Israeli scientists have found the three-dimensional structureof acetylcholinesterase (AChE), an enzyme targeted bytherapies for glaucoma, myasthenia gravis and possiblyAlzheimer's disease, and by drugs to counteract nerve gas.

Writing in today's issue of the journal Science, researchers atthe Weizmann Institute of Science showed that the active siteof the enzyme, where the nerve signaller acetylcholine is splitin two, lies near the bottom of a deep cleft in the enzymemolecule.

Primarily aromatic, or uncharged, amino acids line the cleft."The gorge is so deep and its aromatic surface so extensivethat there must be many different ways and places forsubstrate, agonists and inhibitors to bind to AChE," theresearchers said. Previously, the site was believed to besurrounded by charged amino acids.

The varied actions of anti-AChE drugs can now be explained bytheir different possible means of blocking access to the gorge.Some may fit in the cleft and plug it, while others may be toobulky to enter, but may partially block the entrance andprevent access of acetylcholine.

The powerful toxicity of the organophosphorus nerve poisonsand some pesticides results from their potent blocking ofAChE, which normally can clear acetylcholine exceptionallyfast. Flooded with excess acetylcholine, nerves can't shut offtheir impulses, and muscles contract violently. On the otherhand, drugs to block the enzyme are needed in cases where aboost in acetylcholine action would help.

One theory holds that Alzheimer's disease results from toolittle acetylcholine. Myasthenia gravis causes muscleweakness when the immune system mistakenly attacksacetylcholine transmission.

Now that the detailed model of the enzyme's structure isavailable, scientists can use computer-aided design to craftAChE drugs.

-- Roberta Friedman, Ph.D. Special to BioWorld

(c) 1997 American Health Consultants. All rights reserved.