Acetylcholinesterase: Mechanism of Catalysis and Inhibition

Recent advances in the study of the catalytic properties of acetylcholinesterases have been reviewed. The main biological function of this enzyme is the fast termination of impulse transmission at cholinegric synapses by rapid hydrolysis of the neurotransmitter acetylcholine. Acetylcholinesterase has been often characterized as a perfect enzyme because its catalytic properties have been tuned to the highest possible limit. However, it seems paradoxical that the active site of this enzyme is buried deeply inside the enzyme molecule in the bottom of a narrow gorge restricting the traffic of substrates and products. The analysis of recent advances in enzymology and data on cholinesterase revealed rationality of this organization. The primary task of an enzyme catalyst is to lower the activation barrier for the chemical transformation of the substrate, and the catalytic power of the enzyme originates in polar solvation of the transition state by properly oriented dipoles inside the enzyme molecule. The active site gorge of acetylcholinesterase, containing multiple potential substrate binding areas, is responsible for trapping and delivery of substrate molecules to the active site. The phenomena of allosteric modulation and substrate inhibition arise as secondary effects of the presence of the narrow gorge lined with hydrophobic residues.