<i>N</i>-Acylethanolamine acid amidase | <i>N</i>-Acylethanolamine turnover | IUPHAR/BPS Guide to PHARMACOLOGY

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N-Acylethanolamine acid amidase

target has curated data in GtoImmuPdb

Target id: 1402

Nomenclature: N-Acylethanolamine acid amidase

Abbreviated Name: NAAA

Family: N-Acylethanolamine turnover

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - - NAAA N-acylethanolamine acid amidase
Mouse - - Naaa N-acylethanolamine acid amidase
Rat - - Naaa N-acylethanolamine acid amidase
Previous and Unofficial Names
Acid ceramidase-like protein | N-palmitoylethanolamine acid amidase | ASAH-like protein | N-acylethanolamine-hydrolyzing acid amidase
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Human N-acylethanolamine-hydrolyzing acid amidase (NAAA) precursor (C126A)- reveals the molecular mechanism of activation of the immunoregulatory amidase NAAA
PDB Id:  6DXW
Resolution:  2.3Å
Species:  Human
References:  1
Enzyme Reaction
EC Number: 3.5.1.-
Rank order of affinity (Human)
N-palmitoylethanolamine > MEA > SEAN-oleoylethanolamide > anandamide  [9]

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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
F215 Hs Inhibition 8.1 pIC50 2-3
pIC50 8.1 (IC50 9x10-9 M) [2-3]
ARN726 Hs Irreversible inhibition 7.6 pIC50 7
pIC50 7.6 (IC50 2.7x10-8 M) [7]
ARN726 Rn Irreversible inhibition 7.2 pIC50 7
pIC50 7.2 (IC50 6.3x10-8 M) [7]
ARN19702 Hs Inhibition 6.6 pIC50 4
pIC50 6.6 (IC50 2.3x10-7 M) [4]
Description: Fluorogenic enzyme assay using hNAAA extracted from stably transfected HEK293 cells.
View species-specific inhibitor tables
Immunopharmacology Comments
NAAA is involved in the metabolism of fatty acid ethanolamides and endocannabinoids, which are endogenous ligands known to alleviate pain and inflammation. It is located intracellularly in lysosomes, where it is activated at acidic pH. The molecular mechanism underlying activation of NAAA was revealed by X-ray crystallography [1]. NAAA catalyses the hydrolysis of short unsaturated N-acylethanolamines such as palmitoylethanolamide (PEA). This is in contrast to fatty acid amide hydrolase (FAAH) which preferentially degrades long-chain polyunsaturated N-acylethanolamine substrates, including anandamide.
Pharmacologocal inhibition of NAAA, which induces an increase in fatty acid ethanolamides and endocannabinoids, is a therapeutic approach that is being investigated to enhance the antinociceptive and anti-inflammatory effects of these endogenous modulators [3-6,8].

References

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1. Gorelik A, Gebai A, Illes K, Piomelli D, Nagar B. (2018) Molecular mechanism of activation of the immunoregulatory amidase NAAA. Proc. Natl. Acad. Sci. U.S.A., 115 (43): E10032-E10040. [PMID:30301806]

2. Li Y, Chen Q, Yang L, Li Y, Zhang Y, Qiu Y, Ren J, Lu C. (2017) Identification of highly potent N-acylethanolamine acid amidase (NAAA) inhibitors: Optimization of the terminal phenyl moiety of oxazolidone derivatives. Eur J Med Chem, 139: 214-221. [PMID:28802121]

3. Li Y, Zhou P, Chen H, Chen Q, Kuang X, Lu C, Ren J, Qiu Y. (2018) Inflammation-restricted anti-inflammatory activities of a N-acylethanolamine acid amidase (NAAA) inhibitor F215. Pharmacol. Res., 132: 7-14. [PMID:29572189]

4. Migliore M, Pontis S, Fuentes de Arriba AL, Realini N, Torrente E, Armirotti A, Romeo E, Di Martino S, Russo D, Pizzirani D et al.. (2016) Second-Generation Non-Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis. Angew. Chem. Int. Ed. Engl., 55 (37): 11193-7. [PMID:27404798]

5. Nuzzi A, Fiasella A, Ortega JA, Pagliuca C, Ponzano S, Pizzirani D, Bertozzi SM, Ottonello G, Tarozzo G, Reggiani A et al.. (2016) Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure-activity relationship (SAR) studies. Eur J Med Chem, 111: 138-59. [PMID:26866968]

6. Petrosino S, Campolo M, Impellizzeri D, Paterniti I, Allarà M, Gugliandolo E, D'Amico R, Siracusa R, Cordaro M, Esposito E et al.. (2017) 2-Pentadecyl-2-Oxazoline, the Oxazoline of Pea, Modulates Carrageenan-Induced Acute Inflammation. Front Pharmacol, 8: 308. [PMID:28611664]

7. Ribeiro A, Pontis S, Mengatto L, Armirotti A, Chiurchiù V, Capurro V, Fiasella A, Nuzzi A, Romeo E, Moreno-Sanz G et al.. (2015) A Potent Systemically Active N-Acylethanolamine Acid Amidase Inhibitor that Suppresses Inflammation and Human Macrophage Activation. ACS Chem. Biol., 10 (8): 1838-46. [PMID:25874594]

8. Tuo W, Leleu-Chavain N, Spencer J, Sansook S, Millet R, Chavatte P. (2017) Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors. J. Med. Chem., 60 (1): 4-46. [PMID:27766867]

9. Ueda N, Yamanaka K, Yamamoto S. (2001) Purification and characterization of an acid amidase selective for N-palmitoylethanolamine, a putative endogenous anti-inflammatory substance. J. Biol. Chem., 276 (38): 35552-7. [PMID:11463796]

Contributors

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