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

Abstract

ENDOGENOUS neuromodulatory molecules are commonly coupled to specific metabolic enzymes to ensure rapid signal inactivation. Thus, acetylcholine is hydrolysed by acetylcholine esterase¹ and tryptamine neurotransmitters like serotonin are degraded by monoamine oxidases². Previously, we reported the structure and sleep-inducing properties of cis-9-octadecenamide, a lipid isolated from the cerebrospinal fluid of sleep-deprived cats³, cis-9-Octadecenamide, or oleamide, has since been shown to affect serotonergic systems⁴ and block gap-junction communication in glial cells (our unpublished results).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 acid³. We now report the mechanism-based isolation, cloning and expression of this enzyme activity, originally named oleamide hydrolase⁵, 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 receptor⁶, 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.