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Gene Review

Faah  -  fatty acid amide hydrolase

Rattus norvegicus

Synonyms: Anandamide amidohydrolase 1, Faah1, Fatty-acid amide hydrolase 1, Oleamide hydrolase 1
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Disease relevance of Faah


High impact information on Faah


Biological context of Faah

  • Collectively, these findings suggest that FAAH possesses a specialized active site structure dedicated to a mechanism for competitive amide and ester hydrolysis where nucleophile attack and leaving group protonation occur in a coordinated manner dependent on Lys-142 [9].
  • Here, through a combination of site-directed mutagenesis, enzyme kinetics, and chemical labeling experiments, we provide evidence that each FAAH triad residue plays a distinct role in catalysis [9].
  • Mutagenesis of each of the triad residues in FAAH has been shown to severely reduce amidase activity; however, how these residues contribute, both individually and in cooperation, to catalysis remains unclear [9].
  • The structure of FAAH complexed with an arachidonyl inhibitor reveals how a set of discrete structural alterations allows this enzyme, in contrast to soluble hydrolases of the same family, to integrate into cell membranes and establish direct access to the bilayer from its active site [10].
  • In addition, the hit molecules from the virtual screening of CB2 receptor ligands (reported previously in Salo et al. J. Med. Chem. 2005, 48, 7166) were also tested in our FAAH assay, and four active compounds (7-10) were found with IC50 values between 0.52 and 22 microM [11].

Anatomical context of Faah


Associations of Faah with chemical compounds

  • Fatty acid amide hydrolase (FAAH) is a mammalian amidase signature enzyme that inactivates neuromodulatory fatty acid amides, including the endogenous cannabinoid anandamide and the sleep-inducing substance oleamide [9].
  • Interestingly, although structural evidence indicates that the impact of Lys-142 on catalysis probably occurs through the bridging Ser-217, the mutation of this latter residue to alanine impaired catalytic activity but left the amide/ester hydrolysis ratios of FAAH intact [9].
  • Fatty acid amide hydrolase (FAAH) is a membrane-bound enzyme activity that degrades neuromodulatory fatty acid amides, including oleamide and anandamide [15].
  • In this study we investigated the cellular and subcellular distribution of FAAH at various timepoints during the first postnatal weeks, when GABA is still depolarizing, and plays a crucial role in network events [13].
  • Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats [16].

Regulatory relationships of Faah


Other interactions of Faah


Analytical, diagnostic and therapeutic context of Faah

  • The FAAH distribution in the CNS suggests that degradation of neuromodulatory fatty acid amides at their sites of action influences their effects on sleep, euphoria, and analgesia [15].
  • In situ hybridization revealed profound distribution of FAAH mRNA in neuronal cells throughout the CNS [15].
  • To delineate the structural requirements of AAH substrates, rat brain microsomal AAH hydrolysis of a series of anandamide congeners was studied using two reverse-phase high-performance liquid chromatography (RP-HPLC) assays developed in our laboratory [20].
  • Here we have analysed the distribution of FAAH in rat brain and compared its cellular localization with CB1-type cannabinoid receptors using immunocytochemistry [21].
  • The activity of anandamide amidohydrolase in hind-paw skin also did not change after treatment with formalin [22].


