Ellagic Acid and Polyhydroxylated Urolithins Are Potent Catalytic Inhibitors of Human Topoisomerase II: An in Vitro Study
Ellagic Acid and Polyhydroxylated Urolithins Are Potent Catalytic Inhibitors of Human Topoisomerase II: An in Vitro Study
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DOI：
10.1021/jf302600q
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发表时间：
2012-09-12
影响因子：
6.1
通讯作者：
Gatto, Barbara
中科院分区：
文献类型：
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作者：
Furlanetto, Valentina;Zagotto, Giuseppe;Gatto, Barbara
鞣花酸 (EA) 是一种天然多酚，富含于水果中，在我们的饮食中很常见，目前正在对其多种作用所产生的化学预防活性进行深入研究。 EA 可抑制拓扑异构酶 II，但对尿石素（其单内酯代谢物）的人体酶的影响尚不清楚。因此，评估了几种合成尿石素对拓扑异构酶 II 的作用，结果表明多羟基化尿石素、EA 和 EA 相关化合物在亚微摩尔浓度下是人拓扑异构酶 II α 和 β 亚型的有效抑制剂。竞争测试表明 ATP 与酶的抑制之间存在剂量依赖性关系。对接实验表明，活性化合物与人类酶的 ATP 口袋结合，从而支持了 EA 和多羟基化尿石素作为人类拓扑异构酶 II 的 ATP 竞争性抑制剂的假设。
Ellagic acid (EA), a natural polyphenol abundant in fruits and common in our diet, is under intense investigation for its chemopreventive activity resulting from multiple effects. EA inhibits topoisomerase II, but the effects on the human enzyme of urolithins, its monolactone metabolites, are not known. Therefore, the action of several synthetic urolithins toward topoisomerases II was evaluated, showing that polyhydroxylated urolithins, EA, and EA-related compounds are potent inhibitors of the alpha and beta isoforms of human topoisomerase II at submicromolar concentrations. Competition tests demonstrate a dose-dependent relationship between ATP and the inhibition of the enzyme. Docking experiments show that the active compounds bind the ATP pocket of the human enzyme, thus supporting the hypothesis that EA and polyhydroxylated urolithins act as ATP-competitive inhibitors of human topoisomerase II.