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

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 A beta 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.