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| Fatty acid amide hydrolase (FAAH) dimer shown with covalent inhibitor (MAFP, yellow) bound in the active site. | |
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Fatty acid amide hydrolase
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| Identifiers | |
| Symbol | FAAH |
| Entrez | 2166 |
| HUGO | 3553 |
| OMIM | 602935 |
| PDB | 1MT5 |
| RefSeq | NM_001441 |
| UniProt | O00519 |
| Other data | |
| EC number | 3.5.1.- |
| Locus | Chr. 1 p35-p34 |
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.123 The crystal structure of FAAH was solved by the same laboratory in 2002.3
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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 endocannabinoid5
- Other N-acylethanolamines, such as N-oleoylethanolamine and N-palmitoylethanolamine6
- 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
- ^ Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (November 1996). "Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides". Nature 384 (6604): 83–7. doi:. PMID 8900284.
- ^ Giang DK, Cravatt BF (March 1997). "Molecular characterization of human and mouse fatty acid amide hydrolases". Proc. Natl. Acad. Sci. U.S.A. 94 (6): 2238–42. doi:. PMID 9122178.
- ^ a b Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF (2002). "Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling". Science 298 (5599): 1793–6. doi:. PMID 12459591.
- ^ Patricelli MP, Cravatt BF (October 1999). "Fatty acid amide hydrolase competitively degrades bioactive amides and esters through a nonconventional catalytic mechanism". Biochemistry 38 (43): 14125–30. doi:. PMID 10571985.
- ^ a b Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH (July 2001). "Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase". Proc. Natl. Acad. Sci. U.S.A. 98 (16): 9371–6. doi:. PMID 11470906.
- ^ Saghatelian A, Trauger SA, Want EJ, Hawkins EG, Siuzdak G, Cravatt BF (November 2004). "Assignment of endogenous substrates to enzymes by global metabolite profiling". Biochemistry 43 (45): 14332–9. doi:. PMID 15533037.
- ^ Cravatt BF, Prospero-Garcia O, Siuzdak G, Gilula NB, Henriksen SJ, Boger DL, Lerner RA (June 1995). "Chemical characterization of a family of brain lipids that induce sleep". Science (journal) 268 (5216): 1506–9. PMID 7770779, http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=7770779.
- ^ Saghatelian A, McKinney MK, Bandell M, Patapoutian A, Cravatt BF (August 2006). "A FAAH-regulated class of N-acyl taurines that activates TRP ion channels". Biochemistry 45 (30): 9007–15. doi:. PMID 16866345.
- ^ Cravatt BF, Lichtman AH (October 2004). "The endogenous cannabinoid system and its role in nociceptive behavior". J. Neurobiol. 61 (1): 149–60. doi:. PMID 15362158.
- ^ a b Ahn K, Johnson DS, Fitzgerald LR, Liimatta M, Arendse A, Stevenson T, Lund ET, Nugent RA, Nomanbhoy TK, Alexander JP, Cravatt BF (November 2007). "Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity". Biochemistry 46 (45): 13019–30. doi:. PMID 17949010.
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Wikipedia content modification information:
- This page was last modified on 28 November 2008, at 20:31.
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