Potent Inhibition of Acid Sphingomyelinase by Phosphoinositide Analogues

被引：20

作者：

Roth, Anke Gundula ^{[1
]}

Redmer, Susanne ^{[1
]}

Arenz, Christoph ^{[1
]}

机构：

[1] Humboldt Univ, Inst Chem, D-12489 Berlin, Germany

来源：

CHEMBIOCHEM | 2009年 / 10卷 / 14期

关键词：

enzyme catalysis; phosphoinositides; phospholipases; sphingolipids; structure-activity relationships; TRICYCLIC ANTIDEPRESSANT DESIPRAMINE; NEUTRAL SPHINGOMYELINASE; IRREVERSIBLE INHIBITORS; SPHINGOLIPID METABOLISM; CELL-DEATH; CERAMIDE; IDENTIFICATION; PURIFICATION; DEGRADATION; ACTIVATION;

D O I：

10.1002/cbic.200900281

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The different mammalian sphingomyelinases are involved in cell regulation, apoptosis and inflammatory events. Recent reports suggest pharmacological potential especially for inhibitors of the acid sphingomyelinase. Phosphatidyl inositol-3,5-bisphosphate (Ptdlns3,5P(2)) is the most potent selective acid sphingomyelinase inhibitor known to date. In the present study, we synthesized analogues of Ptdlns3,5P(2) for initial structure-activity-relationship (SAR) studies. We identified an inhibitor that is easy to synthesize, that has superior chemical and biophysical properties when compared to Ptdlns3,5P(2) and that should be stable against virtually all phospholipases. Last but not least, the new inhibitor partially protected cells from dexamethasone-induced cell death.

引用

页码：2367 / 2374

页数：8

共 45 条

[1] MODIFICATIONS OF SPHINGOMYELIN AND PHOSPHATIDYLCHOLINE METABOLISM BY TRICYCLIC ANTIDEPRESSANTS AND PHENOTHIAZINES [J].