Corpus ID: 35842495

Role of the peripheral anionic site on acetylcholinesterase: inhibition by substrates and coumarin derivatives.

  title={Role of the peripheral anionic site on acetylcholinesterase: inhibition by substrates and coumarin derivatives.},
  author={Z. Radi{\'c} and E. Reiner and P. Taylor},
  journal={Molecular pharmacology},
  volume={39 1},
Propidium has been demonstrated in previous studies to be a selective ligand for the peripheral anionic site on acetylcholinesterase (EC Its association with this site can be advantageously monitored by direct fluorescent titration. We have measured the ability of acetylcholine, acetylthiocholine, haloxon [di-(2-chloroethyl)3-chloro-4-methylcoumarin-7-ylphosphate] , and a coumarin derivative (3-chloro-7-hydroxy-4-methylcoumarin) to dissociate propidium from the peripheral anionic site… Expand
Reversible inhibition of acetylcholinesterase and butyrylcholinesterase by 4,4'-bipyridine and by a coumarin derivative.
Modelling of the 4,4'-BP and CHMC binding to wild type mouse AChE substantiated the difference between the inhibitors in their mode of binding which was revealed in the kinetic studies. Expand
Substrate and Product Trafficking through the Active Center Gorge of Acetylcholinesterase Analyzed by Crystallography and Equilibrium Binding*
A comprehensive set of structural snapshots of the steps leading to the intermediates of catalysis and the potential regulation by substrate binding to various allosteric sites at the enzyme surface is provided. Expand
Inhibition of acetylcholinesterase by three new pyridinium compounds and their effect on phosphonylation of the enzyme.
Three new mono-pyridinium compounds were prepared and their binding affinity for the enzyme was compared with their protective effect (PI) on AChE phosphonylation by soman and VX, which agreed with PI calculated from reversible inhibition. Expand
A steric blockade model for inhibition of acetylcholinesterase by peripheral site ligands and substrate.
The nonequilibrium kinetic analysis is employed to extend the steric blockade model to include blockade of the dissociation of substrate hydrolysis products by bound peripheral site ligand and reports that acetylthiocholine can bind to the AChE peripheral site with an equilibrium dissociation constant K(S) of about 1 mM. Expand
Fasciculin inhibition of acetylcholinesterase is prevented by chemical modification of the enzyme at a peripheral site.
Results strongly support FAS binding to an AChE peripheral site which partially overlaps the site of other peripheral site ligands including acetylthiocholine. Expand
The influence of peripheral site ligands on the reaction of symmetric and chiral organophosphates with wildtype and mutant acetylcholinesterases.
Analysis of inhibition by DDVP and haloxon revealed that peripheral site inhibitors increased the second order reaction rates by increasing maximal rates of phosphylation, creating a bell shaped activation profile. Expand
Interaction Kinetics of Reversible Inhibitors and Substrates with Acetylcholinesterase and Its Fasciculin 2 Complex*
Linear free energy relationships between the equilibrium constant and the kinetic constants show that Fas2, presumably through an allosteric influence, markedly alters the position of the transition state in the reaction pathway, and conformational flexibility appears critical for facilitating ligand passage in the narrow active center gorge for both A ChE and the AChE·Fas2 complex. Expand
Structure-functional effects of ethanol on Drosophila melanogaster acetylcholinesterase probed by kinetic studies with substrate and inhibitors.
It is proposed that ethanol affects the enzyme reactivity by modifying the conformation of the aromatic gorge containing the active centre and hence, interactions involved in the molecular recognition of substrates and ligands. Expand
Kinetics of inhibition of acetylcholinesterase in the presence of acetonitrile
The hydrolysis of acetylthiocholine by acetylcholinesterase from Electrophorus’electricus was investigated in the presence of the inhibitors tacrine, gallamine and compound 1, and the determination of the inhibitory parameters of compound 1 revealed that the substance acts as a hyperbolic mixed‐type inhibitor of acetylene‐based enzyme. Expand
Structural insights into ligand interactions at the acetylcholinesterase peripheral anionic site
These structures of AChE provide templates for designing compounds directed to the enzyme surface that modulate specific surface interactions controlling catalytic activity and non‐catalytic heterologous protein associations. Expand