Fatty acid amide hydrolase

"FAAH" redirects here. For other uses, see FAAH (disambiguation).
Fatty acid amide hydrolase

Fatty acid amide hydrolase (FAAH) dimer shown with covalent inhibitor (MAFP, yellow) bound in the active site.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols FAAH ; FAAH-1; PSAB
External IDs OMIM: 602935 MGI: 109609 HomoloGene: 68184 IUPHAR: 1400 GeneCards: FAAH Gene
EC number 3.5.1.99
Orthologs
Species Human Mouse
Entrez 2166 14073
Ensembl ENSG00000117480 ENSMUSG00000034171
UniProt O00519 O08914
RefSeq (mRNA) NM_001441 NM_010173.4
RefSeq (protein) NP_001432 NP_034303.3
Location (UCSC) Chr 1:
46.39 – 46.41 Mb		 Chr 4:
115.99 – 116.02 Mb
PubMed search

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

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.[11][12][13]

A mutation in FAAH has been linked to drug abuse and dependence.[14] 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.[15]

Inhibitors and inactivators

Based on the hydrolytic mechanism of fatty acid amide hydrolase, a large number of irreversible and reversible inhibitors of this enzyme have been developed.[16][17][18][19][20][21][22][23]

Some of the more significant compounds are listed below;

  • AM374, palmitylsulfonyl fluoride, one of the first FAAH inhibitors developed for in vitro use, but too reactive for research in vivo
  • ARN2508, derivative of flurbiprofen, dual FAAH / COX inhibitor
  • BIA 10-2474 (Bial-Portela & Ca. SA, Portugal) has been linked to severe adverse events affecting 5 patients in a drug trial in Rennes, France, and at least one death, in January 2016.[24] It is important however, to note that many other pharmaceutical companies have previously taken other FAAH inhibitors into clinical trials without reporting such adverse events.
  • BMS-469908[25]
  • CAY-10402
  • JNJ-245
  • JNJ-1661010[26]
  • JNJ-28833155
  • JNJ-40413269
  • JNJ-42119779
  • JNJ-42165279 in clinical trials against social anxiety and depression,[27] trials suspended as a precautionary measure following serious adverse event with BIA 10-2474[28]
  • LY-2183240 [29]
  • Cannabidiol[30]
  • MK-3168
  • MK-4409
  • MM-433593
  • OL-92
  • OL-135
  • PF-622
  • PF-750 [31]
  • PF-3845
  • PF-04457845 "exquisitely selective" for FAAH over other serine hydrolases, but failed in clinical trials against osteoarthritis[32]
  • PF-04862853
  • RN-450
  • SA-47
  • SA-73
  • SSR-411298 well tolerated in clinical trials but insufficient efficacy against depression, subsequently trialled against cancer pain as an adjunctive treatment.[33][34]
  • ST-4068, reversible inhibitor of FAAH
  • TK-25
  • URB524
  • URB597 (KDS-4103, Kadmus Pharmaceuticals), is an irreversible inactivator with a carbamate-based mechanism, and appears in one report as a somewhat selective, though it also inactivates other serine hydrolases (e.g., carboxylesterases) in peripheral tissues.[31]
  • URB694
  • URB937
  • VER-156084[35]
  • V-158866 in clinical trials for neuropathic pain following spinal injury,[36] and spasticity associated with multiple sclerosis. Structure not revealed though Vernalis holds several patents in the area.[37][38]

Assays

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.[39][40]

Structures

The first crystal structure of FAAH was published in 2002 (PDB code 1MT5).[4] Structures of FAAH with drug-like ligands were first reported in 2008, and include non-covalent inhibitor complexes and covalent adducts.[41]

