Differential effects of 'peripheral' site ligands on Torpedo and chicken acetylcholinesterase

J. Eichler, A. Anselmet, J. L. Sussman, J. Massoulie, I. Silman

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Comparison of the effect of three 'peripheral' site ligands, propidium, d- tubocurarine, and gallamine, on acetylcholinesterase (acetylcholine hydrolase; EC 3.1.1.7) of Torpedo and chicken shows that all three are substantially more effective inhibitors of the Torpedo enzyme than of the chicken enzyme. In contrast, edrophonium, which is directed to the 'anionic' subsite of the active site, inhibits the chicken and Torpedo enzymes equally effectively. Two bisquaternary ligands, decamethonium and 1,5-bis(4- allyldimethylammoniumphenyl)pentan-3-one dibromide, which are believed to bridge the anionic subsite of the active site and the 'peripheral' anionic site, are much weaker inhibitors of the chicken enzyme than of Torpedo acetylcholinesterase, whereas the shorter bisquaternary ligand hexamethonium inhibits the two enzymes similarly. The concentration dependence of activity towards the natural substrate acetylcholine is almost identical for the two enzymes, whereas substrate inhibition of chicken acetylcholinesterase is somewhat weaker than that of the Torpedo enzyme. The experimental data can be rationalized on the basis of the three-dimensional structure of the Torpedo enzyme and alignment of the chicken and Torpedo sequences; it is suggested that the absence, in the chicken enzyme, of two aromatic residues, Tyr-70 and Trp-279, that contribute to the peripheral site of Torpedo acetylcholinesterase is responsible for the differential effects of peripheral site ligands on the two enzymes.

Original languageEnglish
Pages (from-to)335-340
Number of pages6
JournalMolecular Pharmacology
Volume45
Issue number2
StatePublished - 1 Jan 1994
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Fingerprint

Dive into the research topics of 'Differential effects of 'peripheral' site ligands on Torpedo and chicken acetylcholinesterase'. Together they form a unique fingerprint.

Cite this