Dana Kaplan

Structural and Functional Correlates of Human Acetylcholinesterase Mutants for Evaluating Alzheimer’s Disease Treatments

Inhibitors of AChE constitute presently the only successful approach to symptomatic treatment of senile dementia of the Alzheimer’s type, with three such agents (tacrine, E2020 and rivastigmine) in clinical use1. The intensive effort to develop more therapeutically efficatious inhibitors is currently aided by the remarkable progress, made during the last decade, in elucidating the structural and functional properties of the enzyme through x-ray crystallography 2,3 and site directed mutagenesis 4–8. Investigation of the specific roles for most of the residues in this active-center gorge allowed for identification of several functional subsites including the catalytic triad (S203(200)**, H447(440) , E334(327)); the acyl pocket (F295(288) and F297(290)) and the ‘hydrophobic subsite’. The latter accommodates the alcoholic portion of the covalent adduct (tetrahedral intermediate) and may include residues W86 (84) , Y133 (130) , Y337(330) and F338(331), which operate through nonpolar and/or stacking interactions, depending on the substrate. Stabilization of the charged moieties of substrates and other ligands at the active-centre is mediated by cation -π interactions with the residue at position 86 rather than through true ionic interactions2,6,8