通过基于活性的蛋白质谱分析评估内源性大麻素生物合成抑制剂的选择性。
Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling.
作者信息
Hoover Heather S, Blankman Jacqueline L, Niessen Sherry, Cravatt Benjamin F
机构信息
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.
出版信息
Bioorg Med Chem Lett. 2008 Nov 15;18(22):5838-41. doi: 10.1016/j.bmcl.2008.06.091. Epub 2008 Jul 2.
Abstract
The endocannabinoid 2-arachidonoylglycerol (2-AG) has been implicated as a key retrograde mediator in the nervous system based on pharmacological studies using inhibitors of the 2-AG biosynthetic enzymes diacyglycerol lipase alpha and beta (DAGL-alpha/beta). Here, we show by competitive activity-based protein profiling that the DAGL-alpha/beta inhibitors, tetrahydrolipstatin (THL) and RHC80267, block several brain serine hydrolases with potencies equal to or greater than their inhibitory activity against DAGL enzymes. Interestingly, a minimal overlap in target profiles was observed for THL and RHC80267, suggesting that pharmacological effects observed with both agents may be viewed as good initial evidence for DAGL-dependent events.
摘要
基于使用2-花生四烯酸甘油酯（2-AG）生物合成酶二酰基甘油脂肪酶α和β（DAGL-α/β）抑制剂的药理学研究，内源性大麻素2-花生四烯酸甘油酯（2-AG）被认为是神经系统中的一种关键逆行介质。在此，我们通过基于活性的竞争性蛋白质谱分析表明，DAGL-α/β抑制剂四氢脂抑素（THL）和RHC80267可阻断多种脑丝氨酸水解酶，其效力等于或大于它们对DAGL酶的抑制活性。有趣的是，观察到THL和RHC80267的靶点谱有最小程度的重叠，这表明用这两种药物观察到的药理作用可能被视为DAGL依赖性事件的良好初步证据。
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本文引用的文献
1
Enzymatic pathways that regulate endocannabinoid signaling in the nervous system.调节神经系统内源性大麻素信号传导的酶促途径。
Chem Rev. 2008 May;108(5):1687-707. doi: 10.1021/cr0782067. Epub 2008 Apr 23.
2
Activity-based protein profiling: from enzyme chemistry to proteomic chemistry.基于活性的蛋白质谱分析：从酶化学到蛋白质组化学
Annu Rev Biochem. 2008;77:383-414. doi: 10.1146/annurev.biochem.75.101304.124125.
3
A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.水解内源性大麻素2-花生四烯酸甘油酯的脑酶综合概况。
Chem Biol. 2007 Dec;14(12):1347-56. doi: 10.1016/j.chembiol.2007.11.006.
4
Biosynthetic pathways of the endocannabinoid anandamide.内源性大麻素花生四烯乙醇胺的生物合成途径。
Chem Biodivers. 2007 Aug;4(8):1842-57. doi: 10.1002/cbdv.200790155.
5
Endocannabinoids and related compounds: walking back and forth between plant natural products and animal physiology.内源性大麻素及相关化合物：穿梭于植物天然产物与动物生理学之间
Chem Biol. 2007 Jul;14(7):741-56. doi: 10.1016/j.chembiol.2007.05.014.
6
Pharmacological evidence for the involvement of diacylglycerol lipase in depolarization-induced endocanabinoid release.二酰基甘油脂肪酶参与去极化诱导的内源性大麻素释放的药理学证据。
Neuropharmacology. 2008 Jan;54(1):58-67. doi: 10.1016/j.neuropharm.2007.06.002. Epub 2007 Jun 22.
7
A functional proteomic strategy to discover inhibitors for uncharacterized hydrolases.一种用于发现未知水解酶抑制剂的功能蛋白质组学策略。
J Am Chem Soc. 2007 Aug 8;129(31):9594-5. doi: 10.1021/ja073650c. Epub 2007 Jul 13.
8
Roles of phospholipase Cbeta and NMDA receptor in activity-dependent endocannabinoid release.磷脂酶Cβ和N-甲基-D-天冬氨酸受体在活性依赖性内源性大麻素释放中的作用。
J Physiol. 2007 Oct 15;584(Pt 2):373-80. doi: 10.1113/jphysiol.2007.137497. Epub 2007 Jul 5.
9
A key role for diacylglycerol lipase-alpha in metabotropic glutamate receptor-dependent endocannabinoid mobilization.二酰基甘油脂肪酶α在代谢型谷氨酸受体依赖性内源性大麻素动员中的关键作用。
Mol Pharmacol. 2007 Sep;72(3):612-21. doi: 10.1124/mol.107.037796. Epub 2007 Jun 21.
10
Subcellular arrangement of molecules for 2-arachidonoyl-glycerol-mediated retrograde signaling and its physiological contribution to synaptic modulation in the striatum.2-花生四烯酸甘油介导的逆行信号分子的亚细胞排列及其对纹状体突触调制的生理贡献。
J Neurosci. 2007 Apr 4;27(14):3663-76. doi: 10.1523/JNEUROSCI.0448-07.2007.
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