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)

Male mice were treated orally with the organophosphorus insecticides fenamiphos and dichlorvos at 10 and 150 mg/kg, respectively. The insecticides produced signs of toxicosis characteristic of cholinesterase inhibition, and induced death in all treated mice. Pretreatment of mice with diphenhydramine HCl (20 and 30 mg/kg, subcutaneously) 15 min before either insecticide significantly (P less than 0.05) reduced the incidence of toxic manifestations (excessive salivation, Straub tail, and whole body tremor), delayed the onset of death, and increased the percentage of survivors. Doses of diphenhydramine less than 20 mg/kg were not so effective. The data indicated a protective property of diphenhydramine against organophosphorus insecticide-induced toxicosis.
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PMID:Effect of diphenhydramine on organophosphorus insecticide toxicity in mice. 281 94

We have previously shown that asymmetric collagen-tailed acetylcholinesterase (AChE) is anchored to the extracellular matrix (ECM) by heparan sulfate proteoglycans (HSPGs). Here we present our studies on the characterization of such PGs from the ECM of rat skeletal muscles. After radiolabeling with 35SO4 for 24h, PGs were extracted from the muscle ECM with 4.0 M guanidine-HCl containing protease inhibitors. PGs were subsequently isolated using sequential DEAE-Sephacel chromatography, digestion with chondroitinase ABC, and Sepharose CL-4B. Two different hydrodynamic size species of HSPGs were found. One type had a Mr of 4-6 X 10(5) (Kav = 0.25) as estimated by gel chromatography in the presence of 1% SDS and accounted for 75% of the total HSPGs. The other HSPG had a Mr 1.5-2.5 X 10(5) (Kav = 0.41). The glycosaminoglycan (GAG) side chains (Mr 20,000 and 12,000) were found composed only of heparan sulfate as determined by nitrous acid oxidation and heparitinase treatment. The large-sized HSPG, which is concentrated in synaptic regions, contains only GAG chains of Mr 20,000, suggesting that each HSPG contains only one kind of heparan sulfate chain in its structure. Our results definitively establish by biochemical criteria that the basement membrane of mammalian skeletal muscle contains HSPGs, the likely matrix receptor for the immobilization of the asymmetric collagen-tailed AChE at the neuromuscular junction.
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PMID:Isolation of the heparan sulfate proteoglycans from the extracellular matrix of rat skeletal muscle. 295 79

Acetylcholinesterase (AChE, EC 3.1.1.7) from Electrophorus electricus, purified by affinity chromatography to a specific activity of 7000-10,000 U/mg protein, was studied at 27 degrees C in conduction-type microcalorimeters for the heats of reaction, with the subsite-specific cationic ligands edrophonium and propidium and with the irreversible inhibitor diisopropylfluorophosphate (DFP), in an ion-free aqueous medium. Edrophonium and propidium, each at 0.5 x 10(-5) M, yielded reaction heats of +3.2 and -1.5 kcal/mol (1 kcal = 4.184 J) respectively, with 1.3 x 10(-5) M AChE active sites. DFP (1.3 x 10(-5) M) reacted exothermically yielding -0.5 kcal/mol at stoichiometric level with AchE active sites. Circular dichroic spectra showed that a ternary complex of AChE (6.5 x 10(-7) M active sites) and the two ligands (each at 1 x 10(-3) M) in 1 mM Tris-HCl buffer (pH 8.0) had a positive Cotton effect at 235 nm. Neither DFP nor phosphoric acid 2,2-dichloroethenyl dimethyl ester (DDVP) caused any appreciable change. DFP-AChE, however, behaved like a normal enzyme in showing a positive Cotton effect in association with the two ligands. DDVP-AChE showed an increase in negative ellipticity at 287 nm in the presence of the two ligands. Another cationic ligand, d-tubocurarine, when present together with edrophonium, increased negative ellipticity at 302 nm and blue-shifted a 265-nm peak of the normal AChE. DFP interactions with AChE appear to be energetically different from those of edrophonium, the latter of which is believed to associate with the acetylcholine-binding subsite.
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PMID:Energetics of ligand and inhibitor interactions with acetylcholinesterase. 344 86

