Studies on the Substrate and Stereo/Regioselectivity of Adipose Triglyceride Lipase, Hormone-sensitive Lipase, and Diacylglycerol-O-acyltransferases
Studies on the Substrate and Stereo/Regioselectivity of Adipose Triglyceride Lipase, Hormone-sensitive Lipase, and Diacylglycerol-O-acyltransferases
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DOI：
10.1074/jbc.m112.400416
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发表时间：
2012-11-30
影响因子：
4.8
通讯作者：
Zechner, Rudolf
中科院分区：
文献类型：
--
作者：
Eichmann, Thomas O.;Kumari, Manju;Zechner, Rudolf
脂肪甘油三酯脂肪酶（ATGL）是三酰甘油（TAG）水解的起始步骤，产生二酰甘油（DAG）和脂肪酸的限速酶。DAG以三种立体化学异构体存在。在这里，我们表明，ATGL表现出强烈的偏好水解的长链脂肪酸酯在sn-2位置的甘油骨架。ATGL的选择性扩大到sn-1位置时，酶的刺激，其共活化剂CGI-58。sn-1，3 DAG是酶敏感性脂肪酶连续水解的优选底物。有趣的是，存在于内质网和脂滴上的二酰基甘油-O-酰基转移酶2优先使sn-1，3 DAG变性。这表明ATGL和二酰基甘油-O-酰基转移酶2在脂滴上TAG的水解/再酯化循环中协同作用。由于ATGL优先产生sn-1，3和sn-2，3，这表明TAG衍生的DAG在没有预先异构化的情况下不能直接进入磷脂合成或激活蛋白激酶C。
Adipose triglyceride lipase (ATGL) is rate-limiting for the initial step of triacylglycerol (TAG) hydrolysis, generating diacylglycerol (DAG) and fatty acids. DAG exists in three stereochemical isoforms. Here we show that ATGL exhibits a strong preference for the hydrolysis of long-chain fatty acid esters at the sn-2 position of the glycerol backbone. The selectivity of ATGL broadens to the sn-1 position upon stimulation of the enzyme by its co-activator CGI-58. sn-1,3 DAG is the preferred substrate for the consecutive hydrolysis by hormone-sensitive lipase. Interestingly, diacylglycerol-O-acyltransferase 2, present at the endoplasmic reticulum and on lipid droplets, preferentially esterifies sn-1,3 DAG. This suggests that ATGL and diacylglycerol-O-acyltransferase 2 act coordinately in the hydrolysis/re-esterification cycle of TAGs on lipid droplets. Because ATGL preferentially generates sn-1,3 and sn-2,3, it suggests that TAG-derived DAG cannot directly enter phospholipid synthesis or activate protein kinase C without prior isomerization.