Fatty acid amide hydrolase

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Fatty acid amide hydrolase
Fatty acid amide hydrolase
Mass / length primary structure 63066 Da , 579 amino acids
Secondary to quaternary structure Homodimer
Identifier
External IDs
Enzyme Classifications
EC, category 3.5.1.99 ,  hydrolase
Response type hydrolysis
Substrate Anandamide + H 2 O
Products Arachidonic acid + ethanolamine
EC, category 3.5.1.99 ,  hydrolase
Response type hydrolysis
Substrate Oleamide + H 2 O
Products Oleic acid + NH 3
Orthologue
human House mouse
Entrez 2166 14073
Ensemble ENSG00000117480 ENSMUSG00000034171
UniProt O00519 O08914
Refseq (mRNA) NM_001441 NM_010173.4
Refseq (protein) NP_001432 NP_034303.3
Gene locus Chr 1: 46.39 - 46.41 Mb Chr 4: 115.99 - 116.02 Mb
PubMed search 2166 14073

The fatty acid amide hydrolase ( FAAH , synonym: oleamide hydrolase , anandamide amidohydrolase ) is an enzyme from lipid metabolism and is involved in the endocannabinoid system .

properties

The fatty acid amide hydrolase is a serine hydrolase and a transmembrane protein . It was first described in 1993 as an anandamide- degrading enzyme. The fatty acid amide hydrolase hydrolyzes various fatty acid amides. For example, anandamide ( N -arachidonylethanolamine) 1 is split into arachidonic acid 2 and ethanolamine by the action of water and FAAH :

Hydrolysis of anandamide by FAAH

The hydrolysis reaction takes place as a catalyzed equilibrium reaction . In the same way, N- acylethanolamines such as N- oleoylethanolamine, N -palmitoylethanolamine, N- acyl- taurine or oleic acid amide can be cleaved hydrolytically. The hydrolysis of oleic acid amide 3 leads, for example, to the formation of oleic acid 4 and ammonia .

Hydrolysis of oleic acid amide by FAAH

FAAH has a esterase - and amidase - enzyme activity . It is increasingly formed in the pancreas , the brain , the kidneys , the skeletal muscles and the placenta . In contrast to rats and mice, the human organism does not have the isoform of the enzyme (FAAH2). When stressed, the FAAH in the amygdala is activated, which lowers the concentration of anandamide. Therefore, the FAAH is involved in the regulation of anxiety , among other things . Inhibition of the FAAH is being studied as a treatment for anxiety. Furthermore, an inhibition of the FAAH in chronic inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) is being investigated. The inhibition of the FAAH is also being investigated for the treatment of tumor diseases .

Inhibitors

Various inhibitors for fatty acid amide hydrolase have been developed, e.g. B. URB597 (KDS-4103), LY-2183240 , PF-622 and PF-750 , MK-4409 , and 4-nonylphenylboronic acid .

The active ingredient BIA 10-2474 (from Bial-Portela & Ca. SA, Portugal ) resulted in a phase I clinical study in January 2016 in adverse drug reactions in which one test person died. This drug effect had not previously been seen with other FAAH inhibitors. In 2012, for example, Pfizer discontinued development of the FAAH inhibitor PF-04457845 due to ineffectiveness in a phase 2 study. Before that, however, there had been no negative reactions. In addition to this published study for the indication of pain caused by arthritis of the knee, the information page of the National Institutes of Health (NIH) lists three further studies with PF-04457845 in January 2016, one of which has been completed, the other two are still Recruit Volunteers. Indications are Tourette's syndrome and the treatment of cannabis withdrawal . Continue to have Vernalis and Sanofi developed FAAH inhibitors. Vernalis has completed a phase 1 and a phase 2 study with the FAAH inhibitor V158866. Sanofi has completed a phase 2 study with the FAAH inhibitor SSR411298 and canceled another. Even Abbott Laboratories , Amgen and Renovis have non-covalent FAAH inhibitors developed. URB597 (KDS-4103) from Kandus Pharmaceuticals is also being discussed as a promising selective FAAH inhibitor .