See also

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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 20071. PMID 9122178.
  4. 1 2 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.
  5. ↑ 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.
  6. 1 2 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 55427. PMID 11470906.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ Sałaga M, Sobczak M, Fichna J. Inhibition of fatty acid amide hydrolase (FAAH) as a novel therapeutic strategy in the treatment of pain and inflammatory diseases in the gastrointestinal tract. Eur J Pharm Sci. 2014 Feb 14;52:173-9. doi: 10.1016/j.ejps.2013.11.012 PMID 24275607
  12. ↑ 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
  13. ↑ 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
  14. ↑ 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.
  15. ↑ Friedman RA (6 March 2015). "The Feel-Good Gene". New York Times. Retrieved 9 March 2015.
  16. ↑ Janero DR, Vadivel SK, Makriyannis A. Pharmacotherapeutic modulation of the endocannabinoid signalling system in psychiatric disorders: drug-discovery strategies. Int Rev Psychiatry. 2009 Apr;21(2):122-33. doi: 10.1080/09540260902782778 PMID 19367506
  17. ↑ Kay Ahn, Douglas S. Johnson, and Benjamin F. Cravatt. Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders. Expert Opin Drug Discov. 2009 Jul; 4(7): 763–784. doi: 10.1517/17460440903018857
  18. ↑ 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
  19. ↑ Minkkilä A, Saario S, Nevalainen T. Discovery and development of endocannabinoid-hydrolyzing enzyme inhibitors. Curr Top Med Chem. 2010;10(8):828-58. PMID 20370710
  20. ↑ Khanna IK, Alexander CW (2011). "Fatty acid amide hydrolase inhibitors--progress and potential". CNS Neurol Disord Drug Targets 10 (5): 545–58. doi:10.1517/17460441.2013.780021. PMID 21631410.
  21. ↑ Bisogno T, Maccarrone M (2013). "Latest advances in the discovery of fatty acid amide hydrolase inhibitors". Expert Opinion on Drug Discovery 8 (5): 509–22. doi:10.1517/17460441.2013.780021. PMID 23488865.
  22. ↑ 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.
  23. ↑ Lodola A, Castelli R, Mor M, Rivara S (2015). "Fatty acid amide hydrolase inhibitors: a patent review (2009 - 2014)". Expert Opinion on Therapeutic Patents 25 (11): 1247–66. doi:10.1517/13543776.2015.1067683. PMID 26413912.
  24. ↑ Enserink M (2016). "More Details Emerge on Fateful French Drug Trial" (online). Science (January 16). Retrieved 16 January 2016.
  25. ↑ Blankman JL, Cravatt BF (2013). "Chemical probes of endocannabinoid metabolism". Pharmacological Reviews 65 (2): 849–71. doi:10.1124/pr.112.006387. PMC 3639726. PMID 23512546.
  26. ↑ 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 3088576. PMID 21502526.
  27. ↑ 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 (2015). "Preclinical Characterization of the FAAH Inhibitor JNJ-42165279". ACS Medicinal Chemistry Letters 6 (12): 1204–8. doi:10.1021/acsmedchemlett.5b00353. PMID 26713105.
  28. ↑ "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.
  29. ↑ Moore SA, Nomikos GG, Dickason-Chesterfield AK, Schober DA, Schaus JM, Ying BP, Xu YC, Phebus L, Simmons RM, Li D, Iyengar S, Felder CC (Dec 2005). "Identification of a High-Affinity Binding Site Involved in the Transport of Endocannabinoids". Proc. Natl. Acad. Sci. U.S.A 102 (49): 17852–7. doi:10.1073/pnas.0507470102. PMC 1295594. PMID 16314570.
  30. ↑ Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS (2012). "Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 367 (1607): 3364–78. doi:10.1098/rstb.2011.0389. PMC 3481531. PMID 23108553.
  31. 1 2 Ahn K, Johnson DS, Fitzgerald LR, Liimatta M, Arendse A, Stevenson T, Lund ET, Nugent RA, Nomanbhoy TK, Alexander JP, Cravatt BF (Nov 2007). "Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity". Biochemistry 46 (45): 13019–30. doi:10.1021/bi701378g. PMID 17949010.
  32. ↑ 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.
  33. ↑ Clinical trial number NCT00822744 for "An Eight-week Study of SSR411298 as Treatment for Major Depressive Disorder in Elderly Patients (FIDELIO)" at ClinicalTrials.gov
  34. ↑ "Clinical trials for SSR411298.". EU Clinical Trials Register.
  35. ↑ 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
  36. ↑ 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
  37. ↑ US granted 8450346, "Azetidine derivatives as FAAH inhibitors", published 28 May 2013, assigned to Vernalis (R&D) Ltd.
  38. ↑ 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
  39. ↑ Wang Y, Jones P (2009). "A scintillation proximity assay for fatty acid amide hydrolase compatible with inhibitor screening". Methods in Molecular Biology (Clifton, N.J.) 572: 247–59. doi:10.1007/978-1-60761-244-5_16. PMID 20694697.
  40. ↑ 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 3760509. PMID 23044255.
  41. ↑ 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 2529035. PMID 18753625.

External links

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