Fatty acid amide hydrolase

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Fatty acid amide hydrolase
Faah w mafp.png
Fatty acid amide hydrolase (FAAH) dimer shown with covalent inhibitor (MAFP, yellow) bound in the active site.
Identifiers
Symbol FAAH
Entrez 2166
HUGO 3553
OMIM 602935
PDB 1MT5 (RCSB PDB PDBe PDBj)
RefSeq NM_001441
UniProt O00519
Other data
EC number 3.5.1.99
Locus Chr. 1 p35-p34

Fatty acid amide hydrolase or FAAH (EC 3.5.1.99, oleamide hydrolase, anandamide amidohydrolase) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide in 1993.[1] In humans, it is encoded by the gene FAAH.[2][3][4]

Function[edit]

FAAH is an integral membrane hydrolase with a single N-terminal transmembrane domain. In vitro, FAAH has esterase and amidase activity.[5] 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:

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.[10] Finally, because of their impaired ability to degrade anandamide, FAAH KOs also display supersensitivity to exogenous anandamide, a cannabinoid receptor (CB) agonist.[6]

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[edit]

Both non-selective and selective inhibitors of the enzyme have been described. Examples of non-selective inhibitors include PMSF (phenylmethylsulfonylfluoride),[11] MAFP,[12][13] and ATMK (arachidonoyltrifluoromethylketone).[14] URB597 is a relatively selective, irreversible, carbamate-based inhibitor, though it also inhibits other serine hydrolases, such as carboxylesterases, in peripheral tissues.[15] Urea-based inhibitors such as PF-622 and PF-750 are more potent and more selective inhibitors of FAAH than URB597.[15]

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.

Structure[edit]

The first crystal structure of FAAH was published in 2002 (PDB ID: 1mt5).[16] Structures of FAAH with drug-like ligands were first reported in 2008, and include covalent (e.g. 2vya, 2wap, 2wj1, 3qkv) and non-covalent (e.g. 3qj9) inhibitors.

See also[edit]

References[edit]

  1. ^ Deutsch DG, Chin SA. (November 1993). "Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist.". Biochem Pharmacol. 46 (5): 791–6. doi:10.1016/0006-2952(93)90486-G. PMID 8373432. 
  2. ^ 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:10.1038/384083a0. PMID 8900284. 
  3. ^ 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:10.1073/pnas.94.6.2238. PMC 20071. PMID 9122178. 
  4. ^ 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:10.1126/science.1076535. PMID 12459591. 
  5. ^ 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:10.1021/bi991876p. PMID 10571985. 
  6. ^ 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:10.1073/pnas.161191698. PMC 55427. PMID 11470906. 
  7. ^ 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:10.1021/bi0480335. PMID 15533037. 
  8. ^ 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 268 (5216): 1506–9. doi:10.1126/science.7770779. PMID 7770779. 
  9. ^ 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:10.1021/bi0608008. PMID 16866345. 
  10. ^ Cravatt BF, Lichtman AH (October 2004). "The endogenous cannabinoid system and its role in nociceptive behavior". J. Neurobiol. 61 (1): 149–60. doi:10.1002/neu.20080. PMID 15362158. 
  11. ^ Deutsch DG, Chin SA. (November 1993). "Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist". Biochem Pharmacol. 46 (5): 791–6. doi:10.1016/0006-2952(93)90486-G. PMID 8373432. 
  12. ^ Deutsch DG, Omeir R, Arreaza G, Salehani D, Prestwich GD, Huang Z, Howlett A. (Feb 1997). "Methyl arachidonyl fluorophosphonate: a potent irreversible inhibitor of anandamide amidase". Biochem Pharmacol. 53 (3): 255–60. doi:10.1016/S0006-2952(96)00830-1. PMID 9065728. 
  13. ^ De Petrocellis L, Melck D, Ueda N, Maurelli S, Kurahashi Y, Yamamoto S, Marino G, Di Marzo V. (Feb 1997). "Novel inhibitors of brain, neuronal, and basophilic anandamide amidohydrolase". Biocehm Biophys Res Commun 231 (1): 82–8. doi:10.1006/bbrc.1997.6000. PMID 9070224. 
  14. ^ Koutek B, Prestwich GD, Howlett AC, Chin SA, Salehani D, Akhavan N, Deutsch DG. (Sep 1994). "Inhibitors of arachidonoyl ethanolamide hydrolysis.". J Biol Chem. 269 (37): 22937–40. PMID 8083191. 
  15. ^ 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:10.1021/bi701378g. PMID 17949010. 
  16. ^ Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF (November 2002). "Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling". Science 298 (5599): 1793–6. doi:10.1126/science.1076535. PMID 12459591. 

External links[edit]