Individual evidence

  1. ↑ DG Deutsch, SA Chin: Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. In: Biochemical pharmacology. Volume 46, Number 5, September 1993, pp. 791-796, PMID 8373432 .
  2. ↑ BF Cravatt, K. Demarest, MP Patricelli, MH Bracey, DK Giang, BR Martin, AH Lichtman: Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. In: Proceedings of the National Academy of Sciences . Volume 98, Number 16, July 2001, pp. 9371-9376, doi: 10.1073 / pnas.161191698 , PMID 11470906 , PMC 55427 (free full text).
  3. ^ MG Cascio, P. Marini: Biosynthesis and Fate of Endocannabinoids. In: Handbook of experimental pharmacology. Volume 231, 2015, pp. 39-58, doi : 10.1007 / 978-3-319-20825-1_2 , PMID 26408157 .
  4. ↑ D. Piomelli: More surprises lying ahead. The endocannabinoids keep us guessing. In: Neuropharmacology. Volume 76 Pt B, January 2014, pp. 228-234, doi: 10.1016 / j.neuropharm.2013.07.026 , PMID 23954677 , PMC 3855347 (free full text).
  5. ↑ A. Saghatelian, SA Trauger, EJ Want, EC Hawkins, G. Siuzdak, BF Cravatt: Assignment of endogenous substrate to enzymes by global metabolite profiling. In: Biochemistry. Volume 43, Number 45, November 2004, pp. 14332-14339, doi: 10.1021 / bi0480335 , PMID 15533037 .
  6. ↑ A. Saghatelian, MK McKinney, M. Bandell, A. Patapoutian , BF Cravatt: A FAAH-regulated class of N-acyl taurines did the activates TRP ion channels. In: Biochemistry. Volume 45, Number 30, August 2006, pp. 9007-9015, doi: 10.1021 / bi0608008 , PMID 16866345 .
  7. ^ BF Cravatt, O. Prospero-Garcia, G. Siuzdak, NB Gilula, SJ Henriksen, DL Boger, RA Lerner: Chemical characterization of a family of brain lipids that induce sleep. In: Science. Volume 268, Number 5216, June 1995, pp. 1506-1509, PMID 7770779 .
  8. ↑ MP Patricelli, BF Cravatt: Fatty acid amide hydrolase competitively degrades bioactive amides and esters through a nonconventional catalytic mechanism. In: Biochemistry. Volume 38, Number 43, October 1999, pp. 14125-14130, PMID 10571985 .
  9. ^ O. Gunduz-Cinar, MN Hill, BS McEwen, A. Holmes: Amygdala FAAH and anandamide: mediating protection and recovery from stress. In: Trends in pharmacological sciences. Volume 34, number 11, November 2013, pp. 637-644, doi: 10.1016 / j.tips.2013.08.008 , PMID 24325918 , PMC 4169112 (free full text).
  10. ^ CJ Fowler: The potential of inhibitors of endocannabinoid metabolism as anxiolytic and antidepressive drugs - A practical view. In: European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology. Volume 25, number 6, June 2015, pp. 749-762, doi: 10.1016 / j.euroneuro.2015.02.005 , PMID 25791296 .
  11. ↑ M. Sałaga, M. Sobczak, J. Fichna: Inhibition of fatty acid amide hydrolase (FAAH) as a novel therapeutic strategy in the treatment of pain and inflammatory diseases in the gastrointestinal tract. In: European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences. Volume 52, February 2014, pp. 173-179, doi: 10.1016 / j.ejps.2013.11.012 , PMID 24275607 .
