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Chem Biol. 2005 Nov;12(11):1179-87.

Mechanism of carbamate inactivation of FAAH: implications for the design of covalent inhibitors and in vivo functional probes for enzymes.

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  • 1The Skaggs Institute for Chemical Biology and Departments of Cell Biology and Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.

Abstract

Fatty acid amide hydrolase (FAAH) regulates a large class of signaling lipids, including the endocannabinoid anandamide. Carbamate inhibitors of FAAH display analgesic and anxiolytic properties in rodents. However, the mechanism by which carbamates inhibit FAAH remains obscure. Here, we provide biochemical evidence that carbamates covalently modify the active site of FAAH by adopting an orientation opposite of that originally predicted from modeling. Based on these results, a series of carbamates was designed that display enhanced potency. One agent was converted into a "click chemistry" probe to comprehensively evaluate the proteome reactivity of FAAH-directed carbamates in vivo. These inhibitors were selective for FAAH in the nervous system, but they reacted with several enzymes in peripheral tissues. The experimental strategy described herein can be used to create in vivo probes for any enzyme susceptible to covalent inhibition.

Comment in

PMID:
16298297
[PubMed - indexed for MEDLINE]
PMCID:
PMC1994809
Free PMC Article

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