MOLECULAR CHARACTERIZATION OF AN ENZYME THAT DEGRADES NEUROMODULATORYFATTY-ACID AMIDES

ENDOGENOUS neuromodulatory molecules are commonly coupled to specific metabolic enzymes to ensure rapid signal inactivation, Thus, acetylcho line is hydrolysed by acetylcholine esterase(1) and tryptamine neurotr ansmitters like serotonin are degraded by monoamine oxidases(2). Previ ously, we reported the structure and sleep-inducing properties of cis- 9-octadecenamide, a lipid isolated from the cerebrospinal fluid of sle ep-deprived cats(3). cis-9-Octadecenamide, or oleamide, has since been shown to affect serotonergic systems(4) and block gap-junction commun ication in glial cells (our unpublished results). We also identified a membrane-bound enzyme activity that hydrolyses oleamide to its inacti ve acid, oleic acid(3). We now report the mechanism-based isolation, c loning and expression of this enzyme activity, originally named oleami de hydrolase(5), from rat liver plasma membranes. We also show that ol eamide hydrolase converts anandamide, a fatty-acid amide identified as the endogenous ligand for the cannabinoid receptor(6), to arachidonic acid, indicating that oleamide hydrolase may serve as the general ina ctivating enzyme for a growing family of bioactive signalling molecule s, the fatty-acid amides(6-8). Therefore we will hereafter refer to ol eamide hydrolase as fatty-acid amide hydrolase, in recognition of the plurality of fatty-acid amides that the enzyme can accept as substrate s.