Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides

ENDOGENOUS neuromodulatory molecules are commonly coupled to specific metabolic enzymes to ensure rapid signal inactivation. Thus, acetylcholine is hydrolysed by acetylcholine esterase 1 and tryptamine neurotransmitters like serotonin are degraded by monoamine oxidases 2 . Previously, we reported the structure and sleep-inducing properties of cis -9-octadecenamide, a lipid isolated from the cerebrospinal fluid of sleep-deprived cats 3 , cis -9-Octadecenamide, or oleamide, has since been shown to affect serotonergic systems 4 and block gap-junction communication in glial cells (our unpublished results). We also identified a membrane-bound enzyme activity that hydrolyses oleamide to its inactive acid, oleic acid 3 . We now report the mechanism-based isolation, cloning and expression of this enzyme activity, originally named oleamide hydrolase 5 , from rat liver plasma mem-branes. We also show that oleamide hydrolase converts anandamide, a fatty-acid amide identified as the endogenous ligand for the cannabinoid receptor 6 , to arachidonic acid, indi-cating that oleamide hydrolase may serve as the general inactivating enzyme for a growing family of bioactive signalling molecules, the fatty-acid amides 6–8 . Therefore we will hereafter refer to oleamide hydrolase as fatty-acid amide hydrolase, in recognition of the plurality of fatty-acid amides that the enzyme can accept as substrates.