Dietary polyphenols as topoisomerase II poisons: B ring and C ring substituents determine the mechanism of enzyme-mediated DNA cleavage enhancement
Dietary polyphenols as topoisomerase II poisons: B ring and C ring substituents determine the mechanism of enzyme-mediated DNA cleavage enhancement
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DOI：
10.1021/tx8000785
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发表时间：
2008-06-01
影响因子：
4.1
通讯作者：
Osheroff, Neil
中科院分区：
文献类型：
--
作者：
Bandele, Omari J.;Clawson, Sara J.;Osheroff, Neil
膳食多酚是一组与人类健康有关的复杂的化合物。它们的许多作用被归因于对拓扑异构酶II的毒性(即，增强DNA切割)的能力。多酚至少通过两种不同的机制对该酶起作用。一些化合物是传统的不依赖氧化还原的拓扑异构酶II毒药，以非共价方式与酶相互作用。相反，另一些则以氧化还原依赖的方式促进DNA裂解，这需要与拓扑异构酶II进行共价加合。不幸的是，决定多酚毒害拓扑异构酶II机制的结构元素尚未确定。为了解决这个问题，研究了两类多酚类化合物对人类拓扑异构酶IIα的活性。第一类是儿茶素系列，包括(-)-表儿茶素没食子酸酯(EGCG)、(-)-表儿茶素没食子酸酯(EGC)、(-)-表儿茶素没食子酸酯(CG)和(-)-表儿茶素(EC)。第二个是黄酮醇系列，包括杨梅素、栎素和山奈酚。化合物分为四类：EGCG和EGC是氧化还原依赖的拓扑异构酶II类毒物，山奈酚和槲皮素是传统的毒物，杨梅素利用这两种机制，而心电和EC没有显示出显著的活性。在这些发现的基础上，提出了一套预测生物黄酮类化合物对拓扑异构酶II作用机制的规则。第一规则以B环为中心。虽然C4‘-OH是化合物作为传统毒物发挥作用的关键，但C3’和C5‘上-OH基团的添加增加了B环的氧化还原活性，并允许化合物作为氧化还原依赖的毒物。第二条规则以C环为中心。黄酮醇中的C环的结构是芳香的和平面的，并包括C4-酮基，该基团允许与C5-OH形成假环。这些元素的破坏取消了酶的结合，并排除了作为传统拓扑异构酶II毒物的能力。
Dietary polyphenols are a diverse and complex group of compounds that are linked to human health. Many of their effects have been attributed to the ability to poison (i.e., enhance DNA cleavage by) topoisomerase II. Polyphenols act against the enzyme by at least two different mechanisms. Some compounds are traditional, redox-independent topoisomerase II poisons, interacting with the enzyme in a noncovalent manner. Conversely, others enhance DNA cleavage in a redox-dependent manner that requires covalent adduction to topoisomerase II. Unfortunately, the structural elements that dictate the mechanism by which polyphenols poison topoisomerase II have not been identified. To resolve this issue, the activities of two classes of polyphenols against human topoisomerase II alpha were examined. The first class was a catechin series, including (-)-epigallocatechin gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epicatechin (EC). The second was a flavonol series, including myricetin, quercetin, and kaempferol. Compounds were categorized into four distinct groups: EGCG and EGC were redox-dependent topoisomerase II poisons, kaempferol and quercetin were traditional poisons, myricetin utilized both mechanisms, and ECG and EC displayed no significant activity. On the basis of these findings, a set of rules is proposed that predicts the mechanism of bioflavonoid action against topoisomerase II. The first rule centers on the B ring. While the C4'-OH is critical for the compound to act as a traditional poison, the addition of-OH groups at C3' and C5' increases the redox activity of the B ring and allows the compound to act as a redox-dependent poison. The second rule centers on the C ring. The structure of the C ring in the flavonols is aromatic and planar and includes a C4-keto group that allows the formation of a proposed pseudo ring with the C5-OH. Disruption of these elements abrogates enzyme binding and precludes the ability to function as a traditional topoisomerase II poison.