A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol
A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol
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DOI：
10.1016/j.chembiol.2007.11.006
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发表时间：
2007-12-01
影响因子：
--
通讯作者：
Cravatt, Benjamin F.
中科院分区：
文献类型：
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作者：
Blankman, Jacqueline L.;Simon, Gabriel M.;Cravatt, Benjamin F.
大麻素受体的内源性配体（“内源性大麻素”）包括脂质递质花生四烯酸和2-花生四烯酸甘油（2-AG）。内源性大麻素调节一系列不同的生理过程，并受到酶的生物合成和降解的严格调控。脂肪酸酰胺水解酶（FAAH）终止花生四烯酸信号传导的特点很好，但鲜为人知的是2-AG，它可以在体外被多种酶水解，包括FAAH和单酰基甘油脂肪酶（MAGL）的失活。在这里，我们已经采取了功能蛋白质组学的方法，全面映射2-AG水解酶在小鼠大脑。我们的数据表明，大约85%的大脑2-AG水解酶活性可归因于MAGL，其余15%主要由两种未表征的酶ABHD 6和ABHD 12催化。有趣的是，MAGL，ABHD 6和ABHD 12显示不同的亚细胞分布，这表明它们可能控制神经系统中不同的2-AG池。
Endogenous ligands for cannabinoid receptors ("endocannabinoids") include the lipid transmitters anandamide and 2-arachidonoylglycerol (2-AG). Endocannabinoids modulate a diverse set of physiological processes and are tightly regulated by enzymatic biosynthesis and degradation. Termination of anandamide signaling by fatty acid amide hydrolase (FAAH) is well characterized, but less is known about the inactivation of 2-AG, which can be hydrolyzed by multiple enzymes in vitro, including FAAH and monoacylglycerol lipase (MAGL). Here, we have taken a functional proteomic approach to comprehensively map 2-AG hydrolases in the mouse brain. Our data reveal that similar to 85% of brain 2-AG hydrolase activity can be ascribed to MAGL, and that the remaining 15% is mostly catalyzed by two uncharacterized enzymes, ABHD6 and ABHD12. Interestingly, MAGL, ABHD6, and ABHD12 display distinct subcellular distributions, suggesting that they may control different pools of 2-AG in the nervous system.