Fatty acid amide hydrolase

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"FAAH" redirects here. For other uses, see FAAH (disambiguation).
Aliases FAAH, fatty acid amide hydrolase, FAAH-1, PSAB
External IDs MGI: 109609 HomoloGene: 68184 GeneCards: 2166
Targeted by Drug
PF-04457845, URB597[1]
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 1: 46.39 – 46.41 Mb Chr 4: 115.97 – 116.02 Mb
PubMed search [2] [3]
View/Edit Human View/Edit Mouse

Fatty acid amide hydrolase or FAAH (EC, oleamide hydrolase, anandamide amidohydrolase) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide in 1993.[4] In humans, it is encoded by the gene FAAH.[5][6][7]


FAAH is an integral membrane hydrolase with a single N-terminal transmembrane domain. In vitro, FAAH has esterase and amidase activity.[8] 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.[13] Finally, because of their impaired ability to degrade anandamide, FAAH KOs also display supersensitivity to exogenous anandamide, a cannabinoid receptor (CB) agonist.[9]

Due to the ability of FAAH to regulate nociception, it is currently viewed as an attractive drug target for the treatment of pain.[14][15][16]

A mutation in FAAH has been linked to drug abuse and dependence.[17] Individuals with the mutation have higher levels of anandamide, the so-called "bliss" molecule, because of lower levels of FAAH, which may reduce anxiety and post-traumatic stress disorder.[18]

Inhibitors and inactivators[edit]

Based on the hydrolytic mechanism of fatty acid amide hydrolase, a large number of irreversible and reversible inhibitors of this enzyme have been developed.[19][20][21][22][23][24][25][26]

Some of the more significant compounds are listed below;


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.[42][43]


The first crystal structure of FAAH was published in 2002 (PDB code 1MT5).[7] Structures of FAAH with drug-like ligands were first reported in 2008, and include non-covalent inhibitor complexes and covalent adducts.[44]

See also[edit]


