Blankman Jacqueline L, Simon Gabriel M, Cravatt Benjamin F
The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Chem Biol. 2007 Dec;14(12):1347-56. doi: 10.1016/j.chembiol.2007.11.006.
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 approximately 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.
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乙醇胺和2-花生四烯酸甘油酯（2-AG）。内源性大麻素调节多种生理过程，并受到酶促生物合成和降解的严格调控。脂肪酸酰胺水解酶（FAAH）对花生四烯乙醇胺信号的终止作用已得到充分表征，但对2-AG失活的了解较少，2-AG在体外可被多种酶水解，包括FAAH和单酰甘油脂肪酶（MAGL）。在此，我们采用功能蛋白质组学方法全面绘制小鼠脑中2-AG水解酶图谱。我们的数据显示，约85%的脑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ABHD6和ABHD12催化。有趣的是，MAGL、ABHD6和ABHD12表现出不同的亚细胞分布，这表明它们可能控制神经系统中不同的2-AG库。
