Structure‐Activity Relationships in Acetylcholinesterase Reactions

Abstract

The Michaelis-Menten parameters k_cat K_s(app) and the second-order rate constants k₁₁= k₂/K_s of acetylcholinesterase-catalyzed hydrolysis of 25 acetic esters with note-ionic leaving groups have been determined at 25 °C and pH 7.5 in 0.15 M KCL A linear relationship between the substrate non-covalent binding capacity and the leaving group hydrophobicity, and a multiparameter correlation of the acetylation reaction rate constant logarithm with the leaving group, inductive effect, hydrophobicity, and steric effect, have been established. The acetyl-enzyme deacetylation rate constant has been calculated. Taken together, a fairly complete understanding of acetylcholinesterase specificity is possible. The data are consistent with a model of the acetylcholinesterase active site, in which the catalytically active groups are located at the bottom of a jaws-like slit with a limited range of hydrophobic walls that provide the sorption of the substrate leaving groups not longer than that in n-butyl acetate.