  1. ^ "Drugs that physically interact with Fatty-acid amide hydrolase 1 view/edit references on wikidata". 
  2. ^ "Human PubMed Reference:". 
  3. ^ "Mouse PubMed Reference:". 
  4. ^ Deutsch DG, Chin SA (Sep 1993). "Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist". Biochemical Pharmacology. 46 (5): 791–6. doi:10.1016/0006-2952(93)90486-G. PMID 8373432. 
  5. ^ Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (Nov 1996). "Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides". Nature. 384 (6604): 83–7. doi:10.1038/384083a0. PMID 8900284. 
  6. ^ Giang DK, Cravatt BF (Mar 1997). "Molecular characterization of human and mouse fatty acid amide hydrolases". Proceedings of the National Academy of Sciences of the United States of America. 94 (6): 2238–42. doi:10.1073/pnas.94.6.2238. PMC 20071free to read. PMID 9122178. 
  7. ^ a b PDB: 1MT5​; Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF (Nov 2002). "Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling". Science. 298 (5599): 1793–6. doi:10.1126/science.1076535. PMID 12459591. 
  8. ^ Patricelli MP, Cravatt BF (Oct 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. 
  9. ^ a b Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH (Jul 2001). "Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase". Proceedings of the National Academy of Sciences of the United States of America. 98 (16): 9371–6. doi:10.1073/pnas.161191698. PMC 55427free to read. PMID 11470906. 
  10. ^ Saghatelian A, Trauger SA, Want EJ, Hawkins EG, Siuzdak G, Cravatt BF (Nov 2004). "Assignment of endogenous substrates to enzymes by global metabolite profiling". Biochemistry. 43 (45): 14332–9. doi:10.1021/bi0480335. PMID 15533037. 
  11. ^ Cravatt BF, Prospero-Garcia O, Siuzdak G, Gilula NB, Henriksen SJ, Boger DL, Lerner RA (Jun 1995). "Chemical characterization of a family of brain lipids that induce sleep". Science. 268 (5216): 1506–9. doi:10.1126/science.7770779. PMID 7770779. 
  12. ^ Saghatelian A, McKinney MK, Bandell M, Patapoutian A, Cravatt BF (Aug 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. 
  13. ^ Cravatt BF, Lichtman AH (Oct 2004). "The endogenous cannabinoid system and its role in nociceptive behavior". Journal of Neurobiology. 61 (1): 149–60. doi:10.1002/neu.20080. PMID 15362158. 
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  15. ^ Ulugöl A. The endocannabinoid system as a potential therapeutic target for pain modulation. Balkan Med J. 2014 Jun;31(2):115-20. doi: 10.5152/balkanmedj.2014.13103 PMID 25207181
  16. ^ Ghosh S, Kinsey SG, Liu QS, Hruba L, McMahon LR, Grim TW, Merritt CR, Wise LE, Abdullah RA, Selley DE, Sim-Selley LJ, Cravatt BF, Lichtman AH. Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice. J Pharmacol Exp Ther. 2015 Aug;354(2):111-20. doi: 10.1124/jpet.115.222851 PMID 25998048
  17. ^ Sipe JC, Chiang K, Gerber AL, Beutler E, Cravatt BF (Jun 2002). "A missense mutation in human fatty acid amide hydrolase associated with problem drug use". Proceedings of the National Academy of Sciences of the United States of America. 99 (12): 8394–9. doi:10.1073/pnas.082235799. PMID 12060782. 
  18. ^ Friedman RA (6 March 2015). "The Feel-Good Gene". New York Times. Retrieved 9 March 2015. 
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  21. ^ Petrosino S, Di Marzo V. FAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels. Curr Opin Investig Drugs. 2010 Jan;11(1):51-62. PMID 20047159
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  25. ^ Pertwee RG (2014). "Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications". The Proceedings of the Nutrition Society. 73 (1): 96–105. doi:10.1017/S0029665113003649. PMID 24135210. 
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  27. ^ Enserink M (2016). "More Details Emerge on Fateful French Drug Trial" (online). Science (January 16). Retrieved 16 January 2016. 
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  29. ^ Min X, Thibault ST, Porter AC, Gustin DJ, Carlson TJ, Xu H, Lindstrom M, Xu G, Uyeda C, Ma Z, Li Y, Kayser F, Walker NP, Wang Z (2011). "Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH)". Proceedings of the National Academy of Sciences of the United States of America. 108 (18): 7379–84. doi:10.1073/pnas.1016167108. PMC 3088576free to read. PMID 21502526. 
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  31. ^ "Janssen Research & Development, LLC Voluntarily Suspends Dosing in Phase 2 Clinical Trials of Experimental Treatment for Mood Disorders". Janssen.com. 17 January 2016. Retrieved 21 January 2016. 
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  36. ^ Clinical trial number NCT00822744 for "An Eight-week Study of SSR411298 as Treatment for Major Depressive Disorder in Elderly Patients (FIDELIO)" at ClinicalTrials.gov
  37. ^ "Clinical trials for SSR411298.". EU Clinical Trials Register. 
  38. ^ Hart T, Macias AT, Benwell K, Brooks T, D'Alessandro J, Dokurno P, Francis G, Gibbons B, Haymes T, Kennett G, Lightowler S, Mansell H, Matassova N, Misra A, Padfield A, Parsons R, Pratt R, Robertson A, Walls S, Wong M, Roughley S. Fatty acid amide hydrolase inhibitors. Surprising selectivity of chiral azetidine ureas. Bioorg Med Chem Lett. 2009 Aug 1;19(15):4241-4. doi: 10.1016/j.bmcl.2009.05.097 PMID 19515560
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  41. ^ Roughley SD, Browne H, Macias AT, Benwell K, Brooks T, D'Alessandro J, Daniels Z, Dugdale S, Francis G, Gibbons B, Hart T, Haymes T, Kennett G, Lightowler S, Matassova N, Mansell H, Merrett A, Misra A, Padfield A, Parsons R, Pratt R, Robertson A, Simmonite H, Tan K, Walls SB, Wong M. Fatty acid amide hydrolase inhibitors. 3: tetra-substituted azetidine ureas with in vivo activity. Bioorg Med Chem Lett. 2012 Jan 15;22(2):901-6. doi: 10.1016/j.bmcl.2011.12.032 PMID 22209458
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  43. ^ Han B, Wright R, Kirchhoff AM, Chester JA, Cooper BR, Davisson VJ, Barker E (2013). "Quantitative LC-MS/MS analysis of arachidonoyl amino acids in mouse brain with treatment of FAAH inhibitor". Analytical Biochemistry. 432 (2): 74–81. doi:10.1016/j.ab.2012.09.031. PMC 3760509free to read. PMID 23044255. 
  44. ^ PDB: 2VYA​; Mileni M, Johnson DS, Wang Z, Everdeen DS, Liimatta M, Pabst B, Bhattacharya K, Nugent RA, Kamtekar S, Cravatt BF, Ahn K, Stevens RC (2008). "Structure-guided inhibitor design for human FAAH by interspecies active site conversion". Proc. Natl. Acad. Sci. U.S.A. 105 (35): 12820–4. doi:10.1073/pnas.0806121105. PMC 2529035free to read. PMID 18753625. 

External links[edit]