N-acylethanolamine Acid Amidase (NAAA): Structure, Functions and Inhibition.

N-Acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase primarily found in the endosomal-lysosomal compartment of innate and adaptive immune cells. NAAA catalyzes the hydrolytic deactivation of palmitoylethanolamide (PEA), a lipid-derived peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist that exerts profound anti-inflammatory effects in animal models. Emerging evidence points to NAAA-regulated PEA signaling at PPAR-alpha as a critical control point for the induction and the resolution of inflammation, and to NAAA itself as a target for anti-inflammatory medicines. The present perspective discusses three key aspects of this hypothesis: the role of NAAA in controlling the signaling activity of PEA; the structural bases for NAAA function and inhibition by covalent and non-covalent agents; and, finally, the potential value of NAAA-targeting drugs in the treatment of human inflammatory disorders.