Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycine was applied at a range of different concentrations to test possible effects at the neuromuscular junction of the mouse. The presynaptic control of acetylcholine (ACh) release and the postsynaptic activation of the nicotinic receptor have been analysed by means of extracellular recording with an EPC7 Patch Clamp amplifier. The results indicated that glycine did not modify in a significant manner the release of ACh and the postsynaptic cholinergic receptor function. Nevertheless, a significant increase in the rate of the conformational change of the receptor-ion channel complex seemed to be noteworthy. Glycine at 30 and 300 microM increased in a dose dependent manner the decay time of the spontaneous miniature current. Concentrations of glycine exceeding 10mM completely blocked the activity of the end-plate in this preparation. In conclusion, we proved that glycine does not affect most of the parameters of neurotransmission in the mouse but, it increases the conformational change of the postsynaptic complex, perhaps inhibiting the acetylcholinesterase activity.
 ...
PMID:Effects of glycine on the mouse neuromuscular junction. 886 62

The simulated binding profiles of acetylcholine, ACh, and the inhibitor (+/-)-2,3-dihydro-5,6- dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-on e hydrochloride (E2020), 1, and some of its analogs to acetylcholinesterase, AChE, were determined using full force field energetics and allowing complete conformational flexibility in both the ligand and receptor. A new mode of binding of ACh to AChE was found which involves the carboxyl oxygen of ACh interacting with Gly 118 and 119. Multiple modes of binding of 1 and some of its analogs were found which include alignment models observed in previous more restricted modeling studies. The key ligand-receptor interactions identified, and the corresponding energetics, are consistent on a relative basis, with observed binding constants for both the individual isomers of each of the inhibitors, as well as among the inhibitors themselves. The multiple modes of binding of 1 to AChE arises from small changes in binding at a single subsite and also from multiple subsite changes. Thus, an independent subsite model for ligand-receptor binding holds for some modes of binding, but not for others. A comparison of the simulated AChE-1 (and analog inhibitors) binding models to the receptor-independent 3D-QSARs previously developed for this class of inhibitors reveals extensive mutual consistency. The findings from these two modeling studies provides greater guidelines for inhibitor design than can be realized from either one. The combined docking and 3D-QSAR studies permit a detailed understanding of the SAR of more than 100 compound 1 analog inhibitors. A simple molecular recognition model can also be gleaned from the docking studies. A cylindrical "plug" (the inhibitor) having a large dipole moment must sterically fit into a cylindrical hole (the active site gorge of AChE), the lining of which also has a large dipole moment. Our simulations suggest that the dynamic "back door" to the active site of AChE does not form a large enough opening for sufficiently long time periods so as to be an effective entrance/exit pathway.
 ...
PMID:The simulated binding of (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]meth yl] -1H-inden-1-one hydrochloride (E2020) and related inhibitors to free and acylated acetylcholinesterases and corresponding structure-activity analyses. 889 40

Effects of soman, an irreversible cholinesterase (ChE) inhibitor, on [3H]norepinephrine (NE) release evoked by N-methyl-d-aspartate (NMDA) were studied in rat brain cortical slices. Soman inhibited NMDA-stimulated [3H]NE release in a concentration-dependent manner. This effect was neither reversed by atropine, an antagonist of the muscarinic receptor, nor by d-tubocurarine, an antagonist of the nicotinic receptor. Incubation of the slices with NMDA antagonists, AP5, MK-801, ketamine or magnesium, resulted in inhibitory effects on NMDA-stimulated [3H]NE release. Soman significantly shifted the inhibition curves downward and significant interactions between these chemicals and soman were observed. Glycine potentiated the release of [3H]NE stimulated by NMDA, and soman did not alter this effect of glycine. Soman also inhibited the release of [3H]NE evoked by K+ in a concentration-dependent manner. NMDA-stimulated [3H]NE release was inhibited by tetrodotoxin (TTX), an antagonist of voltage-dependent sodium channels, and a significant interaction between soman and TTX was observed. The [3H]NE release induced by NMDA was dependent on extracellular calcium concentrations and was inhibited by nifedipine, a selective blocker of the L-type voltage-dependent calcium channels (VDCC), or cadmium, a non-specific blocker of VDCC. However, no significant interaction between the effects of soman and calcium, nifedipine, or cadmium was observed. Taken together, the results suggested that: (1) soman has a direct action at non-cholinergic sites; (2) soman may interfere with some of the regulatory sites of the NMDA receptor-ion channel complex; and (3) the voltage-dependent sodium channel, but not VDCC, may be a site of action for soman.
 ...
PMID:Inhibition by soman of NMDA-stimulated [3H]norepinephrine release from rat cortical slices, studies of non-cholinergic effect. 951 77

