Fatty acid amide hydrolase or FAAH is a member of the serine hydrolase family of enzymes. In humans, it is encoded by the gene FAAH. FAAH was cloned in 1996 by Benjamin Cravatt and co-workers at The Scripps Research Institute where it continues to be intensively studied and characterized.^[1][2][3] The crystal structure of FAAH was solved by the same laboratory in 2002.^[3]

Function

In vitro, FAAH has esterase and amidase activity.^[4] In vivo, FAAH is the principal catabolic enzyme for a class of bioactive lipids called the fatty acid amides (FAAs). Members of the FAAs include:

• Anandamide (N-arachidonoylethanolamine), an endocannabinoid^[5]

• Other N-acylethanolamines, such as N-oleoylethanolamine and N-palmitoylethanolamine^[6]

• The sleep-inducing lipid oleamide^[7]

• The N-acyltaurines, which are agonists of the transient receptor potential (TRP) family of calcium channels.^[8]

FAAH knockout mice display highly elevated (>15-fold) levels of N-acylethanolamines and N-acyltaurines in various tissues. Because of their significantly elevated anandamide levels, FAAH KOs have an analgesic phenotype, showing reduced pain sensation in the hot plate test, the formalin test, and the tail flick test.^[9] Finally, because of their impaired ability to degrade anandamide, FAAH KOs also display heightened sensitivity to the cannabinoid receptor (CB) agonist anandamide.^[5]

Due to the ability of FAAH to regulate nociception, it is currently viewed as an attractive drug target for the treatment of pain.

Inhibitors and assays

Both non-selective and selective inhibitors of the enzyme have been described. Examples of non-selective inhibitors include PMSF (phenylmethylsulfonylfluoride), MAFP, and ATMK (arachidonoyltrifluoromethylketone). URB597 is a relatively selective, irreversible, carbamate-based inhibitor, though it also inhibits other serine hydrolases, such as carboxylesterases, in peripheral tissues.^[10] Urea-based inhibitors such as PF-622 and PF-750 are more potent and more selective inhibitors of FAAH than URB597.^[10]

The enzyme is typically assayed making use of a radiolabelled anandamide substrate, which generates free labelled ethanolamine, although alternative LC-MS methods have also been described.

References

External links

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