  12. ↑ M. Nikan, SM Nabavi, A. Manayi: Ligands for cannabinoid receptors, promising anticancer agents. In: Life sciences. [Electronic publication before printing] January 2016, doi: 10.1016 / j.lfs.2015.12.053 , PMID 26764235 .
  13. ↑ Khanna IK, Alexander CW: Fatty acid amide hydrolase inhibitors - progress and potential . In: CNS Neurol Disord Drug Targets . 10, No. 5, 2011, pp. 545-58. doi : 10.1517 / 17460441.2013.780021 . PMID 21631410 .
  14. ↑ Bisogno T, Maccarrone M: Latest advances in the discovery of fatty acid amide hydrolase inhibitors . In: Expert Opinion on Drug Discovery . 8, No. 5, 2013, pp. 509-22. doi : 10.1517 / 17460441.2013.780021 . PMID 23488865 .
  15. ↑ JL Blankman, BF Cravatt: Chemical probes of endocannabinoid metabolism. In: Pharmacological reviews. Volume 65, number 2, April 2013, pp. 849-871, doi: 10.1124 / pr.112.006387 , PMID 23512546 , PMC 3639726 (free full text).
  16. ↑ a b Ahn K, Johnson DS, Fitzgerald LR, Liimatta M, Arendse A, Stevenson T, Lund ET, Nugent RA, Nomanbhoy TK, Alexander JP, Cravatt BF: Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity . In: Biochemistry . 46, No. 45, November 2007, pp. 13019-30. doi : 10.1021 / bi701378g . PMID 17949010 .
  17. ^ 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: Identification of a High-Affinity Binding Site Involved in the Transport of endocannabinoids . In: Proc. Natl. Acad. Sci. USA . 102, No. 49, December 2005, pp. 17852-7. doi : 10.1073 / pnas.0507470102 . PMID 16314570 . PMC 1295594 (free full text).
  18. ↑ Chobanian HR, Guo Y, Liu P, Chioda MD, Fung S, Lanza TJ, Chang L, Bakshi RK, Dellureficio JP, Hong Q, McLaughlin M, Belyk KM, Krska SW, Makarewicz AK, Martel EJ, Leone JF, Frey L, Karanam B, Madeira M, Alvaro R, Shuman J, Salituro G, Terebetski JL, Jochnowitz N, Mistry S, McGowan E, Hajdu R, Rosenbach M, Abbadie C, Alexander JP, Shiao LL, Sullivan KM, Nargund RP, Wyvratt MJ, Lin LS, DeVita RJ: Discovery of MK-4409, a Novel Oxazole FAAH Inhibitor for the Treatment of Inflammatory and Neuropathic Pain . In: ACS Medicinal Chemistry Letters . 5, No. 6, 2014, pp. 717-21. doi : 10.1021 / ml5001239 . PMID 24944750 . PMC 4060928 (free full text).
  19. ↑ Minkkilä A, Saario SM, Käsnänen H, Leppänen J, Poso A, Nevalainen T: Discovery of boronic acids as novel and potent inhibitors of fatty acid amide hydrolase . In: Journal of Medicinal Chemistry . 51, No. 22, November 2008, pp. 7057-60. doi : 10.1021 / jm801051t . PMID 18983140 .
  20. ↑ Enserink: More Details Emerge on Fateful French Drug Trial . (online) In: Science . No. January 16, 2016.
  21. ↑ JP Huggins, TS Smart, S. Langman, L. Taylor, T. Young: An efficient randomized, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee. Pain 153, No. 9, 2012, 1837-1846, PMID 22727500 .
  22. ↑ clinicaltrials.gov
  23. ↑ JM Keith: Preclinical Characterization of the FAAH Inhibitor JNJ-42165279 . In: ACS Medicinal Chemistry, Vol. 6, No. 12. 2015, pp. 1204-1208.
  24. Jump up ↑ C. Grimaldi, A. Capasso: The Endocannabinoid System in the Cancer Therapy: An Overview . In: Current Medicinal Chemistry . 18, No. 11, 2011, ISSN  0929-8673 , pp. 1575-1583. doi : 10.2174 / 092986711795471374 .