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N-Acylethanolamine acid amidase

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Immunopharmacology Ligand  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 Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 359 4q21.1 NAAA N-acylethanolamine acid amidase
Mouse - 362 5 E2 Naaa N-acylethanolamine acid amidase
Rat - 362 14p22 Naaa N-acylethanolamine acid amidase
Previous and Unofficial Names Click here for help
Acid ceramidase-like protein | N-palmitoylethanolamine acid amidase | ASAH-like protein | N-acylethanolamine-hydrolyzing acid amidase
Database Links Click here for help
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
Selected 3D Structures Click here for help
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 Click here for help
EC Number: 3.5.1.-
Rank order of affinity (Human)
N-palmitoylethanolamine > MEA > SEAN-oleoylethanolamide > anandamide  [10]

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Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
F215 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 8.1 pIC50 2-3
pIC50 8.1 (IC50 9x10-9 M) [2-3]
ARN726 Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Irreversible inhibition 7.6 pIC50 8
pIC50 7.6 (IC50 2.7x10-8 M) [8]
ARN726 Small molecule or natural product Immunopharmacology Ligand Rn Irreversible inhibition 7.2 pIC50 8
pIC50 7.2 (IC50 6.3x10-8 M) [8]
ARN19702 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand 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 USA, 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, 63 (14): 7475-7490. [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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