Proteomics-based target identification - Bengamides as a new class of methionine aminopeptidase inhibitors
Proteomics-based target identification - Bengamides as a new class of methionine aminopeptidase inhibitors
复制标题
DOI：
10.1074/jbc.m309039200
复制
发表时间：
2003-12-26
影响因子：
4.8
通讯作者：
Phillips, PE
中科院分区：
文献类型：
--
作者：
Towbin, H;Bair, KW;Phillips, PE
LAF389 is a synthetic analogue of bengamides, a class of marine natural products that produce inhibitory effects on tumor growth in vitro and in vivo. A proteomics-based approach has been used to identify signaling pathways affected by bengamides. LAF389 treatment of cells resulted in altered mobility of a subset of proteins on two-dimensional gel electrophoresis. Detailed analysis of one of the proteins, 14-3-3gamma, showed that bengamide treatment resulted in retention of the amino-terminal methionine, suggesting that bengamides directly or indirectly inhibited methionine aminopeptidases (MetAps). Both known MetAps are inhibited by LAF389. Short interfering RNA suppression of MetAp2 also altered amino-terminal processing of 14-3-3gamma. A high resolution structure of human MetAp2 co-crystallized with a bengamide shows that the compound binds in a manner that mimics peptide substrates. Additionally, the structure reveals that three key hydroxyl groups on the inhibitor coordinate the di-cobalt center in the enzyme active site.
