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Fatty acid amide hydrolase-2

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Target id: 1401

Nomenclature: Fatty acid amide hydrolase-2

Abbreviated Name: FAAH2

Family: N-Acylethanolamine turnover

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 532 Xp11.21 FAAH2 fatty acid amide hydrolase 2 5
Previous and Unofficial Names Click here for help
AMDD | FAAH-2
Database Links Click here for help
Alphafold Q6GMR7 (Hs)
BRENDA 3.5.1.99
CATH/Gene3D 3.90.1300.10
ChEMBL Target CHEMBL1628475 (Hs)
Ensembl Gene ENSG00000165591 (Hs)
Entrez Gene 158584 (Hs)
Human Protein Atlas ENSG00000165591 (Hs)
KEGG Enzyme 3.5.1.99
KEGG Gene hsa:158584 (Hs)
OMIM 300654 (Hs)
Pharos Q6GMR7 (Hs)
UniProtKB Q6GMR7 (Hs)
Wikipedia FAAH2 (Hs)
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)
oleamide > N-oleoylethanolamide > anandamide > N-palmitoylethanolamine  [5]

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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
LY2077855 Small molecule or natural product Hs Inhibition 8.5 pIC50 1
⤷ pIC50 8.5 (IC50 3x10-9 M) [1]
OL135 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.9 – 8.4 pIC50 1,5
⤷ pIC50 7.9 – 8.4 (IC50 1.26x10-8 – 4x10-9 M) [1,5]
URB597 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.5 – 8.3 pIC50 1,5
⤷ pIC50 7.5 – 8.3 (IC50 3.16x10-8 – 5.01x10-9 M) [1,5]
ASP8477 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.2 pIC50 4
⤷ pIC50 7.2 (IC50 5.73x10-8 M) [4]
JNJ1661010 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.2 pIC50 1
⤷ pIC50 5.2 (IC50 5.7x10-6 M) [1]
Description: 20 min preincubation
Clinically-Relevant Mutations and Pathophysiology Click here for help
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Type Species Amino acid change Nucleotide change Description Reference
Missense Human Ala458Ser 1372 G>T This mutation causes partial inactivation of FAAH2 in vitro. 3
Clinically-Relevant Mutations and Pathophysiology Comments
The missense mutation Ala458Ser was identified in a male with autistic features identified in early development, accompanied by later developing features including anxiety, pseudoseizures, ataxia, supranuclear gaze palsy, and isolated learning disabilities [3]. The authors propose that compromised FAAH2 activity and altered endocannabinoid signaling underlies the patent's phenotype.
General Comments
FAAH and FAAH2 show distinct but overlapping tissue expression patterns [5]. The absence of FAAH2 in mice and rats should be considered when extrapolating experimental findings in the endocannabinoid pathway across species.
Genome wide association studies (GWAS) have identified FAAH2 as a possible candidate gene for X-linked intellectual disability [6] and autism spectrum disorders [2].

References

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1. Karbarz MJ, Luo L, Chang L, Tham CS, Palmer JA, Wilson SJ, Wennerholm ML, Brown SM, Scott BP, Apodaca RL et al.. (2009) Biochemical and biological properties of 4-(3-phenyl-[1,2,4] thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide, a mechanism-based inhibitor of fatty acid amide hydrolase. Anesth Analg, 108 (1): 316-29. [PMID:19095868]

2. Lim ET, Raychaudhuri S, Sanders SJ, Stevens C, Sabo A, MacArthur DG, Neale BM, Kirby A, Ruderfer DM, Fromer M et al.. (2013) Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders. Neuron, 77 (2): 235-42. [PMID:23352160]

3. Sirrs S, van Karnebeek CD, Peng X, Shyr C, Tarailo-Graovac M, Mandal R, Testa D, Dubin D, Carbonetti G, Glynn SE et al.. (2015) Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms. Orphanet J Rare Dis, 10: 38. [PMID:25885783]

4. 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]

5. 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]

6. Whibley AC, Plagnol V, Tarpey PS, Abidi F, Fullston T, Choma MK, Boucher CA, Shepherd L, Willatt L, Parkin G et al.. (2010) Fine-scale survey of X chromosome copy number variants and indels underlying intellectual disability. Am J Hum Genet, 87 (2): 173-88. [PMID:20655035]

Contributors

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