engleski

Mechanism of interaction of oximes with acetylcholinesterase and butyrylcholinesterase

The binding of five pyridinium and two imidazolium oximes, and of coumarin, propidium and 4, 4"-bipyridine (BP) to acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) was studied. The enzyme/ligand dissociation constans and their binding sites were evaluated from the kinetics of competition between substrates (acetylthiocholine and propionylthiocholine) and the ligands. The dissociation constants were also evaluated from the effect of the ligands upon rates of enzyme phosphorylation with sarin, soman, tabun, VX and other OP compounds. Coumarin, propidium and the two imidazolium oximes bind only to the allosteric site of AChE. Binding to the allosteric site protects the catalytic site of AChE against phosphorylation. The pyridinium oximes and BP bind to both, the catalytic and the allosteric sites of AChE. The degree of protection of the catalytic site against phosphorylation is a function of both, catalytic and allosteric enzyme/ligand dissociation constants. The kinetics of BChE inhibition with P2AM, HI-6 and BP indicates that BChE also has two binding sites for reversible ligands. By analogy with AChE it is suggested that the second binding site is an allosteric site. For a given studied ligand, the UU, FS and AA human serum BChE variants have affinities in the same order of magnitude. All studied ligands protect BChE against phosphorylation.

acetylcholinesterase; butyrylcholinesterase; oximes; reversible inhibition; protection in phosphylation; organophosphorus compounds

nije evidentirano