The contribution of the oxyanion hole to the functional architecture and to the hydrolytic efficiency of human acetylcholinesterase (HuAChE) was investigated through single replacements of its elements, residues Gly-121, Gly-122 and the adjacent residue Gly-120, by alanine. All three substitutions resulted in about 100-fold decrease of the bimolecular rate constants for hydrolysis of acetylthiocholine; however, whereas replacements of Gly-120 and Gly-121 affected only the turnover number, mutation of residue Gly-122 had an effect also on the Michaelis constant. The differential behavior of the G121A and G122A enzymes was manifested also toward the transition state analog m-(N,N, N-trimethylammonio)trifluoroacetophenone (TMTFA), organophosphorous inhibitors, carbamates, and toward selected noncovalent active center ligands. Reactivity of both mutants toward TMTFA was 2000-11, 000-fold lower than that of the wild type HuAChE; however, the G121A enzyme exhibited a rapid inhibition pattern, as opposed to the slow binding kinetics shown by the G122A enzyme. For both phosphates (diethyl phosphorofluoridate, diisopropyl phosphorofluoridate, and paraoxon) and phosphonates (sarin and soman), the decrease in inhibitory activity toward the G121A enzyme was very substantial (2000-6700-fold), irrespective of size of the alkoxy substituents on the phosphorus atom. On the other hand, for the G122A HuAChE the relative decline in reactivity toward phosphonates (500-460-fold) differed from that toward the phosphates (12-95-fold). Although formation of Michaelis complexes with substrates does not seem to involve significant interaction with the oxyanion hole, interactions with this motif are a major stabilizing element in accommodation of covalent inhibitors like organophosphates or carbamates. These observations and molecular modeling suggest that replacements of residues Gly-120 or Gly-121 by alanine alter the structure of the oxyanion hole motif, abolishing the H-bonding capacity of residue at position 121. These mutations weaken the interaction between HuAChE and the various ligands by 2.7-5.0 kcal/mol. In contrast, variations in reactivity due to replacement of residue Gly-122 seem to result from steric hindrance at the active center acyl pocket.
 ...
PMID:Functional characteristics of the oxyanion hole in human acetylcholinesterase. 967 73

Recombinant alpha-D-galactosidase (rGal) from soybean (Glycine max) hydrolyzed the immunodominant alpha-D-galactose residue from the B epitope of red blood cells. This converted type B erythrocytes to type O which are "universally" transfusable. Type B red blood cells were obtained from four different donors and enzymatically converted. Cell function parameters, including red cell indices, pH, methemoglobin, carboxyhemoglobin, osmotic fragility, hemolysis, 2,3-diphosphoglycerate, cholinesterase, ATP, and antigen typing of treated cells were compared to controls. These pilot studies indicate that rGal could have potential biotechnical application in the production of universally transfusable red blood cells.
 ...
PMID:Seroconversion of type B to O erythrocytes using recombinant Glycine max alpha-D-galactosidase. 978 52

Nasonovia ribisnigri, a main pest of salad crops, has developed resistance to various insecticides in southern France, including the carbamate pirimicarb and the cyclodiene endosulfan, two insecticides widely used to control this aphid. Here we have investigated the mechanisms of resistance to these two insecticides by studying cross-resistance, synergism, activity of detoxifying enzymes, and possible modifications of the target proteins. Resistance to pirimicarb was shown to be mainly due to a decreased sensitivity of the target acetylcholinesterase; this modification conferred also, resistance to propoxur but not to methomyl and the two tested organophosphates (acephate and paraoxon). Endosulfan resistance was associated with a moderate level of resistance to dieldrin, and resistance to both insecticides was due, in part, to increased detoxification by glutathione S-transferases (GST). The endosulfan resistant strain displayed the same amino acid at position 302 of the Rdl gene (GABA receptor) as susceptible aphids (e.g. Ala), indicating that the Ala to Ser (or to Gly) mutation observed among dieldrin resistant strains of other insect species was not present.
 ...
PMID:Mechanisms of insecticide resistance in the aphid Nasonovia ribisnigri (Mosley) (Homoptera: Aphididae) from France. 1033 76

