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Gene Review

Fa2h  -  fatty acid 2-hydroxylase

Mus musculus

Synonyms: FAAH, Faah, Fatty acid 2-hydroxylase, Fatty acid alpha-hydroxylase, Faxdc1, ...
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Disease relevance of Fa2h

  • Intravenous administration of 107 LPS-treated mouse macrophages to anesthetized rats elicits hypotension, which is much greater in response to FAAH-/- than FAAH+/+ cells and is susceptible to inhibition by SR141716, a cannabinoid CB1 receptor antagonist [1].
  • Anandamide produced analgesia, catalepsy, and hypothermia in FAAH (-/-) mice, but failed to elicit any of these effects in the other three genotypes [2].

High impact information on Fa2h

  • Fatty acid amide hydrolase (FAAH) is a mammalian integral membrane enzyme that degrades the fatty acid amide family of endogenous signaling lipids, which includes the endogenous cannabinoid anandamide and the sleep-inducing substance oleamide [3].
  • Investigations into the structure and function of FAAH, in combination with complementary studies of other AS enzymes, have engendered provocative molecular models to explain how this enzyme integrates into cell membranes and terminates fatty acid amide signaling in vivo [3].
  • Interestingly, however, FAAH-NS mice still exhibited an antiinflammatory phenotype similar in magnitude to FAAH(-/-) mice, indicating that this activity, which was not blocked by cannabinoid receptor antagonists, was mediated by peripherally elevated FAAs [4].
  • LPS similarly induces AEA, but not 2-AG, in mouse peritoneal macrophages where basal AEA levels are higher, and the LPS-stimulated increase in AEA is potentiated in cells from FAAH-/- as compared with FAAH+/+ mice [1].
  • Carbamate inhibitors of FAAH display analgesic and anxiolytic properties in rodents [5].

Biological context of Fa2h

  • This anatomically restricted biochemical phenotype correlated with a reversion of the reduced pain sensitivity of FAAH(-/-) mice, consistent with the FAA anandamide producing this effect by acting on cannabinoid receptors in the nervous system [4].
  • Here, we provide biochemical evidence that carbamates covalently modify the active site of FAAH by adopting an orientation opposite of that originally predicted from modeling [5].
  • Accordingly, AEA as well as FAAH inhibitors, including arachidonoyltrifluoromethyl ketone (ATFMK), blocked [3H]2-AG hydrolysis by N18TG2 and RBL-2H3 membranes, whereas 2-AG inhibited [14C]AEA hydrolysis [6].
  • The changes in free 2-hydroxy fatty acid levels coincided with fatty acid 2-hydroxylase activity and with the upregulation of FA2H expression [7].
  • In conclusion, the expression of FAAH mRNA is different in the non-pregnant and pregnant rat uterus and sex hormones up-regulate FAAH gene expression [8].

Anatomical context of Fa2h

  • Global metabolite profiling revealed high concentrations of long chain (> or = C20) saturated NATs in the central nervous system (CNS) of FAAH(-/-) mice [9].
  • These data demonstrate that Sertoli cells partake in the peripheral endocannabinoid system, and that FSH reduces the apoptotic potential of AEA by activating FAAH [10].
  • Concentrations of anandamide, prostamide E(2), and prostamide D(2) in liver, kidney, lung, and small intestine were much higher in the anandamide-treated FAAH -/- mice than those of the anandamide-treated control mice [11].
  • In this report, we test the hypothesis that FA2H is the major fatty acid 2-hydroxylase in mouse brain and that free 2-hydroxy fatty acids are formed as precursors of myelin 2-hydroxy galactolipids [7].
  • The activities of FAAH in the paws and spinal cords of the inflamed vehicle-treated mice were significantly lower than the corresponding activities in the noninflamed mice [12].

Associations of Fa2h with chemical compounds

  • Structure-based design of a FAAH variant that discriminates between the N-acyl ethanolamine and taurine families of signaling lipids [13].
  • FAAH blockade by ATFMK preserved from inactivation the 2-AG synthesized de novo by intact N18TG2 cells stimulated with ionomycin [6].
  • Most of the physiological substrates of FAAH characterized to date belong to the N-acyl ethanolamine (NAE) class of fatty acid amides, including the endocannabinoid anandamide, the anti-inflammatory lipid N-palmitoyl ethanolamine, and the satiating factor N-oleoyl ethanolamine [9].
  • Ethanol intake and preference were increased only in female FAAH(-/-) mice [14].
  • Thiopental, however, is a noncompetitive inhibitor of FAAH at a concentration of 2 mM [15].

