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首页> 外文期刊>Biochemistry >Endocannabinoid Metabolism in the Absence of Fatty Acid Amide Hydrolase (FAAH):Discovery of Phosphorylcholine Derivatives of iV-Acyl Ethanolamines
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Endocannabinoid Metabolism in the Absence of Fatty Acid Amide Hydrolase (FAAH):Discovery of Phosphorylcholine Derivatives of iV-Acyl Ethanolamines

机译：脂肪酸酰胺水解酶（FAAH）缺乏时的内源性大麻素代谢：iV-酰基乙醇胺的磷酸胆碱衍生物的发现

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摘要

Lipid transmitters are tightly regulated by a balance of biosynthetic and degradative enzymes.Termination of the activity of the N-acyl ethanolamine (NAE) class of lipid-signaling molecules,including the endocannabinoid anandamide (AEA),is principally mediated by the integral membrane enzyme fatty acid amide hydrolase (FAAH) in vivo.FAAH(-/-) mice are highly sensitized to the pharmacological effects of AEA;however,these animals eventually recover from AEA treatment,implying the existence of alternative routes for NAE metabolism.Here,we have pursued the characterization of these pathways by profiling the metabolome of FAAH(-/-) mice treated with AEA.Multiple AEA-induced metabolites were observed in brains from FAAH(-/-) mice,including a major product with a mass shift of+165 Da (m/z 513).The structure of this product was determined to be O-phoshorylcholine (PC)-AEA.Analysis of untreated mice identified PC-NAEs as endogenous constituents of the central nervous system (CNS) that were highly elevated in FAAH(-/-) animals.PC-NAEs were very poor substrates for FAAH;however,a vanadate-sensitive enzymatic activity was detected in brain membranes that converted PC- NAEs back to their parent NAEs.The choline-specific phosphodiesterase NPP6 was identified as a candidate enzyme responsible for this activity.These data indicate the presence of a complete metabolic pathway for the production and degradation of PC-NAEs in the CNS that constitutes an alternative route for endocannabinoid metabolism.
机译：脂类递质受到生物合成和降解酶的平衡的严格调节。N-酰基乙醇胺（NAE）类脂信号分子的活性的终止，包括内源性大麻素anandamide（AEA），主要由整合膜酶介导。脂肪酸酰胺水解酶（FAAH）体内。FAAH（-/-）小鼠对AEA的药理作用高度敏感;但是，这些动物最终从AEA治疗中恢复过来，这暗示着存在NAE代谢的替代途径。已经通过分析用AEA处理的FAAH（-/-）小鼠的代谢组来追踪这些途径的特征，在FAAH（-/-）小鼠的大脑中观察到多种AEA诱导的代谢产物，包括质量转移为+165 Da（m / z 513）。该产品的结构被确定为O-磷酸胆碱（PC）-AEA。未经治疗的小鼠的分析确定PC-NAE是中枢神经系统（CNS）的内源性成分PC-NAEs是FAAH的非常差的底物;但是，在脑膜中检测到了钒酸盐敏感的酶活性，将PC-NAEs转换回其亲本NAEs。胆碱特异性磷酸二酯酶NPP6被认为是负责这种活性的候选酶，这些数据表明CNS中存在完整的代谢途径，用于PC-NAE的产生和降解，构成了内源性大麻素代谢的另一种途径。

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