFP to 2694 for sarin. The enzyme was stable for at least 2 months at -90 degrees but was inactivated by heating at 100 degrees for 5 min. Elution profiles from gel filtration by high pressure liquid chromatography showed that the hydrolytic activity for the OP inhibitors eluted in a single peak, suggesting that a single enzyme was responsible for the observed hydrolysis. Further purification and characterization of this enzyme should prove useful for the development of methods for detection, detoxification, and decontamination of these cholinesterase inhibitors.
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PMID:Partial characterization of an enzyme that hydrolyzes sarin, soman, tabun, and diisopropyl phosphorofluoridate (DFP). 291 Mar 6


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