New Inhibitors of the Peripheral Site in Acetylcholinesterase that Specifically Block Organophosphorylation
Abstract
Acetyicholinesterase (AChE) is one of the most efficient enzymes known. The AChE active site consists of a narrow gorge with two separate ligand binding sites: an acylation site at the bottom of the gorge where substrate hydrolysis occurs and a peripheral site at the gorge mouth. In recent studies, we showed that ligands which bind specifically to the peripheral site can slow the rates at which other ligands enter and exit the acylation site, a feature we denoted steric blockade. We also demonstrated that cationic substrates can form a low affinity complex at the peripheral site that accelerates catalytic hydrolysis at low substrate concentrations but results in substrate inhibition at high concentrations because of steric blockade of product release. AChE is inactivated by organophosphates in pesticides and chemical warfare agents because organophosphates can pass through the peripheral site and phosphorylate the catalytic serine in the acylation site. We are investigating the design of cyclic inhibitors that will bind specifically to the peripheral site and present a pronounced steric blockade to organophosphates while allowing selective passage of acetylcholine to the acylation site. Cyclic inhibitors with affinities for the peripheral site in the sub-micromolar range have been identified.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2000
- Accession Number
- ADB259791
Entities
People
- Terrone L. Rosenberry
Organizations
- Mayo Clinic