Title : Three distinct domains in the cholinesterase molecule confer selectivity for acetyl- and butyrylcholinesterase inhibitors - Radic_1993_Biochemistry_32_12074
Author(s) : Radic Z , Pickering NA , Vellom DC , Camp S , Taylor P
Ref : Biochemistry , 32 :12074 , 1993
Abstract :

By examining inhibitor interactions with single and multiple site-specific mutants of mouse acetylcholinesterase, we have identified three distinct domains in the cholinesterase structure that are responsible for conferring selectivity for acetyl- and butyrylcholinesterase inhibitors. The first domain is the most obvious; it defines the constraints on the acyl pocket dimensions where the side chains of F295 and F297 primarily outline this region in acetylcholinesterase. Replacement of these phenylalanine side chains with the aliphatic residues found in butyrylcholinesterase allows for the catalysis of larger substrates and accommodates butyrylcholinesterase-selective alkyl phosphates such as isoOMPA. Also, elements of substrate activation characteristic of butyrylcholinesterase are evident in the F297I mutant. Substitution of tyrosines for F295 and F297 further alters the catalytic constants. The second domain is found near the lip of the active center gorge defined by two tyrosines, Y72 and Y124, and by W286; this region appears to be critical for the selectivity of bisquaternary inhibitors, such as BW284C51. The third domain defines the site of choline binding. Herein, in addition to conserved E202 and W86, a critical tyrosine, Y337, found only in the acetylcholinesterases is responsible for sterically occluding the binding site for substituted tricyclic inhibitors such as ethopropazine. Analysis of a series of substituted acridines and phenothiazines defines the groups on the ligand and amino acid side chains in this site governing binding selectivity. Each of the three domains is defined by a cluster of aromatic residues. The two domains stabilizing the quaternary ammonium moieties each contain a negative charge, which contributes to the stabilization energy of the respective complexes.

PubMedSearch : Radic_1993_Biochemistry_32_12074
PubMedID: 8218285

Related information

Mutation B5-174-A175-575_mouse-chimerae-ACHE-BCHE    B5-174-A175-487-B488-575_mouse-chimerae-ACHE-BCHE    Y72N_mouse-ACHE    Y72N\/Y124Q_mouse-ACHE    Y72N\/W286R_mouse-ACHE    Y72N\/Y124Q\/W286A_mouse-ACHE    Y72N\/Y124Q\/W286R_mouse-ACHE    Y72N\/D74N\/Y124Q\/W286A_mouse-ACHE    Y72N\/D74N\/Y124Q\/W286R_mouse-ACHE    D74N_mouse-ACHE    Y124Q_mouse-ACHE    Y124Q\/W286R_mouse-ACHE    W286R_mouse-ACHE    F295Y_mouse-ACHE    F297I_mouse-ACHE    F297Y_mouse-ACHE    Y337A_mouse-ACHE    Y337F_mouse-ACHE    F338G_mouse-ACHE    WT_mouse-ACHE    WT_mouse-BCHE    F295L_mouse-ACHE    R296S_mouse-ACHE    V300G_mouse-ACHE    F295L\/F297I_mouse-ACHE
Inhibitor B5-174-A175-575_mouse-chimerae-ACHE-BCHE    B5-174-A175-487-B488-575_mouse-chimerae-ACHE-BCHE    Y72N_mouse-ACHE    Y72N\/Y124Q_mouse-ACHE    Y72N\/W286R_mouse-ACHE    Y72N\/Y124Q\/W286A_mouse-ACHE    Y72N\/Y124Q\/W286R_mouse-ACHE    Y72N\/D74N\/Y124Q\/W286A_mouse-ACHE    Y72N\/D74N\/Y124Q\/W286R_mouse-ACHE    D74N_mouse-ACHE    Y124Q_mouse-ACHE    Y124Q\/W286R_mouse-ACHE    W286R_mouse-ACHE    F295Y_mouse-ACHE    F297I_mouse-ACHE    F297Y_mouse-ACHE    Y337A_mouse-ACHE    Y337F_mouse-ACHE    F338G_mouse-ACHE    WT_mouse-ACHE    WT_mouse-BCHE    F295L_mouse-ACHE    R296S_mouse-ACHE    V300G_mouse-ACHE    F295L\/F297I_mouse-ACHE    9-Aminoacridine    Acridine    Chlorpromazine    Edrophonium    Ethopropazine    N-Methyl-acridinium    Promazine    Promethazine    Tacrine
Substrate B5-174-A175-575_mouse-chimerae-ACHE-BCHE    B5-174-A175-487-B488-575_mouse-chimerae-ACHE-BCHE    Y72N_mouse-ACHE    Y72N\/Y124Q_mouse-ACHE    Y72N\/W286R_mouse-ACHE    Y72N\/Y124Q\/W286A_mouse-ACHE    Y72N\/Y124Q\/W286R_mouse-ACHE    Y72N\/D74N\/Y124Q\/W286A_mouse-ACHE    Y72N\/D74N\/Y124Q\/W286R_mouse-ACHE    D74N_mouse-ACHE    Y124Q_mouse-ACHE    Y124Q\/W286R_mouse-ACHE    W286R_mouse-ACHE    F295Y_mouse-ACHE    F297I_mouse-ACHE    F297Y_mouse-ACHE    Y337A_mouse-ACHE    Y337F_mouse-ACHE    F338G_mouse-ACHE    WT_mouse-ACHE    WT_mouse-BCHE    F295L_mouse-ACHE    R296S_mouse-ACHE    V300G_mouse-ACHE    F295L\/F297I_mouse-ACHE    9-Aminoacridine    Acridine    Chlorpromazine    Edrophonium    Ethopropazine    N-Methyl-acridinium    Promazine    Promethazine    Tacrine    Acetylthiocholine

Citations formats

Radic Z, Pickering NA, Vellom DC, Camp S, Taylor P (1993)
Three distinct domains in the cholinesterase molecule confer selectivity for acetyl- and butyrylcholinesterase inhibitors
Biochemistry 32 :12074

Radic Z, Pickering NA, Vellom DC, Camp S, Taylor P (1993)
Biochemistry 32 :12074