Kerriamycin B inhibits protein SUMOylation
Kerriamycin B inhibits protein SUMOylation
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DOI：
10.1038/ja.2009.10
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发表时间：
2009-04-01
影响因子：
3.3
通讯作者：
Yoshida, Minoru
中科院分区：
文献类型：
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作者：
Fukuda, Isao;Ito, Akihiro;Yoshida, Minoru
小泛素相关修饰蛋白（SUMO）与蛋白质底物的翻译后偶联（SUMO化）是动物和其他真核生物中主要的翻译后调节系统之一。SUMO结合由类似于泛素化的多步酶促反应级联催化。1在第一步中，SUMO前体在C-末端附近被SUMO特异性蛋白酶切割以暴露C-末端双甘氨酸。然后，成熟SUMO的C-末端甘氨酸与SUMO激活酶（E1）的半胱氨酸残基（Aos 1/Uba 2异源二聚体）形成硫酯键，以ATP依赖性方式生成E1-SUMO中间体。接下来，SUMO通过另一个硫酯键转移到SUMO缀合酶（E2）Ubc 9的半胱氨酸残基的活性位点。在最后一步中，E2和SUMO连接酶（E3）催化底物蛋白在内部赖氨酸残基的e-氨基上的SUMO化。虽然E1和E2的酶促反应在大多数情况下足以催化体外SUMO化，但E3促进体内和体外缀合，并且对底物特异性很重要。1 SUMO与泛素结构相似，但功能不同。SUMO化调节蛋白质的亚细胞定位、酶活性和蛋白质稳定性，这些与细胞周期、转录、DNA修复和先天免疫有关。2，3此外，SUMO化最近与疾病如阿尔茨海默病和亨廷顿病、4病毒感染5和癌症有因果关系。6，7尽管SUMO化在调节多种生命现象和疾病中的重要性，但SUMO化的小分子抑制剂尚未开发。在这里，我们报告了新的活性的kerriamycin B，抑制蛋白质SUMO化，这将提供有用的信息SUMO化在细胞和药物开发中的作用。
Post-translational conjugation of small ubiquitin-related modifier protein (SUMO) to protein substrates (SUMOylation) has been revealed as one of the major post-translational regulatory systems in animals and other eukaryotes. SUMO conjugation is catalyzed by a multi-step enzymatic reaction cascade similar to ubiquitinylation. 1 In the first step, the SUMO precursor is cleaved near the C-terminus by SUMO-specific proteases to expose a C-terminal diglycine. The C-terminal glycine of mature SUMO then forms a thioester linkage to the cysteine residue of SUMO-activating enzyme (E1), the Aos1/Uba2 heterodimer, to generate the E1-SUMO intermediate in an ATP-dependent manner. Next, SUMO is transferred to the active site of the cysteine residue of the SUMO-conjugating enzyme (E2), Ubc9, through another thioester bond. In the last step, E2 and the SUMO ligase (E3) catalyze SUMOylation of substrate proteins at the e-amino group of internal lysine residues. Although enzymatic reactions by E1 and E2 are sufficient for catalyzing in vitro SUMOylation in most cases, E3s facilitate both in vivo and in vitro conjugation and are important for substrate specificity. 1The structure of SUMO is similar to that of ubiquitin, but its functions are different. SUMOylation regulates protein subcellular localization, enzymatic activity and protein stability, which are associated with the cell cycle, transcription, DNA repair and innate immunity. 2, 3 In addition, SUMOylation has been recently linked causally to diseases, such as Alzheimer’s and Huntington’s diseases, 4 viral infection 5 and cancer. 6, 7 Notwithstanding the importance of SUMOylation in regulating diverse life phenomena and diseases, small molecule inhibitors of SUMOylation have been unexplored. Here, we report novel activity of kerriamycin B that inhibits protein SUMOylation, which will provide useful information about the role of SUMOylation in cells and drug development.