Towbin Harry, Bair Kenneth W, DeCaprio James A, Eck Michael J, Kim Sunkyu, Kinder Frederick R, Morollo Anthony, Mueller Dieter R, Schindler Patrick, Song Hyun Kyu, van Oostrum Jan, Versace Richard W, Voshol Hans, Wood Jeanette, Zabludoff Sonya, Phillips Penny E
Novartis Pharma AG, CH-4036 Basle, Switzerland.
J Biol Chem. 2003 Dec 26;278(52):52964-71. doi: 10.1074/jbc.M309039200. Epub 2003 Oct 8.
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.
LAF389是苯甲酰胺类的一种合成类似物，苯甲酰胺是一类海洋天然产物，在体外和体内均对肿瘤生长产生抑制作用。一种基于蛋白质组学的方法已被用于鉴定受苯甲酰胺影响的信号通路。用LAF389处理细胞导致二维凝胶电泳上一部分蛋白质的迁移率发生改变。对其中一种蛋白质14-3-3γ的详细分析表明，苯甲酰胺处理导致氨基末端甲硫氨酸保留，这表明苯甲酰胺直接或间接抑制甲硫氨酸氨基肽酶（MetAps）。已知的两种MetAps均被LAF389抑制。MetAp2的短发夹RNA抑制也改变了14-3-3γ的氨基末端加工。与苯甲酰胺共结晶的人MetAp2的高分辨率结构表明，该化合物以模拟肽底物的方式结合。此外，该结构显示抑制剂上的三个关键羟基与酶活性位点中的二钴中心配位。
