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Fatty acid amide hydrolase

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Target not currently curated in GtoImmuPdb

Target id: 1400

Nomenclature: Fatty acid amide hydrolase

Abbreviated Name: FAAH

Family: Hydrolases, N-Acylethanolamine turnover

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 579 1p34-p35 FAAH fatty acid amide hydrolase 6,19
Mouse 1 579 4 D1 Faah fatty acid amide hydrolase 6
Rat 1 579 5q36 Faah fatty acid amide hydrolase
Previous and Unofficial Names Click here for help
FAAH1 | Oleamide hydrolase, anandamide hydrolase | anandamide amidohydrolase 1
Database Links Click here for help
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
UniProtKB
Wikipedia
Enzyme Reaction Click here for help
EC Number: 3.5.1.99 anandamide + H2O <=> arachidonic acid + ethanolamine
oleamide + H2O <=> oleic acid + NH3
Description Reaction Reference
The enzyme is responsible for the catabolism of neuromodulatory fatty acid amides, including anandamide and oleamide anandamide + H2O <=> arachidonic acid + ethanolamine
oleamide + H2O <=> oleic acid + NH3
Rank order of affinity (Human)
anandamide > oleamide > N-oleoylethanolamide > N-palmitoylethanolamine  [21]

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
dual sEH/FAAH inhibitor 11 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.4 pKi 14
pKi 7.4 (Ki 3.7x10-8 M) [14]
JNJ40355003 Small molecule or natural product Primary target of this compound Hs Inhibition 8.9 pIC50 9
pIC50 8.9 (IC50 1.4x10-9 M) [9]
JZL195 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.7 pIC50 15
pIC50 8.7 (IC50 2x10-9 M) [15]
Description: in vitro assay
PF-04457845 Small molecule or natural product Hs Inhibition 8.0 – 9.0 pIC50 8,18
pIC50 8.0 – 9.0 (IC50 1x10-8 – 1x10-9 M) [8,18]
Description: Inhibition of human FAAH in vitro.
ASP8477 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.4 pIC50 20
pIC50 8.4 (IC50 3.99x10-9 M) [20]
compound 19y [Kiss et al., 2011] Small molecule or natural product Rn Inhibition 8.2 pIC50 13
pIC50 8.2 (IC50 6x10-9 M) [13]
Description: Measured in rat brain homogenate.
dual sEH/FAAH inhibitor 11 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.1 pIC50 7
pIC50 8.1 (IC50 8x10-9 M) [7]
(S)-ARN2508 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 16
pIC50 8.0 (IC50 9.4x10-9 M) [16]
(R)-ARN2508 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 16
pIC50 8.0 (IC50 9.9x10-9 M) [16]
JNJ1661010 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.8 pIC50 10
pIC50 7.8 (IC50 1.58x10-8 M) [10]
JNJ40355003 Small molecule or natural product Rn Inhibition 7.5 pIC50 9
pIC50 7.5 (IC50 3.3x10-8 M) [9]
example 13 [WO2009109743] Small molecule or natural product Hs Inhibition 7.4 pIC50 17
pIC50 7.4 (IC50 3.8x10-8 M) [17]
OL135 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.4 pIC50 21
pIC50 7.4 (IC50 3.98x10-8 M) [21]
PF750 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.3 – 8.2 pIC50 1,14
pIC50 8.2 (IC50 6.4x10-9 M) [14]
Description: Following a 5 min preincubation with inhibitor.
pIC50 6.3 – 7.8 (IC50 5.01x10-7 – 1.58x10-8 M) [1]
BIA 10-2474 Small molecule or natural product Hs Inhibition 7.2 – 7.3 pIC50 18
pIC50 7.2 – 7.3 (IC50 7x10-8 – 5x10-8 M) [18]
Description: Inhibition of human FAAH expressed in HEK293T cells.
BIA 10-2639 Small molecule or natural product Hs Inhibition 7.2 – 7.3 pIC50 18
pIC50 7.2 – 7.3 (IC50 7x10-8 – 5x10-8 M) [18]
Description: In situ inhibition in HEK3293T cells expressing human FAAH.
JNJ-42165279 Small molecule or natural product Primary target of this compound Hs Inhibition 7.1 pIC50 11
pIC50 7.1 (IC50 7.5x10-8 M) [11]
MM-433593 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 7.0 pIC50
pIC50 7.0 (IC50 1x10-7 M)
BIA 10-2474 Small molecule or natural product Rn Inhibition ~6.7 pIC50 12
pIC50 ~6.7 (IC50 ~2x10-7 M) [12]
Description: This value is an extrapolated estimate from % inhibition data provided in Table 1 of the referenced patent.
URB597 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.3 – 7.0 pIC50 21
pIC50 6.3 – 7.0 (IC50 5.01x10-7 – 1x10-7 M) [21]
PF3845 Small molecule or natural product Hs Inhibition 6.6 pIC50 2
pIC50 6.6 (IC50 2.51x10-7 M) [2]
dual sEH/FAAH inhibitor 11 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Rn Inhibition 6.5 pIC50 14
pIC50 6.5 (IC50 3x10-7 M) [14]
Description: Following a 60 min preincubation with inhibitor.
JNJ-42165279 Small molecule or natural product Rn Inhibition 6.5 pIC50 11
pIC50 6.5 (IC50 3.2x10-7 M) [11]
dual sEH/FAAH inhibitor 11 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Mm Inhibition 5.8 pIC50 14
pIC50 5.8 (IC50 1.4x10-6 M) [14]
View species-specific inhibitor tables
Physiological Functions Click here for help
FAAH regulates anandamide signaling in vivo, setting an endogenous cannabinoid tone that modulates pain perception.
Species:  Mouse
Tissue: 
References:  5
Physiological Consequences of Altering Gene Expression Click here for help
FAAH-null mice manifest an impaired ability to degrade anandamide, leading to elevated brain anandamide levels and show reduced pain sensation. Treating these animals with a CB1 receptor antagonist (SR141716A) can reverse these effects.
Species:  Mouse
Tissue:  Brain and in vivo.
Technique:  Gene knockout
References:  5
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Polysubstance abuse, susceptibility to; PSAB
OMIM: 606581
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human Pro129Thr C>A This missense mutation has been associated with a propensity to drug abuse or alcoholism and pain insensitivity. 3-4
Biologically Significant Variants Click here for help
Type:  Missense mutation
Species:  Human
Description:  FAAH polymorphism associated with some substance use disorders and pain tolerance.
Amino acid change:  Pro129Thr
Nucleotide change:  C>A
Global MAF (%):  26
SNP accession: 
Validation:  1000 Genomes
References:  3-4
General Comments
FAAH is the molecular target of the investigational drug BIA 10-274, which caused serious, and in one case fatal, effects in volunteers in a Phase I clinical trial in France in January 2016.

