<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

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
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
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
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  [10]

Download all structure-activity data for this target as a CSV file

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 8
pIC50 7.6 (IC50 2.7x10-8 M) [8]
ARN726 Rn Irreversible inhibition 7.2 pIC50 8
pIC50 7.2 (IC50 6.3x10-8 M) [8]
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 [7]. It is located intracellularly in lysosomes of innate and adaptive immune cells, 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). PEA, as an agonist of peroxisome proliferator-activated receptor-α (PPARα), mediates a pro-inflammatory effect. Hydrolytic deactivation of PEA by NAAA reduces this PEA-PPARα activity. NAAA's function is in contrast to that of fatty acid amide hydrolase (FAAH) which preferentially degrades long-chain polyunsaturated N-acylethanolamine substrates, including anandamide.
Pharmacological 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 [3-7,9].


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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. Piomelli D, Scalvini L, Fotio Y, Lodola A, Spadoni G, Tarzia G, Mor M. (2020) N-Acylethanolamine Acid Amidase (NAAA): Structure, Function, and Inhibition. J. Med. Chem., [Epub ahead of print]. [PMID:32191459]

8. 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]

9. 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]

10. 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]


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