Fatty acid amide hydrolase

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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.[11] 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.[12][13][14]

A mutation in FAAH was initially provisionally linked to drug abuse and dependence but this was not borne out in subsequent studies.[15]

Studies in cells and animals and genetic studies in humans have shown that inhibiting FAAH may be a useful strategy to treat anxiety disorders.[15][16][17]

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.[18][19][20][21][22][23][24][25]

Some of the more significant compounds are listed below;

Inhibition and binding

Structural and conformational properties that contribute to enzyme inhibition and substrate binding imply an extended bound conformation, and a role for the presence, position, and stereochemistry of a delta cis double bond.[41]

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.[42][43]

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.[44]

See also

References

  1. 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.
  2. 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.
  3. 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 20071. PMID 9122178.
  4. 4.0 4.1 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.
  5. 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.
  6. 6.0 6.1 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 55427. PMID 11470906.
  7. "The fatty acid amide hydrolase (FAAH)". Chemistry and Physics of Lipids. 108 (1–2): 107–121. 2000-11-01. doi:10.1016/S0009-3084(00)00190-0. ISSN 0009-3084.
  8. 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.
  9. 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.
  10. 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.
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  15. 15.0 15.1 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 3662489. PMID 23333350.
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  19. 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 2882713. PMID 20544003.
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  44. 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 2529035. PMID 18753625.

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