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Curr Opin Pharmacol. 2005 Jun;5(3):293-302.

Acetylcholinesterase: 'classical' and 'non-classical' functions and pharmacology.

Author information

1
Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel. Israel.Silman@weizmann.ac.il

Abstract

The synaptic enzyme acetylcholinesterase (AChE) terminates transmission at cholinergic synapses by rapidly hydrolysing acetylcholine. It is anchored within the synaptic cleft by a highly specialized anchoring device in which catalytic subunit tetramers assemble around a polyproline II helix. AChE is the target of nerve agents, insecticides and therapeutic drugs, in particular the first generation of anti-Alzheimer drugs. Both target-guided synthesis and structure-based drug design have been used effectively to obtain potent anticholinesterase agents. In addition, AChE is believed to play 'non-classical' roles in addition to its 'classical' role in terminating synaptic transmission (e.g. as an adhesion protein). It also accelerates assembly of Abeta into amyloid fibrils. Both of these actions involve the so-called 'peripheral' anionic site at the entrance to the active-site gorge. Novel anticholinesterases are targeted against this site, rather than against the active site at the bottom of the gorge.

PMID:
15907917
DOI:
10.1016/j.coph.2005.01.014
[Indexed for MEDLINE]

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