References

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1. Ahn K, Johnson DS, Fitzgerald LR, Liimatta M, Arendse A, Stevenson T, Lund ET, Nugent RA, Nomanbhoy TK, Alexander JP et al.. (2007) Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity. Biochemistry, 46 (45): 13019-30. [PMID:17949010]

2. Ahn K, Johnson DS, Mileni M, Beidler D, Long JZ, McKinney MK, Weerapana E, Sadagopan N, Liimatta M, Smith SE et al.. (2009) Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain. Chem. Biol., 16 (4): 411-20. [PMID:19389627]

3. Bühler KM, Huertas E, Echeverry-Alzate V, Giné E, Moltó E, Montoliu L, López-Moreno JA. (2014) Risky alcohol consumption in young people is associated with the fatty acid amide hydrolase gene polymorphism C385A and affective rating of drug pictures. Mol. Genet. Genomics, 289 (3): 279-89. [PMID:24407958]

4. Cajanus K, Holmström EJ, Wessman M, Anttila V, Kaunisto MA, Kalso E. (2016) Effect of endocannabinoid degradation on pain: role of FAAH polymorphisms in experimental and postoperative pain in women treated for breast cancer. Pain, 157 (2): 361-9. [PMID:26808012]

5. Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH. (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc. Natl. Acad. Sci. U.S.A., 98 (16): 9371-6. [PMID:11470906]

6. Giang DK, Cravatt BF. (1997) Molecular characterization of human and mouse fatty acid amide hydrolases. Proc. Natl. Acad. Sci. U.S.A., 94 (6): 2238-42. [PMID:9122178]

7. Hammock B, Kodani S. (2017) Inhibitors for soluble epoxide hydrolase (seh) and fatty acid amide hydrolase (faah). Patent number: WO2017160861A1. Assignee: The Regents Of The University Of California. Priority date: 15/03/2016. Publication date: 21/09/2017.

