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Gallamine and tubocurarine as possible allosteric modifiers of soluble acetylcholinesterase activity at physiological ionic strength.

Abstract：

: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.

journal_name

Neurochem Int

journal_title

Neurochemistry international

authors

Dawson RM,Poretski M,Upsher CM

doi

10.1016/0197-0186(81)90061-9

subject

Has Abstract

pub_date

1981-01-01 00:00:00

pages

405-9

issue

6

eissn

0197-0186

issn

1872-9754

pii

0197-0186(81)90061-9

journal_volume

3

pub_type

杂志文章

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