Sordarin inhibits fungal protein synthesis by blocking translocation differently to fusidic acid
Sordarin inhibits fungal protein synthesis by blocking translocation differently to fusidic acid
复制标题
DOI：
10.1074/jbc.274.32.22423
复制
发表时间：
1999-08-06
影响因子：
4.8
通讯作者：
Martín, JJ
中科院分区：
文献类型：
--
作者：
Domínguez, JM;Gómez-Lorenzo, MG;Martín, JJ
索达林衍生物是真菌蛋白质合成的选择性抑制剂，其特异性地损害延伸因子2（EF-2）功能。我们研究了在没有任何其他翻译系统成分的情况下，索达林对白念珠菌EF-2的核糖体依赖性GTdR活性的影响。索达林的作用结果是依赖于核糖体与EF-2的比例和核糖体的性质。当EF-2的量超过核糖体的量时，Sordarin抑制GTdR活性，呈倒钟形剂量-反应曲线，而当EF-2和核糖体在等摩尔浓度时，Sordarin产生典型的S形剂量依赖性抑制。然而，当使用蓖麻毒素处理的核糖体时，sordarin刺激GTP的水解。这些结果与夫西地酸的结果进行了比较，表明这两种药物的作用方式不同。所有这些数据都与sordarin在GTP水解之前在易位的初始步骤中阻断延伸周期一致。与这一结论一致，sordarin阻止了白色念珠菌多聚核糖体上肽基-[H-3]嘌呤霉素的形成。
Sordarin derivatives are selective inhibitors of fungal protein synthesis, which specifically impair elongation factor 2 (EF-2) function. We have studied the effect of sordarin on the ribosome-dependent GTPase activity of EF-2 from Candida albicans in the absence of any other component of the translation system. The effect of sordarin turned out to be dependent both on the ratio of ribosomes to EF-2 and on the nature of the ribosomes. When the amount of EF-2 exceeded that of ribosomes sordarin inhibited the GTPase activity following an inverted bell-shaped dose-response curve, whereas when EF-2 and ribosomes were in equimolar concentrations sordarin yielded a typical sigmoidal dose-dependent inhibition. However, when ricin-treated ribosomes were used, sordarin stimulated the hydrolysis of GTP. These results were compared with those obtained with fusidic acid, showing that both drugs act in a different manner. All these data are consistent with sordarin blocking the elongation cycle at the initial steps of translocation, prior to GTP hydrolysis, In agreement with this conclusion, sordarin prevented the formation of peptidyl-[H-3]puromycin on polysomes from Candida albicans.