Title : Molecular mechanism of activation of the immunoregulatory amidase
NAAA
Abstract :
- Palmitoylethanolamide is a bioactive lipid that strongly alleviates pain and inflammation in animal models and in humans
- Its signaling activity is terminated through degradation by N-acylethanolamine acid amidase ( NAAA ), a cysteine hydrolase expressed at high levels in immune cells
- Pharmacological inhibitors of NAAA activity exert profound analgesic and antiinflammatory effects in rodent models, pointing to this protein as a potential target for therapeutic drug discovery
- To facilitate these efforts and to better understand the molecular mechanism of action of NAAA , we determined crystal structures of this enzyme in various activation states and in complex with several ligands, including both a covalent and a reversible inhibitor
- Self-proteolysis exposes the otherwise buried active site of NAAA to allow catalysis
- Formation of a stable substrate- or inhibitor-binding site appears to be conformationally coupled to the interaction of a pair of hydrophobic helices in the enzyme with lipid membranes, resulting in the creation of a linear hydrophobic cavity near the active site that accommodates the ligand's acyl chain