A lipid analogue that inhibits sphingomyelin hydrolysis and synthesis, increases ceramide, and leads to cell death
A lipid analogue that inhibits sphingomyelin hydrolysis and synthesis, increases ceramide, and leads to cell death
复制标题
DOI：
10.1194/jlr.m500136-jlr200
复制
发表时间：
2005-11-01
影响因子：
6.5
通讯作者：
Schuchman, EH
中科院分区：
文献类型：
--
作者：
Darroch, PI;Dagan, A;Schuchman, EH
本文报道了一种新的鞘磷脂硫脲衍生物（AD 2765）的合成与表征。使用纯酶和/或细胞提取物进行的体外试验表明，该化合物可抑制酸性鞘磷脂酶和Mg 2+依赖性中性鞘磷脂酶对BODIPY结合或C-14标记鞘磷脂的水解。在正常人皮肤成纤维细胞中的研究进一步揭示，AD 2765被细胞摄取并原位抑制BODIPY缀合的鞘磷脂的水解。原位和体外研究还表明，该化合物抑制由BODIPY缀合的神经酰胺合成鞘磷脂。AD 2765对参与鞘磷脂代谢的酶的特异性通过以下事实得到证明：其对酸性神经酰胺酶水解BODIPY结合神经酰胺或由BODIPY结合神经酰胺合成BODIPY结合葡萄糖神经酰胺无影响。AD 2765对鞘磷脂代谢的总体影响具有浓度依赖性，用浓度> 10 μ M的该化合物处理正常人皮肤成纤维细胞或癌细胞导致细胞神经酰胺增加和细胞死亡。因此，AD 2765可用于以各种方式操纵鞘磷脂代谢，可能减少A型和B型尼曼-匹克病患者细胞中的底物蓄积，和/或影响人癌细胞的生长。- 达罗奇，私家侦探，A. Dagan，T. Granot，X.他，S. Gatt和E. H.舒克曼一种抑制鞘磷脂水解和合成、增加神经酰胺并导致细胞死亡的脂质类似物。
We report the synthesis and characterization of a novel thiourea derivative of sphingomyelin (AD2765). In vitro assays using pure enzyme and/or cell extracts revealed that this compound inhibited the hydrolysis of BODIPY-conjugated or C-14-labeled sphingomyelin by acid sphingomyelinase and Mg2+ - dependent neutral sphingomyelinase. Studies in normal human skin fibroblasts further revealed that AD2765 was taken up by cells and inhibited the hydrolysis of BODIPY- conjugated sphingomyelin in situ. In situ and in vitro studies also showed that this compound inhibited the synthesis of sphingomyelin from BODIPY- conjugated ceramide. The specificity of AD2765 for enzymes involved in sphingomyelin metabolism was demonstrated by the fact that it had no effect on the hydrolysis of BODIPY- conjugated ceramide by acid ceramidase or on the synthesis of BODIPY- conjugated glucosylceramide from BODIPY- conjugated ceramide. The overall effect of AD2765 on sphingomyelin metabolism was concentration- dependent, and treatment of normal human skin fibroblasts or cancer cells with this compound at concentrations > 10 mu M led to an increase in cellular ceramide and cell death. Thus, AD2765 might be used to manipulate sphingomyelin metabolism in various ways, potentially to reduce substrate accumulation in cells from types A and B Niemann-Pick disease patients, and/or to affect the growth of human cancer cells. -Darroch, P.I., A. Dagan, T. Granot, X. He, S. Gatt, and E. H. Schuchman. A lipid analogue that inhibits sphingomyelin hydrolysis and synthesis, increases ceramide, and leads to cell death.