N-acylethanolamine acid amidase (NAAA)

N-acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase enzyme that primarily catalyzes the hydrolysis of saturated and monounsaturated N-acylethanolamines, such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). These substrates are bioactive lipids involved in regulating pain, inflammation, and immune responses, mainly through peroxisome proliferator-activated receptor-α (PPAR-α) signaling. NAAA functions optimally at acidic pH in lysosomal/endosomal compartments, is widely expressed especially in immune cells and lung tissue, and its activity regulates endogenous PEA levels that decrease during inflammation and neuropathic pain. Inhibiting NAAA is a promising strategy for treating conditions like chronic pain, inflammation, and chemotherapy-induced neuropathy by restoring or sustaining PEA's analgesic and anti-inflammatory effects. Structurally, NAAA is related to the choloylglycine hydrolase family and acid ceramidase, but it is functionally distinct in substrate specificity and pH optima. Multiple selective inhibitors have been developed with therapeutic interest, although some challenges remain regarding drug stability and selective targeting in vivo[1][3][4][5][6][7][8][9].

Other names

N-acylethanolamine-hydrolysing acid amidaseN-acylethanolamine-hydrolyzing acid amidaseN-acylethanolamine acid amide hydrolaseAcid amidaseASAHL

Competitive/covalent inhibition of NAAA enzymatic activity, leading to increased endogenous levels of PEA and other fatty acid ethanolamides, thereby activating downstream PPAR-α signaling Modulation of inflammatory and neuropathic pain signaling