Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Fatty Acid Amide Hydrolase

  • Filomena Fezza
  • Monica Bari
  • Domenico Fazio
  • Mauro MaccarroneEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101566


Historical Background

A membrane-associated enzyme activity from rat liver that hydrolyzes N-acylethanolamine (NAE) species containing unsaturated and monounsaturated acyl chains was first described in 1985 by Schmid and colleagues (1985). Subsequently, an enzyme activity with similar properties that breaks the sleep-inducing substance cis-9-octadecenamide (oleamide) was reported and suggested to represent a general mechanism for terminating NAEs signaling in vivo. Nonetheless, the actual enzymes involved in NAEs metabolism remained unknown until the late 1990s, when Cravatt and colleagues purified this amidohydrolase activity from rat liver membranes (Cravatt et al. 1996). This enzyme, named fatty acid amide hydrolase (FAAH; E.C., was shown to be specifically inhibitable (Deutsch et al. 1997), was recombinantly expressed, and was found to hydrolyze several endogenous NAEs, including the neuromodulator/neurotransmitter N...

This is a preview of subscription content, log in to check access.



We are grateful to Prof. Enrico Dainese (University of Teramo, Teramo, Italy) for kindly providing FAAH three-dimensional structure. This study was partially supported by the Italian Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN 2012 to F.F. and PRIN 2010–2011 to M.M.).


  1. Ando T, Tamura N, Mera T, Morita C, Takei M, Nakamoto C, Koide M, Hotta M, Naruo T, Kawai K, Nakahara T, Yamaguchi C, Nagata T, Ookuma K, Okamoto Y, Yamanaka T, Kiriike N, Ichimaru Y, Ishikawa T, Komaki G, Japanese Genetic Research Group For Eating Disorders. Association of the c.385C>A (p.Pro129Thr) polymorphism of the fatty acid amide hydrolase gene with anorexia nervosa in the Japanese population. Mol Genet Genomic Med. 2014;2:313–8.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Bari M, Battista N, Valenza M, Mastrangelo N, Malaponti M, Catanzaro G, Centonze D, Finazzi-Agrò A, Cattaneo E, Maccarrone M. In vitro and in vivo models of Huntington’s disease show alterations in the endocannabinoid system. FEBS J. 2013;280:3376–3388.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Bisogno T, Maccarrone M. Latest advances in the discovery of fatty acid amide hydrolase inhibitors. Expert Opin Drug Discov. 2013;8:509–22.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Blankman JL, Cravatt BF. Chemical probes of endocannabinoid metabolism. Pharmacol Rev. 2013;65:849–71.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF. Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science. 2002;298:1793–6.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature. 1996;384:83–7.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Dainese E, De Fabritiis G, Sabatucci A, Oddi S, Angelucci CB, Di Pancrazio C, Giorgino T, Stanley N, Del Carlo M, Cravatt BF, Maccarrone M. Membrane lipids are key modulators of the endocannabinoid-hydrolase FAAH. Biochem J. 2014;457:463–72.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Deutsch DG, Omeir R, Arreaza G, Salehani D, Prestwich GD, Huang Z, Howlett A. Methyl arachidonyl fluorophosphonate: a potent irreversible inhibitor of anandamide amidase. Biochem Pharmacol. 1997;53:255–60.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Fernández-Ruiz J, Romero J, Ramos JA. Endocannabinoids and neurodegenerative disorders: Parkinson’s disease, Huntington’s chorea, Alzheimer’s disease, and others. Handb Exp Pharmacol. 2015;231:233–59.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Fezza F, De Simone C, Amadio D, Maccarrone M. Fatty acid amide hydrolase: a gate-keeper of the endocannabinoid system. Subcell Biochem. 2008;49:101–32.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Fowler CJ. The potential of inhibitors of endocannabinoid metabolism for drug development: a critical review. Handb Exp Pharmacol. 2015;23:95–128.CrossRefGoogle Scholar
  12. Grimaldi P, Pucci M, Di Siena S, Di Giacomo D, Pirazzi V, Geremia R, Maccarrone M. The faah gene is the first direct target of estrogen in the testis: role of histone demethylase LSD1. Cell Mol Life Sci. 2012;69:4177–90.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Hansson AC, Bermúdez-Silva FJ, Malinen H, Hyytiä P, Sanchez-Vera I, Rimondini R, Rodriguez de Fonseca F, Kunos G, Sommer WH, Heilig M. Genetic impairment of frontocortical endocannabinoid degradation and high alcohol preference. Neuropsychopharmacology. 2007;32:117–26.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Lazary J, Eszlari N, Juhasz G, Bagdy G. Genetically reduced FAAH activity may be a risk for the development of anxiety and depression in persons with repetitive childhood trauma. Eur Neuropsychopharmacol. 2016;26:1020–8.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Maccarrone M, Bab I, Bíró T, Cabral GA, Dey SK, Di Marzo V, Konje JC, Kunos G, Mechoulam R, Pacher P, Sharkey KA, Zimmer A. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci. 2015;36:277–96.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Marco EM, Rapino C, Caprioli A, Borsini F, Laviola G, Maccarrone M. Potential therapeutic value of a novel FAAH inhibitor for the treatment of anxiety. PLoS ONE. 2015;10:e0137034.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Mileni M, Johnson DS, Wang Z, Everdeen DS, Liimatta M, Pabst B, Bhattacharya K, Nugent RA, Kamtekar S, Cravatt BF, Ahn K, Stevens RC. Structure-guided inhibitor design for human FAAH by interspecies active site conversion. Proc Natl Acad Sci U S A. 2008;105:12820–4.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Pertwee R.G. Endocannabinoids and Their Pharmacological Actions. In: Handb Exp Pharmacol. Springer. 2015;231:1–37. doi 10.1007/978-3-319-20825-1.Google Scholar
  19. Schmid PC, Zuzarte-Augustin ML, Schmid HH. Properties of rat liver N-acylethanolamine amidohydrolase. J Biol Chem. 1985;260:14145–9.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Filomena Fezza
    • 1
  • Monica Bari
    • 1
  • Domenico Fazio
    • 1
    • 4
  • Mauro Maccarrone
    • 2
    • 3
    Email author
  1. 1.Department of Experimental Medicine and SurgeryTor Vergata University of RomeRomeItaly
  2. 2.Department of MedicineCampus Bio-Medico University of RomeRomeItaly
  3. 3.European Center for Brain Research/IRCCS Santa Lucia FoundationRomeItaly
  4. 4.Unit of Basic and Applied BioscienceUniversity of TeramoTeramoItaly