The role of hypothermia in the antihypoxic effects of drugs was examined in the present experiments. The effects of environmentally induced hypothermia and drugs were tested by exposing mice to 100% nitrogen gas for 80 sec and counting the number of survivors. In a series of 68 vehicle control groups, the mean of mice surviving the test was 8.6% (SEM = 1.4). Hypothermia induced by lowering the ambient temperature or by isolating mice for a brief period increased the number surviving hypoxia, and the per cent of animals surviving was linearly related to body temperature. When the effects of drugs were compared to that of hypothermia, several drugs were found which protected mice from hypoxia to a greater extent than hypothermia alone. Active substances included the anticonvulsant drugs phenobarbital, phenytoin, carbamazepine and diazepam, but not primidone. Physostigmine and the muscarinic agonist oxotremorine also caused significant protection, while the effects of nicotine could be completely accounted for by hypothermia. Arecoline had a biphasic, time-dependent effect that may be explained by a combination of muscarinic and nicotinic actions. The effects of the muscarinic agonists are centrally mediated, since they could be blocked by low doses of scopolamine HCl, but not by the quaternary analog scopolamine methyl nitrate. Furthermore, the antihypoxic effect of physostigmine was not mimicked by the peripherally acting acetylcholinesterase inhibitor, neostigmine. These results suggest that some drugs do have protective effects against hypoxia which are independent of drug-induced hypothermia and that these effects may be mediated through the CNS.
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PMID:Protection against hypoxia-induced lethality in mice: a comparison of the effects of hypothermia and drugs. 359 68

Direct microcalorimetric measurements were made of the reaction between acetylcholine chloride and acetylcholinesterase (EC 3.1.1.7) that was extracted from electric eel (Electrophorus electricus) and purified by affinity chromatography. Tris-HCl, sodium phosphate and potassium phosphate were used as buffers and sources of ions for the reaction. At pH 7.2 and in 0.1-0.2 M phosphate buffer, the delta H for acetylcholine hydrolysis was found to be -0.107 kcal/mol (under buffered conditions) and -0.931 kcal/mol under unbuffered conditions (water). At pH 8.0 in 0.1 M Tris-HCl buffer, values greater than -2.5 kcal/mol were obtained, with the highest value of -9.2 kcal/mol being seen with bovine erythrocyte acetylcholinesterase. Tris-HCl buffer at 4 X 10(-2) M enhanced the reaction velocity by 51.2% over that of 4 X 10(-3) M buffer. Enzyme purity, pH and ionic milieu of reaction mixture, and substrate concentration affected the measured delta H value.
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PMID:Enthalpy of acetylcholine hydrolysis by acetylcholinesterase. 409 75

The appearance of ion channels was induced in phospholipid bilayers by acidification of the bulk solution on one side Of the bilayer, by addition of HCl, acetic acid or by hydrolytic production of protons using purified acetylcholinesterase. Further acidification below an apparent critical pH range led to restoration of a low conductance state similar to that seen at neutral pH. Such experiments were performed with a heterogeneous soybean lecithin extract, with homogeneous synthetic diphytanoylphosphatidylcholine, and with a mixture of cholesterol and synthetic dioleoylphosphatidylcholine. It is proposed that the physical mechanism for this phenomenon involves fluctuations of lipid order induced by fluctuations in protonation of phospholipid head groups within a critical pH range; these, in turn, create conductive defects in the two-dimensional lattice of the lipid bilayer.
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PMID:The induction by protons of ion channels through lipid bilayer membranes. 631 86

The levels of cocaine, benzoylecgonine and ecgonine methyl ester were measured periodically in the urine of dogs and rabbits by gas chromatography-chemical ionization selected ion monitoring mass spectrometry after subcutaneous injection of 2.9 mumol/kg (1.0 mg/kg) cocaine--HCl. Ecgonine methyl ester persisted much longer than benzoylecgonine. Urinary ecgonine methyl ester could be identified for 72 h in all the experimental dogs. The ester accounted for 6.6-27.1% of a dose of cocaine in dogs and 8.8-31.9% in rabbits 24 h after administration. Excretion of benzoylecgonine in urine was 6.3-19.2% in dogs and 7.5-32.9% in rabbits. This confirms that ecgonine methyl ester is one of the major metabolites of cocaine as well as benzoylecgonine. Excretion of the parent drug and its two hydrolyzed metabolites in faeces was very small, less than 1% of administered dose. Tri-o-tolylphosphate and eserine significantly inhibited cocaine hydrolysis to benzoylecgonine and ecgonine methyl ester, respectively. Parathion and EDTA, however, had no effects on cocaine hydrolysis in vivo. In vitro demethylation of cocaine to benzoylecgonine was demonstrated in the plasma from dogs and this production of benzoylecgonine was much more than that of non-enzymatic formation in buffer at physiological pH. It was concluded that a large part of the benzoylecgonine excreted in urine is an in vivo enzymatic product of cocaine. On the other hand, plasma cholinesterase and liver esterase mediated ecgonine methyl ester formation. This liver esterase was abundant in the soluble fraction and could be found in both of microsomal and mitochondrial fractions.
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PMID:In vivo and in vitro studies on cocaine metabolism: ecgonine methyl ester as a major metabolite of cocaine. 651 Aug 53

