The Effect of Peripheral Site Ligands on the Reaction Kinetics of Phosphyl and Carboxyl Esters with Acetylcholinesterase

Abstract

The active serine of acetylcholinesterase (AChE) (EC 3.1.1.7) is readily acylated by organophosphorus compounds (OPs) rendering the enzyme inactive. OPs employed as pesticides or of potential concern as chemical warfare agents typically bear no charge and inhibit the enzyme at rates slower than cationic OPs. The inhibition rates for both cationic and neutral OPs are reduced by most ligands binding reversibly at the active center. However, binding of small cationic ligands, such as tetramethyl- and tetraethyl- ammonium into the AChE active center was also shown to increase rates of carbamylation and sulfonylation by the corresponding acyl fluorides (1, 2). Similarly, enzymic hydrolysis of a series of small neutral acetates is accelerated in the presence of N-methyl acridinium (3) a cationic inhibitor which presumably binds in the choline subsite of the active center. The small size of these neutral acylating agents and the corresponding cations, which modulate the kinetics, allow for their simultaneous coexistence within the AChE active center gorge.