Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides.
Cravatt, Benjamin F.; Giang, Dan K.; Mayfield, Stephen P.; Boger, Dale L.; Lerner, Richard A.; Gilula, Norton B.
[Letter] Nature. 384(6604):83-87, November 7, 1996.

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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has since been shown to affect serotonergic systems [4] and block gap-junction communication in glial cells (our unpublished results).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 membranes. 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, indicating 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 amid hydrolase, in recognition of the plurality of fatty-acid amides that the enzyme can accept as substrates.

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