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)

Half-saturation constants have been determined for the choline carrier with cationic substrates and their uncharged carbon analogs: (a) choline and 3,3-dimethyl-1-butanol and (b) 2-dimethylaminoethanol and isoamyl alcohol. The constants are 6.3 microM and 16 mM for the first pair, and 19 microM and 45mM for the second. In both cases, the charged molecules have the higher affinity by a factor of more than 2000. This is to be compared with a factor of less than 10 for charged and neutral substrates of acetylcholinesterase, and with a similar factor in antigen-antibody reactions. To account for the unusually strong ionic bond, a very close association between the carrier site and the substrate is suggested, probably with exclusion of water of hydration. This is supported by the fact that gradual replacement of N-methyl groups in the substrate by N-ethyl groups sharply reduces affinity for the carrier with a 110-fold reduction overall, but has no significant effect on the enzymes.
 ...
PMID:The electrostatic contribution to binding in the choline transport system of erythrocytes. 741 Mar 75

Esters of dimethylcarbamic acid are known to be poor substrates of acetylcholinesterase. They carbamylate the active catalytic site of the enzyme and the subsequent decarbamylation is a slow but measurable process. Similarly, acetylcholinesterase can be phosphonylated, and the dephosphonylation is extremely slow. Rapid hydrolysis of phosphonylated acetylcholinesterase can be brought about by oximes, but dealkylation of the phosphonyl group on the enzyme (known as ageing) renders the inhibited enzyme insensitive to oximes. In the present work, decarbamylation of dimethylcarbamyl-acetylcholinesterase and ageing of isopropylmethylphosphonyl-acetylcholinesterase were studied at a physiological ionic strength (154 mM). Gallamine, d-tubocurarine and alcuronium accelerated reactivation of dimethylcarbamyl-acetylcholinesterase. Gallamine and tubocurarine enhanced the effect of the nucleophile 3,3-dimethyl-1-butanol on decarbamylation, and the interaction was synergistic in the case of gallamine. Gallamine and tubocurarine retarded ageing of isopropylmethylphosphonyl-acetylcholinesterase, whereas 3,3-dimethyl-1-butanol had no effect. Nevertheless 3,3-dimethyl-1-butanol enhanced the retarding effects of gallamine and tubocurarine. All these effects, except the effects of 3,3-dimethyl-1-butanol on ageing, had been previously observed at low ionic strength, in which case the effects were more marked and were observed at lower concentrations of the drugs. The effects at low ionic strength have been attributed to binding of the drugs to a peripheral site on the enzyme with a consequent change in conformation at the active site, leading to altered kinetic properties. The present results suggest that such allosteric effects may persist at physiological ionic strength. There have been few indications previously that this is so, particularly in the case of solubilised acetylcholinesterase.
 ...
PMID:Gallamine and tubocurarine as possible allosteric modifiers of soluble acetylcholinesterase activity at physiological ionic strength. 2048 40

The local anaesthetic procaine showed the properties of an allosteric effector of bovine erythrocyte acetylcholinesterase at low ionic strength; it antagonised inhibition of substrate hydrolysis caused by decamethonium, decreased the rate of ageing of isopropylmethylphosphonyl-acetylcholinesterase, increased the rate of decarbamylation of dimethylcarbamyl-acetylcholinesterase, and interacted synergistically with the nucleophilic alcohol 3,3-dimethyl-1-butanol in the acceleration of decarbamylation. These allosteric effects almost completely disappeared as the ionic strength was increased to a physiological level, and they could not be demonstrated at the physiological ionic strength with membrane-bound human erythrocyte acetylcholinesterase. There was no evidence of significant cooperativity in the binding of procaine to the enzyme, nor in the binding of the substrate acetylthiocholine in the presence of procaine, contrary to reports in the literature for other sources of acetylcholinesterase. Procaine was not hydrolysed by acetylcholinesterase (EC 3.1.1.7) although it is a substrate for serum cholinesterase (EC 3.1.1.8). The possibility that the results at low ionic strength can be explained on the basis of procaine binding to the active site of acetylcholinesterase (at low concentrations) and also to a peripheral allosteric site (at higher concentrations) is discussed. The results confirm the complexity of the kinetics of acetylcholinesterase, and extend the range of compounds with the ability to modify rates of decarbamylation and ageing.
 ...
PMID:Procaine as a substrate and possible allosteric effector of cholinesterases. 2048 82

Gallamine and tubocurarine increased the rate of decarbamylation of carbamylated Triton-solubilized rabbit brain acetylcholinesterase and interacted synergistically with 3,3-dimethyl-1-butanol in the acceleration of decarbamylation at low ionic strength. Gallamine and tubocurarine also accelerated decarbamylation at a physiological ionic strength, but in this case the interaction with 3,3-dimethyl-1-butanol was not synergistic. Tubocurarine decreased the rate of ageing of isopropylmethyl-phosphonyl-acetylcholinesterase at low ionic strength, but gallamine and tubocurarine had no effect on ageing at a physiological ionic strength, nor did gallamine at low ionic strength. However reductions in the rate of ageing were observed for gallamine/3,3-dimethyl-1-butanol and tubocurarine/3,3-dimethyl-1-butanol mixtures at low ionic strength. Gallamine increased the maximum velocity of hydrolysis of acetylthiocholine at low ionic strength, but not at physiological ionic strength. Gallamine increased the rate of carbamylation of acetylcholinesterase by physostigmine and neostigmine at low ionic strength; however the data were not consistent with a simple model of complexing inhibition by these carbamates. Overall, the kinetic properties of Triton-solubilized rabbit brain acetylcholinesterase were less sensitive to modification by proposed allosteric effectors than bovine erythrocyte acetylcholinesterase, the allosteric properties of which have been reported previously, and millimolar concentrations of gallamine and tubocurarine were required to produce observable effects at physiological ionic strength. Further experiments are required to determine whether acetylcholinesterase is similarly insensitive to allosteric regulation in vivo.
 ...
PMID:Modification of the kinetic properties of Triton-solubilized rabbit brain acetylcholinesterase by allosteric effectors at low ionic strength. 2050 64