Acetylcholinesterase: Mechanism of Catalysis and Inhibition

Abstract

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.

Bifunctional phenolic-choline conjugates as anti-oxidants and acetylcholinesterase inhibitors

“…[38][39][40] The active site is buried in a narrow deep gorge, which is mostly surrounded by aromatic residues, and it includes two main subsites. The catalytic anionic subsite (CAS) is formed by Trp84, Phe330, and Glu199 (sequence numbering of Torpedo californica AChE, TcAChE) [38][39][40] , and can establish cationic-π interactions with the positively charged choline, and help the stabilization of the transition state. The catalytic triad (Ser200, His440, and Glu327; Figure 5 and Figure S1 of Supplementary Material) binds covalently to the substrate (through Ser200) and, aided by a water molecule, leads to the hydrolysis of the acetylcholine, generating choline and acetic acid.…”

Medicinal Plants Anti-cholinesterase Activity and the Potential for Alzheimer’s Disease Treatment

“…According to Orhan, Senol [78], Salvia genus emerge to be a choice target for researchers for AD treatment in Turkey. As such, in their continued extensive screening for Salvia species the authors screened 90 aerial and root extracts of 14 species.…”

Synthesis of Some Unique Carbamate Derivatives bearing 2-Furoyl-1-piperazine as Valuable Therapeutic Agents

“…The chief function of AChE and BChE is to catalyze the hydrolysis of the neurotransmitter acetylcholine. 13,14 It has been found that BChE is present in appreciably higher quantities in Alzheimer's plaques in the normal age related to non dementia of brains. Cholinesterase inhibitors increase the amount of acetylcholine offered for neuromuscular and neuronal transmission through their reversible or irreversible inhibitory activity.…”