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Pac Man Like Enzyme Key to New Diabetes Drug

Posted: Thursday, October 19, 2006

Scientists have deciphered the structure of a "Pac Man"-like enzyme that could form the basis of new treatments for diabetes and Alzheimer's disease.

The insulin-degrading enzyme (IDE) breaks down insulin and amyloid-beta protein which forms plaque in the brain that is the hallmark of Alzheimer's. Like the video game character that it resembles, IDE has two bowl-shaped halves that are held together by a type of hinge. But instead of gobbling up everything that gets in its way like Pac-Man, IDE's mouth is usually tightly closed.
Researchers at the University of Chicago in Illinois have described the structure of IDE which could reveal clues about developing novel drugs. They have also figured out how to accelerate its activity.

"We deciphered the three-dimensional makeup of this enzyme. By having that, now we understand how the enzyme recognizes specific hormones," said Dr Wei-Jen Tang, a structural biologist who headed the research team.

"It is a reverse 'Pac Man' because it is always closed and occasionally opens.

Tang and his team also made small changes to the enzyme that speeded up its activity, which could help in the design of treatments for Alzheimer's. "It demonstrated that we can make this enzyme more active in a simple way by making a simple mutation," said Tang.

IDE was discovered more than 50 years ago by biochemist Arthur Mirsky, who thought blocking its action could form the basis of a new therapy for diabetes. Diabetics do not produce enough insulin or do not use it effectively. But without knowing the structure of the enzyme, it was difficult to develop compounds that would inhibit IDE.

More recently scientists realized that speeding up the action of IDE with a drug could prevent the build up of amyloid plaques in patients suffering from Alzheimer's. Now that Tang and his team have mapped out the structure of IDE, they hope it could lead to new drugs for both diabetes and Alzheimer's disease.

"If we control the closing and opening of the enzyme then we can make better use of this molecule and unleash its activity," said Tang, who reported the finding in the journal Nature."Crucially, the authors show that it might be possible to develop not just inhibitors, but activators as well," they said in a commentary in the journal.

Source: Diabetes In Control: Nature Oct, 2006

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