  1. Role of TRPV1 and cannabinoid CB1 receptors in AM 404-evoked hypothermia in rats. Rawls, S.M., Ding, Z., Cowan, A. Pharmacol. Biochem. Behav. (2006) [Pubmed]
  2. Levodopa treatment reverses endocannabinoid system abnormalities in experimental parkinsonism. Maccarrone, M., Gubellini, P., Bari, M., Picconi, B., Battista, N., Centonze, D., Bernardi, G., Finazzi-Agrò, A., Calabresi, P. J. Neurochem. (2003) [Pubmed]
  3. Massive accumulation of N-acylethanolamines after stroke. Cell signalling in acute cerebral ischemia? Berger, C., Schmid, P.C., Schabitz, W.R., Wolf, M., Schwab, S., Schmid, H.H. J. Neurochem. (2004) [Pubmed]
  4. Anandamide metabolism by fatty acid amide hydrolase in intact C6 glioma cells. Increased sensitivity to inhibition by ibuprofen and flurbiprofen upon reduction of extra- but not intracellular pH. Holt, S., Fowler, C.J. Naunyn Schmiedebergs Arch. Pharmacol. (2003) [Pubmed]
  5. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Cravatt, B.F., Giang, D.K., Mayfield, S.P., Boger, D.L., Lerner, R.A., Gilula, N.B. Nature (1996) [Pubmed]
  6. Exceptionally potent inhibitors of fatty acid amide hydrolase: the enzyme responsible for degradation of endogenous oleamide and anandamide. Boger, D.L., Sato, H., Lerner, A.E., Hedrick, M.P., Fecik, R.A., Miyauchi, H., Wilkie, G.D., Austin, B.J., Patricelli, M.P., Cravatt, B.F. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  7. Chemical requirements for inhibition of gap junction communication by the biologically active lipid oleamide. Boger, D.L., Patterson, J.E., Guan, X., Cravatt, B.F., Lerner, R.A., Gilula, N.B. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  8. Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. Högestätt, E.D., Jönsson, B.A., Ermund, A., Andersson, D.A., Björk, H., Alexander, J.P., Cravatt, B.F., Basbaum, A.I., Zygmunt, P.M. J. Biol. Chem. (2005) [Pubmed]
  9. Evidence for distinct roles in catalysis for residues of the serine-serine-lysine catalytic triad of fatty acid amide hydrolase. McKinney, M.K., Cravatt, B.F. J. Biol. Chem. (2003) [Pubmed]
  10. Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Bracey, M.H., Hanson, M.A., Masuda, K.R., Stevens, R.C., Cravatt, B.F. Science (2002) [Pubmed]
  11. Fatty acid amide hydrolase inhibitors from virtual screening of the endocannabinoid system. Saario, S.M., Poso, A., Juvonen, R.O., Järvinen, T., Salo-Ahen, O.M. J. Med. Chem. (2006) [Pubmed]
  12. Endocannabinoid system in frog and rodent testis: type-1 cannabinoid receptor and fatty acid amide hydrolase activity in male germ cells. Cobellis, G., Cacciola, G., Scarpa, D., Meccariello, R., Chianese, R., Franzoni, M.F., Mackie, K., Pierantoni, R., Fasano, S. Biol. Reprod. (2006) [Pubmed]
  13. The spatial and temporal pattern of fatty acid amide hydrolase expression in rat hippocampus during postnatal development. Morozov, Y.M., Ben-Ari, Y., Freund, T.F. Eur. J. Neurosci. (2004) [Pubmed]
  14. Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Gulyas, A.I., Cravatt, B.F., Bracey, M.H., Dinh, T.P., Piomelli, D., Boscia, F., Freund, T.F. Eur. J. Neurosci. (2004) [Pubmed]
  15. Fatty acid amide hydrolase, the degradative enzyme for anandamide and oleamide, has selective distribution in neurons within the rat central nervous system. Thomas, E.A., Cravatt, B.F., Danielson, P.E., Gilula, N.B., Sutcliffe, J.G. J. Neurosci. Res. (1997) [Pubmed]
  16. Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats. Solinas, M., Justinova, Z., Goldberg, S.R., Tanda, G. J. Neurochem. (2006) [Pubmed]
  17. Cannabinoid CB1 receptor protein expression in the rat choroid plexus: a possible involvement of cannabinoids in the regulation of cerebrospinal fluid. Ashton, J.C., Appleton, I., Darlington, C.L., Smith, P.F. Neurosci. Lett. (2004) [Pubmed]
  18. Dendritically released transmitters cooperate via autocrine and retrograde actions to inhibit afferent excitation in rat brain. Hirasawa, M., Schwab, Y., Natah, S., Hillard, C.J., Mackie, K., Sharkey, K.A., Pittman, Q.J. J. Physiol. (Lond.) (2004) [Pubmed]
  19. Acidic nonsteroidal anti-inflammatory drugs inhibit rat brain fatty acid amide hydrolase in a pH-dependent manner. Fowler, C.J., Holt, S., Tiger, G. Journal of enzyme inhibition and medicinal chemistry. (2003) [Pubmed]
  20. Substrate specificity and stereoselectivity of rat brain microsomal anandamide amidohydrolase. Lang, W., Qin, C., Lin, S., Khanolkar, A.D., Goutopoulos, A., Fan, P., Abouzid, K., Meng, Z., Biegel, D., Makriyannis, A. J. Med. Chem. (1999) [Pubmed]
  21. A new perspective on cannabinoid signalling: complementary localization of fatty acid amide hydrolase and the CB1 receptor in rat brain. Egertová, M., Giang, D.K., Cravatt, B.F., Elphick, M.R. Proc. Biol. Sci. (1998) [Pubmed]
  22. Role of the endogenous cannabinoid system in the formalin test of persistent pain in the rat. Beaulieu1, P., Bisogno1, T., Punwar, S., Farquhar-Smith, W.P., Ambrosino, G., Di Marzo, V., Rice, A.S. Eur. J. Pharmacol. (2000) [Pubmed]
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