Fatty acid amide hydrolase

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FAAH
Identifiers
Aliases FAAH, fatty acid amide hydrolase, FAAH-1, PSAB
External IDs MGI: 109609 HomoloGene: 68184 GeneCards: FAAH
Targeted by Drug
pf-04457845, urb-597[1]
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001441

NM_010173

RefSeq (protein)

NP_001432.2

NP_034303.3

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

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.[4] In humans, it is encoded by the gene FAAH.[5][6][7]

Function[edit]

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 was initially provisionally linked to drug abuse and dependence but this was not borne out in subsequent studies.[17]

Studies in cells and animals and genetic studies in humans have shown that inhibiting FAAH may be a useful strategy to treat anxiety disorders.[17][18][19]

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.[20][21][22][23][24][25][26][27]

Some of the more significant compounds are listed below;

Assays[edit]

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.[43][44]

Structures[edit]

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.[45]

See also[edit]

References[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 (September 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 (November 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 (March 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 20071Freely accessible. PMID 9122178. 
  7. ^ a b PDB: 1MT5​; 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. 
  8. ^ 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. 
  9. ^ 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". Proceedings of the National Academy of Sciences of the United States of America. 98 (16): 9371–6. doi:10.1073/pnas.161191698. PMC 55427Freely accessible. PMID 11470906. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ Cravatt BF, Lichtman AH (October 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. 
  14. ^ Sałaga M, Sobczak M, Fichna J (2014). "Inhibition of fatty acid amide hydrolase (FAAH) as a novel therapeutic strategy in the treatment of pain and inflammatory diseases in the gastrointestinal tract". European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences. 52: 173–9. doi:10.1016/j.ejps.2013.11.012. PMID 24275607. 
  15. ^ Ulugöl A (2014). "The endocannabinoid system as a potential therapeutic target for pain modulation". Balkan Medical Journal. 31 (2): 115–20. doi:10.5152/balkanmedj.2014.13103. PMC 4115931Freely accessible. PMID 25207181. 
  16. ^ Ghosh S, Kinsey SG, Liu QS, Hruba L, McMahon LR, Grim TW, et al. (2015). "Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice". The Journal of Pharmacology and Experimental Therapeutics. 354 (2): 111–20. doi:10.1124/jpet.115.222851. PMC 4518073Freely accessible. PMID 25998048. 
  17. ^ a b Panlilio LV, Justinova Z, Goldberg SR (2013). "Inhibition of FAAH and activation of PPAR: new approaches to the treatment of cognitive dysfunction and drug addiction". Pharmacology & Therapeutics. 138 (1): 84–102. doi:10.1016/j.pharmthera.2013.01.003. PMC 3662489Freely accessible. PMID 23333350. 
  18. ^ Gunduz-Cinar O, Hill MN, McEwen BS, Holmes A (November 2013). "Amygdala FAAH and anandamide: mediating protection and recovery from stress". Trends in Pharmacological Sciences. 34 (11): 637–44. doi:10.1016/j.tips.2013.08.008sd. PMC 4169112Freely accessible. PMID 24325918. 
  19. ^ Berardi A, Schelling G, Campolongo P (September 2016). "The endocannabinoid system and Post Traumatic Stress Disorder (PTSD): From preclinical findings to innovative therapeutic approaches in clinical settings". Pharmacological Research. 111: 668–78. doi:10.1016/j.phrs.2016.07.024. PMID 27456243. 
  20. ^ Janero DR, Vadivel SK, Makriyannis A (April 2009). "Pharmacotherapeutic modulation of the endocannabinoid signalling system in psychiatric disorders: drug-discovery strategies". International Review of Psychiatry (Abingdon, England). 21 (2): 122–33. doi:10.1080/09540260902782778. PMID 19367506. 
  21. ^ Ahn K, Johnson DS, Cravatt BF (July 2009). "Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders". Expert Opinion on Drug Discovery. 4 (7): 763–784. doi:10.1517/17460440903018857. PMC 2882713Freely accessible. PMID 20544003. 
  22. ^ Petrosino S, Di Marzo V (January 2010). "FAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels". Current Opinion in Investigational Drugs (London, England : 2000). 11 (1): 51–62. PMID 20047159. 
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  30. ^ 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 (May 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 3088576Freely accessible. PMID 21502526. 
  31. ^ Keith JM, Jones WM, Tichenor M, Liu J, Seierstad M, Palmer JA, Webb M, Karbarz M, Scott BP, Wilson SJ, Luo L, Wennerholm ML, Chang L, Rizzolio M, Rynberg R, Chaplan SR, Breitenbucher JG (December 2015). "Preclinical Characterization of the FAAH Inhibitor JNJ-42165279". ACS Medicinal Chemistry Letters. 6 (12): 1204–8. doi:10.1021/acsmedchemlett.5b00353. PMID 26713105. 
  32. ^ "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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  35. ^ 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. 
  36. ^ Fowler CJ (2015). "The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review". Handbook of Experimental Pharmacology. 231: 95–128. doi:10.1007/978-3-319-20825-1_4. PMID 26408159. 
  37. ^ Clinical trial number NCT00822744 for "An Eight-week Study of SSR411298 as Treatment for Major Depressive Disorder in Elderly Patients (FIDELIO)" at ClinicalTrials.gov
  38. ^ "Clinical trials for SSR411298.". EU Clinical Trials Register. 
  39. ^ Hart T, Macias AT, Benwell K, Brooks T, D'Alessandro J, Dokurno P, et al. (August 2009). "Fatty acid amide hydrolase inhibitors. Surprising selectivity of chiral azetidine ureas". Bioorganic & Medicinal Chemistry Letters. 19 (15): 4241–4. doi:10.1016/j.bmcl.2009.05.097. PMID 19515560. 
  40. ^ Clinical trial number NCT01748695 NCT01748695 for " A Safety, Tolerability and Efficacy Study of V158866 in Central Neuropathic Pain Following Spinal Cord Injury" at ClinicalTrials.gov
  41. ^ US granted 8450346, "Azetidine derivatives as FAAH inhibitors", published 28 May 2013, assigned to Vernalis (R&D) Ltd. 
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  44. ^ Han B, Wright R, Kirchhoff AM, Chester JA, Cooper BR, Davisson VJ, Barker E (January 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 3760509Freely accessible. PMID 23044255. 
  45. ^ 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 (September 2008). "Structure-guided inhibitor design for human FAAH by interspecies active site conversion". Proceedings of the National Academy of Sciences of the United States of America. 105 (35): 12820–4. doi:10.1073/pnas.0806121105. PMC 2529035Freely accessible. PMID 18753625. 

External links[edit]