8. Johnson DS, Stiff C, Lazerwith SE, Kesten SR, Fay LK, Morris M, Beidler D, Liimatta MB, Smith SE, Dudley DT et al.. (2011) Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor. ACS Med Chem Lett, 2 (2): 91-96. [PMID:21666860]

9. Keith JM, Apodaca R, Tichenor M, Xiao W, Jones W, Pierce J, Seierstad M, Palmer J, Webb M, Karbarz M et al.. (2012) Aryl Piperazinyl Ureas as Inhibitors of Fatty Acid Amide Hydrolase (FAAH) in Rat, Dog, and Primate. ACS Med Chem Lett, 3 (10): 823-7. [PMID:24900385]

10. Keith JM, Apodaca R, Xiao W, Seierstad M, Pattabiraman K, Wu J, Webb M, Karbarz MJ, Brown S, Wilson S et al.. (2008) Thiadiazolopiperazinyl ureas as inhibitors of fatty acid amide hydrolase. Bioorg. Med. Chem. Lett., 18 (17): 4838-43. [PMID:18693015]

11. Keith JM, Liu J. (2011) Modulators of fatty acid amide hydrolase. Patent number: WO2011139951 A1. Assignee: Janssen Pharmaceutica Nv. Priority date: 03/05/2010. Publication date: 10/11/2011.

12. Kiss LE et al.. (2010) Pharmaceutical compounds. Patent number: WO2010074588 A2. Assignee: BIAL- PORTELA & Cª, S.A. Priority date: 24/12/2008. Publication date: 01/07/2010.

13. Kiss LE, Ferreira HS, Beliaev A, Torrao L, Bonafacio MJ Learmonth DA. (2011) Design, synthesis, and structure–activity relationships of 1,3,4-oxadiazol-2(3H)-ones as novel FAAH inhibitors. Medchemcomm., 2: 889-894.

14. Kodani SD, Wan D, Wagner KM, Hwang SH, Morisseau C, Hammock BD. (2018) Design and Potency of Dual Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase Inhibitors. ACS Omega, 3 (10): 14076-14086. DOI: 10.1021/acsomega.8b01625 [PMID:30411058]

15. Long JZ, Nomura DK, Vann RE, Walentiny DM, Booker L, Jin X, Burston JJ, Sim-Selley LJ, Lichtman AH, Wiley JL et al.. (2009) Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo. Proc. Natl. Acad. Sci. U.S.A., 106 (48): 20270-5. [PMID:19918051]

16. Migliore M, Habrant D, Sasso O, Albani C, Bertozzi SM, Armirotti A, Piomelli D, Scarpelli R. (2016) Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies. Eur J Med Chem, 109: 216-37. [PMID:26774927]

17. Roughley S, Walls S, Hart T, Parsons R, Brough P, Graham C, Macias A. (2009) Azetidine derivatives. Patent number: WO2009109743 A1. Assignee: Vernalis (R&D) Ltd.. Priority date: 04/03/2008. Publication date: 11/09/2009.

18. van Esbroeck ACM, Janssen APA, Cognetta 3rd AB, Ogasawara D, Shpak G, van der Kroeg M, Kantae V, Baggelaar MP, de Vrij FMS, Deng H et al.. (2017) Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474. Science, 356 (6342): 1084-1087. [PMID:28596366]

19. Wan M, Cravatt BF, Ring HZ, Zhang X, Francke U. (1998) Conserved chromosomal location and genomic structure of human and mouse fatty-acid amide hydrolase genes and evaluation of clasper as a candidate neurological mutation. Genomics, 54 (3): 408-14. [PMID:9878243]

20. Watabiki T, Tsuji N, Kiso T, Ozawa T, Narazaki F, Kakimoto S. (2017) In vitro and in vivo pharmacological characterization of ASP8477: A novel highly selective fatty acid amide hydrolase inhibitor. Eur. J. Pharmacol., 815: 42-48. [PMID:29017758]

21. Wei BQ, Mikkelsen TS, McKinney MK, Lander ES, Cravatt BF. (2006) A second fatty acid amide hydrolase with variable distribution among placental mammals. J. Biol. Chem., 281 (48): 36569-78. [PMID:17015445]

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