Basal lamina (BL) of Torpedo, Discopyge and Electrophorus electric organs was purified in order to establish polypeptide composition and association with acetylcholinesterase (AChE). Results indicate that BL presents a distinct peptide pattern and that the A12 form of AChE is directly attached to it. Comparison of the species studied demonstrated similarities both in polypeptide composition and AChE content of the purified BL. Extractions of BL with solutions of high ionic strength, guanidine-HCl and acetic acid indicated the differential solubilization of various domains of BL polypeptides.
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PMID:The A12 acetylcholinesterase and polypeptide composition of electric organ basal lamina of Electrophorus and some Torpedinae fishes. 667 17

An assay capable of detecting tens-of-picomole quantities of choline and acetylcholine in milliliter volumes of a physiological salt solution has been developed. Silica column chromatography was used to bind and separate 10-3000 pmol [14C]choline and [14C]acetylcholine standards made up in 3 ml of a bicarbonate-buffered Krebs-Ringer solution. The silica columns bound 95-98% of both choline and acetylcholine. Of the bound choline 84-87% was eluted in 1.5 ml of 0.075 N HCl, whereas 95-98% of the bound acetylcholine was eluted in a subsequent wash with 1.5 ml of 0.030 N HCl in 10% 2-butanone. Vacuum centrifugation of the eluants yielded small white pellets with losses of choline and acetylcholine of only 1%. Dried pellets of unlabeled choline and acetylcholine standards were assayed radioenzymatically using [gamma-32P]ATP, choline kinase, and acetylcholinesterase. The net disintegrations per minute of choline[32P]phosphate product was proportional to both the acetylcholine (10-3000 pmol) and choline (30-3000 pmol) standards. The "limit sensitivity" was 8.5 pmol for acetylcholine and 11.4 pmol for choline. Cross-contamination of the choline assay by acetylcholine averaged 1.3%, whereas contamination of the acetylcholine assay by choline averaged 3.1%.
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PMID:Determination of picomole quantities of acetylcholine and choline in physiologic salt solutions. 673 54

We have prepared a series of alpha-ketothiohydroximic acid thioesters and evaluated them in vitro with respect to their ability to reactivate (diisopropylphosphoryl)acetylcholinesterase. The compounds conform to the general formula RC(=O)C(=NOH)S(CH2)nNR2'.HCl, where R = CH3, C6H5, 4-CH3OC6H4, 4-NO2C6H4; n = 2, 3; and R' = CH3, C2H5, or i-C3h7. We also prepared 4-BrC6H4C(=NOH)S(CH2)2N(C2H5)2.HCl and 4-CH3OC6H4C(=O)C(=NOH)S(CH2)2N(C2H5)2.CH3I for comparison. The alpha-ketothiohydroximates exhibit oxime acid dissociation constants (pKa) in the range 6.9 to 8.4, bracketing the value of pKa = 7.9, believed to be optimal for acetylcholinesterase reactivation. The compounds are also good nucleophiles; bimolecular rate constants (kn) for reaction with p-nitrophenyl acetate follow the expression log (kn) = 6.7 - 0.69(14 - pKa = The reactivation of (diisopropylphosphoryl)acetylcholinesterase is highly dependent on the alpha-ketothiohydroximate structure: 4-h incubation of inhibited enzyme at pH 7.6, 25 degrees C, with 1 x 10(-3) M 4-CH3OC6H4C(=O)C(=NOH)S(CH2)3N(CH3)2.HCl gives no detectable restoration of activity, whereas 4-CH3OC6H4C(=O)C(=NOH)S(CH2)2N(C2H5)2.HCl restores inhibited enzyme activity to 58% of control under identical conditions. With alpha-ketothiohydroximate in excess over inhibited enzyme, the kinetics of reactivation are governed by an equilibrium constant (Kr) for binding alpha-ketothiohydroximate to the inhibited enzyme and a nucleophilic displacement rate constant (kr) for attack on phosphorus.
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PMID:Nonquaternary cholinesterase reactivators. Dialkylaminoalkyl thioesters of alpha-ketothiohydroximic acids as reactivators of diisopropyl phosphorofluoridate inhibited acetylcholinesterase. 732 74


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