Cravatt B F, Giang D K, Mayfield S P, Boger D L, Lerner R A, Gilula N B
Department of Chemistry, The Scripps Research Institute, La Jolla, California 92307, USA.
Nature. 1996 Nov 7;384(6604):83-7. doi: 10.1038/384083a0.
Endogenous neuromodulatory molecules are commonly coupled to specific metabolic enzymes to ensure rapid signal inactivation. Thus, acetylcholine is hydrolysed by acetylcholine esterase and tryptamine neurotransmitters like serotonin are degraded by monoamine oxidases. Previously, we reported the structure and sleep-inducing properties of cis-9-octadecenamide, a lipid isolated from the cerebrospinal fluid of sleep-deprived cats. cis-9-Octadecenamide, or oleamide, has since been shown to affect serotonergic systems and block gap-junction communication in glial cells (our unpublished results).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. We now report the mechanism-based isolation, cloning and expression of this enzyme activity, originally named oleamide hydrolase, 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, 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. 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.
内源性神经调节分子通常与特定的代谢酶偶联，以确保信号的快速失活。因此，乙酰胆碱被乙酰胆碱酯酶水解，而色胺类神经递质如5-羟色胺则被单胺氧化酶降解。此前，我们报道了从睡眠剥夺猫的脑脊液中分离出的一种脂质——顺-9-十八碳烯酰胺的结构和诱导睡眠的特性。此后，顺-9-十八碳烯酰胺，即油酰胺，已被证明会影响5-羟色胺能系统，并阻断神经胶质细胞中的缝隙连接通讯（我们未发表的结果）。我们还鉴定出一种膜结合酶活性，它能将油酰胺水解为其无活性的酸——油酸。我们现在报告基于机制的该酶活性的分离、克隆及表达，该酶最初命名为油酰胺水解酶，来自大鼠肝细胞膜。我们还表明，油酰胺水解酶将花生四烯酸乙醇胺（一种被鉴定为大麻素受体内源性配体的脂肪酸酰胺）转化为花生四烯酸，这表明油酰胺水解酶可能作为一类不断增加的生物活性信号分子——脂肪酸酰胺的通用失活酶。因此，考虑到该酶可接受多种脂肪酸酰胺作为底物，我们此后将油酰胺水解酶称为脂肪酸酰胺水解酶。
