Crystallographic Studies on Complexes of Acetylcholinesterase with the Natural Cholinesterase Inhibitors Fasciculin and Huperzine A

Abstract

Acetylcholinesterase (AChE) terminates synaptic transmission at cholinergic synapses by rapid hydrolysis of acetylcholine (ACh) (Quinn, 1987). Anticholinesterase agents are used in the treatment of various disorders (Taylor, 1990), and have been proposed as therapeutic agents for the management of Alzheimer’s disease (Giacobini & Becker, 1991, 1994). Two such anti- cholinesterase agents, both of which act as reversible inhibitors of AChE, have been licensed by the FDA: tacrine (Gauthier & Gauthier, 1991), under the trade name Cognex, and, more recently, E2020 (Sugimoto et al., 1992), under the trade name Aricept. Several other anticholinesterase agents are at advanced stages of clinical evaluation. The acive site of AChE contains a catalytic subsite, and a so-called ‘anionic’subsite, which binds the quaternary group of ACh (Quinn, 1987). A second, ‘peripheral’anionic site is so named since it is distant from the active site (Taylor & Lappi, 1975). Bisquaternary inhibitors of AChE derive their enhanced potency, relative to homologous monoquaternary ligands (Main, 1976), from their ability to span these two ‘anionic’sites, which are ca. 14 Å apart.KeywordsCrystallographic StudyAnionic SiteHydroxyl OxygenQuaternary GroupBovine Pancreatic Trypsin InhibitorThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.