Covalent inhibition of recombinant human carboxylesterase 1 and 2 and monoacylglycerol lipase by the carbamates JZL184 and URB597.
Covalent inhibition of recombinant human carboxylesterase 1 and 2 and monoacylglycerol lipase by the carbamates JZL184 and URB597.
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DOI：
10.1016/j.bcp.2012.08.017
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发表时间：
2012-11-01
影响因子：
5.8
通讯作者：
Ross, Matthew K.
中科院分区：
文献类型：
--
作者：
Crow, J. Allen;Bittles, Victoria;Borazjani, Abdolsamad;Potter, Philip M.;Ross, Matthew K.
关键词：
羧酸酯酶1型（CES 1）和CES 2是位于肝脏和小肠中的丝氨酸水解酶。CES 1和CES 2积极参与多种药物的代谢。最近，氨基甲酸酯化合物被开发用于通过共价修饰活性位点丝氨酸来抑制丝氨酸水解酶家族的成员。URB 597和JZL 184分别抑制脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂肪酶（MAGL）;然而，肝脏中的羧酸酯酶已被确定为主要的脱靶酶。我们报告了URB 597和JZL 184抑制人重组CES 1和CES 2的动力学速率常数。JZL 184和URB 597抑制CES 1的双分子速率常数（kinact/Ki）相似[分别为3.9（±0.2）× 103 M-1 s-1和4.5（±1.3）× 103 M-1 s-1]。然而，JZL 184和URB 597抑制CES 2的kinact/Ki显著不同[分别为2.3（±1.3）× 102 M-1 s-1和3.9（±1.0）× 103 M-1 s-1]。URB 597对CES 1和CES 2的抑制率相似;然而，JZL 184对CES 1和MAGL的抑制作用强于CES 2。我们还确定了自发再活化的动力学常数的CES 1氨甲酰化的JZL 184或URB 597和CES 1二乙基磷酸化的对氧磷。JZL 184抑制的CES 1的再激活速率比URB 597抑制的CES 1显著更慢（4.5倍）。经JZL 184氨甲酰化的CES 1的再活化半衰期为49 ± 15 h，这比HepG 2细胞中羧酸酯酶的周转快。总之，这些结果定义了一类靶向参与药物和脂质代谢的水解酶的药物的抑制动力学。
Carboxylesterase type 1 (CES1) and CES2 are serine hydrolases located in the liver and small intestine. CES1 and CES2 actively participate in the metabolism of several pharmaceuticals. Recently, carbamate compounds were developed to inhibit members of the serine hydrolase family via covalent modification of the active site serine. URB597 and JZL184 inhibit fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively; however, carboxylesterases in liver have been identified as a major off-target. We report the kinetic rate constants for inhibition of human recombinant CES1 and CES2 by URB597 and JZL184. Bimolecular rate constants (kinact/Ki) for inhibition of CES1 by JZL184 and URB597 were similar [3.9 (±0.2) × 103 M-1 s-1 and 4.5 (±1.3) × 103 M-1 s-1, respectively]. However, kinact/Ki for inhibition of CES2 by JZL184 and URB597 were significantly different [2.3 (±1.3) × 102 M-1 s-1 and 3.9 (±1.0) × 103 M-1 s-1, respectively]. Rates of inhibition of CES1 and CES2 by URB597 were similar; however, CES1 and MAGL were more potently inhibited by JZL184 than CES2. We also determined kinetic constants for spontaneous reactivation of CES1 carbamoylated by either JZL184 or URB597 and CES1 diethylphosphorylated by paraoxon. The reactivation rate was significantly slower (4.5x) for CES1 inhibited by JZL184 than CES1 inhibited by URB597. Half life of reactivation for CES1 carbamoylated by JZL184 was 49 ± 15 h, which is faster than carboxylesterase turnover in HepG2 cells. Together, the results define the kinetics of inhibition for a class of drugs that target hydrolytic enzymes involved in drug and lipid metabolism.
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影响因子：
10.4
作者：
FUKUTO, TR
通讯作者：
FUKUTO, TR
影响因子：
120.1
作者：
Bachovchin, Daniel A.;Cravatt, Benjamin F.
通讯作者：
Cravatt, Benjamin F.
影响因子：
2.7
作者：
Sun, Hao
通讯作者：
Sun, Hao
影响因子：
3.9
作者：
Ross, Matthew K.;Borazjani, Abdolsamad;Wang, Ran;Crow, J. Allen;Xie, Shuqi
通讯作者：
Xie, Shuqi
影响因子：
3.8
作者：
Timchalk, C;Nolan, RJ;Mattsson, JL
通讯作者：
Mattsson, JL