Two molecular dynamics simulations were performed for a modeled complex of mouse acetylcholinesterase liganded with huperzine A (HupA). Analysis of these simulations shows that HupA shifts in the active site toward Tyr 337 and Phe 338, and that several residues in the active site area reach out to make hydrogen bonds with the inhibitor. Rapid fluctuations of the gorge width are observed, ranging from widths that allow substrate access to the active site, to pinched structures that do not allow access of molecules as small as water. Additional openings or channels to the active site are found. One opening is formed in the side wall of the active site gorge by residues Val 73, Asp 74, Thr 83, Glu 84, and Asn 87. Another opening is formed at the base of the gorge by residues Trp 86, Val 132, Glu 202, Gly 448, and Ile 451. Both of these openings have been observed separately in the Torpedo californica form of the enzyme. These channels could allow transport of waters and ions to and from the bulk solution.
 ...
PMID:Molecular dynamics of mouse acetylcholinesterase complexed with huperzine A. 1042 44

The asymmetric form of acetylcholinesterase comprises three catalytic tetramers attached to ColQ, a collagen-like tail responsible for the anchorage of the enzyme to the synaptic basal lamina. ColQ is composed of an N-terminal domain which interacts with the catalytic subunits of the enzyme, a central collagen-like domain and a C-terminal globular domain. In particular, the collagen-like domain of ColQ contains two heparin-binding domains which interact with heparan sulfate proteoglycans in the basal lamina. A three-dimensional model of the collagen-like domain of the tail of asymmetric acetylcholinesterase was constructed. The model presents an undulated shape that results from the presence of a substitution and an insertion in the Gly-X-Y repeating pattern, as well as from low imino-acid regions. Moreover, this model permits the analysis of interactions between the heparin-binding domains of ColQ and heparin, and could also prove useful in the prediction of interaction domains with other putative basal lamina receptors.
 ...
PMID:Molecular modeling of the collagen-like tail of asymmetric acetylcholinesterase. 1067 27

Decreased activity of plasma cholinesterase is responsible for prolonged apnea during anesthesia using neuromuscular blockers such as suxamethonium and mivacurium. More than 20 mutations have been identified so far in the BCHE gene resulting in impaired plasma cholinesterase activity. Biochemical tests are not always able to differentiate between pathological and normal sera; hence in some cases unanticipated complications can still occur during anesthesia even after measurements of enzyme activity and dibucaine numbers within the normal range. Therefore, molecular genetic testing is required for the accurate diagnosis of this deficiency. Here we present a study of plasma cholinesterase activity and BCHE genotyping of patients with a history of prolonged neuromuscular block and most of their pedigrees. All four exons of the BCHE gene were directly sequenced from samples and a number of mutations responsible for the reduction of plasma cholinesterase activity were identified. In most cases the atypical mutation in exon 2 (nt 209A --> G, Asp70 --> Gly) was found together with the K-variant mutation in exon 4 (nt 1615G --> A, Ala539 --> Thr), which is in good agreement with previous data suggesting that these mutations along with two others (at nt -116 and nt 1914) are in linkage disequilibrium.
 ...
PMID:Analysis of mutations in the plasma cholinesterase gene of patients with a history of prolonged neuromuscular block during anesthesia. 1174 53

Glutamate, previously demonstrated to participate in regulation of the resting membrane potential in skeletal muscles, also regulates non-quantal acetylcholine (ACh) secretion from rat motor nerve endings. Non-quantal ACh secretion was estimated by the amplitude of endplate hyperpolarization (H-effect) following blockade of skeletal muscle post-synaptic nicotinic receptors by (+)-tubocurarine and cholinesterase by armin (diethoxy-p-nitrophenyl phosphate). Glutamate was shown to inhibit non-quantal release but not spontaneous and evoked quantal secretion of ACh. Glutamate-induced decrease of the H-effect was enhanced by glycine. Glycine alone also lowered the H-effect, probably due to potentiation of the effect of endogenous glutamate present in the synaptic cleft. Inhibition of N-methyl-d-aspartate (NMDA) receptors with (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine (MK801), dl-2-amino-5-phosphopentanoic acid (AP5) and 7-chlorokynurenic acid or the elimination of Ca2+ from the bathing solution prevented the glutamate-induced decrease of the H-effect with or without glycine. Inhibition of muscle nitric oxide synthase by NG-nitro-l-arginine methyl ester (l-NAME), soluble guanylyl cyclase by 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and binding and inactivation of extracellular nitric oxide (NO) by haemoglobin removed the action of glutamate and glycine on the H-effect. The results suggest that glutamate, acting on post-synaptic NMDA receptors to induce sarcoplasmic synthesis and release of NO, selectively inhibits non-quantal secretion of ACh from motor nerve terminals. Non-quantal ACh is known to modulate the resting membrane potential of muscle membrane via control of activity of chloride transport and a decrease in secretion of non-quantal transmitter following muscle denervation triggers the early post-denervation depolarization of muscle fibres.
 ...
PMID:Glutamate regulation of non-quantal release of acetylcholine in the rat neuromuscular junction. 1264 42


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