Different roles for the acyl chain and the amine leaving group in the substrate selectivity of <i>N</i>-Acylethanolamine acid amidase

N-acylethanolamine acid amidase (NAAA) is an N-terminal nucleophile (Ntn) hydrolase that catalyses the intracellular deactivation of endogenous analgesic and anti-inflammatory agent palmitoylethanolamide (PEA). NAAA inhibitors counteract this process exert marked therapeutic effects in animal models pain, inflammation neurodegeneration. While it known preferentially hydrolyses saturated fatty ethanolamides (FAEs), a detailed profile relationship between catalytic efficiency acid-chain length still lacking. In report, we combined enzymatic molecular modelling approaches to determine acyl chain polar head modifications on substrate recognition hydrolysis by NAAA. The results show that, both monounsaturated FAEs, strictly dependent upon length, whereas there wider tolerance for heads. This reflects relative stability enzyme-substrate complexes dynamics simulations.