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New inhibitors of elusive enzymes promise to be valuable scientific tools
Date:10/31/2012

LA JOLLA, CA October 31, 2012 Scientists at The Scripps Research Institute (TSRI) have discovered the first selective inhibitors of an important set of enzymes. The new inhibitors, and chemical probes based on them, now can be used to study the functions of enzymes known as diacylglycerol lipases (DAGL), their products, and the pathways they regulate. Early tests in mouse macrophages suggest that DAGL-inhibiting compounds might also have therapeutic uses, for they suppress the production of a pro-inflammatory molecule that has been implicated in rheumatoid arthritis and related conditions.

"We've developed the first set of chemical probes that effectively allows one to study these DAGL enzymes in living cell and animal models," said Benjamin F. Cravatt, chairman of the Department of Chemical Physiology, professor in the Dorris Neuroscience Center and member of the Skaggs Institute for Chemical Biology at TSRI. Cravatt and his laboratory conducted the new study, published in the current issue of the journal Nature Chemical Biology.

Important But Poorly Understood

DAGL enzymes have been of interest mainly because of their role in making 2-AG (2-Arachidonoylglycerol), an important cannabinoid that is naturally produced in humans and other mammals. Cannabinoids are named for Cannabis (marijuana) plants, because they stimulate the same cellular receptors that are hit by marijuana's active ingredients. Drugs that can enhance 2-AG's signaling in the nervous system are being developed as treatments for pain, depression and anxiety.

But 2-AG exists in various tissues throughout the body, and on the whole, its functions are not well understood. Until now researchers have lacked enzyme inhibitors that can usefully probe those functions by selectively shutting off 2-AG's production. "Existing DAGL inhibitors block many other enzymes, are not very potent, and do a poor job of getting into cells," Cravatt said. "There h
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Contact: Mika Ono
mikaono@scripps.edu
858-784-2052
Scripps Research Institute
Source:Eurekalert  

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