Analytical, diagnostic and therapeutic context of Fa2h


  1. Lipopolysaccharide induces anandamide synthesis in macrophages via CD14/MAPK/phosphoinositide 3-kinase/NF-kappaB independently of platelet-activating factor. Liu, J., Batkai, S., Pacher, P., Harvey-White, J., Wagner, J.A., Cravatt, B.F., Gao, B., Kunos, G. J. Biol. Chem. (2003) [Pubmed]
  2. Assessment of anandamide's pharmacological effects in mice deficient of both fatty acid amide hydrolase and cannabinoid CB(1) receptors. Wise, L.E., Shelton, C.C., Cravatt, B.F., Martin, B.R., Lichtman, A.H. Eur. J. Pharmacol. (2007) [Pubmed]
  3. Structure and function of fatty acid amide hydrolase. McKinney, M.K., Cravatt, B.F. Annu. Rev. Biochem. (2005) [Pubmed]
  4. Functional disassociation of the central and peripheral fatty acid amide signaling systems. Cravatt, B.F., Saghatelian, A., Hawkins, E.G., Clement, A.B., Bracey, M.H., Lichtman, A.H. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  5. Mechanism of carbamate inactivation of FAAH: implications for the design of covalent inhibitors and in vivo functional probes for enzymes. Alexander, J.P., Cravatt, B.F. Chem. Biol. (2005) [Pubmed]
  6. The novel endogenous cannabinoid 2-arachidonoylglycerol is inactivated by neuronal- and basophil-like cells: connections with anandamide. Di Marzo, V., Bisogno, T., Sugiura, T., Melck, D., De Petrocellis, L. Biochem. J. (1998) [Pubmed]
  7. FA2H-dependent fatty acid 2-hydroxylation in postnatal mouse brain. Alderson, N.L., Maldonado, E.N., Kern, M.J., Bhat, N.R., Hama, H. J. Lipid Res. (2006) [Pubmed]
  8. Expression and regulation of the fatty acid amide hydrolase gene in the rat uterus during the estrous cycle and peri-implantation period. Xiao, A.Z., Zhao, Y.G., Duan, E.K. Mol. Hum. Reprod. (2002) [Pubmed]
  9. A FAAH-regulated class of N-acyl taurines that activates TRP ion channels. Saghatelian, A., McKinney, M.K., Bandell, M., Patapoutian, A., Cravatt, B.F. Biochemistry (2006) [Pubmed]
  10. Anandamide activity and degradation are regulated by early postnatal aging and follicle-stimulating hormone in mouse Sertoli cells. Maccarrone, M., Cecconi, S., Rossi, G., Battista, N., Pauselli, R., Finazzi-Agrò, A. Endocrinology (2003) [Pubmed]
  11. Formation of prostamides from anandamide in FAAH knockout mice analyzed by HPLC with tandem mass spectrometry. Weber, A., Ni, J., Ling, K.H., Acheampong, A., Tang-Liu, D.D., Burk, R., Cravatt, B.F., Woodward, D. J. Lipid Res. (2004) [Pubmed]
  12. Inhibitors of fatty acid amide hydrolase reduce carrageenan-induced hind paw inflammation in pentobarbital-treated mice: comparison with indomethacin and possible involvement of cannabinoid receptors. Holt, S., Comelli, F., Costa, B., Fowler, C.J. Br. J. Pharmacol. (2005) [Pubmed]
  13. Structure-based design of a FAAH variant that discriminates between the N-acyl ethanolamine and taurine families of signaling lipids. McKinney, M.K., Cravatt, B.F. Biochemistry (2006) [Pubmed]
  14. Increased ethanol consumption and preference and decreased ethanol sensitivity in female FAAH knockout mice. Basavarajappa, B.S., Yalamanchili, R., Cravatt, B.F., Cooper, T.B., Hungund, B.L. Neuropharmacology (2006) [Pubmed]
  15. The general anesthetic propofol increases brain N-arachidonylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase. Patel, S., Wohlfeil, E.R., Rademacher, D.J., Carrier, E.J., Perry, L.J., Kundu, A., Falck, J.R., Nithipatikom, K., Campbell, W.B., Hillard, C.J. Br. J. Pharmacol. (2003) [Pubmed]
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