Fortune J M, Osheroff N
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Prog Nucleic Acid Res Mol Biol. 2000;64:221-53. doi: 10.1016/s0079-6603(00)64006-0.
Topoisomerase II is an essential enzyme that plays a role in virtually every cellular DNA process. This enzyme interconverts different topological forms of DNA by passing one nucleic acid segment through a transient double-stranded break generated in a second segment. By virtue of its double-stranded DNA passage reaction, topoisomerase II is able to regulate DNA over- and underwinding, and can resolve knots and tangles in the genetic material. Beyond the critical physiological functions of the eukaryotic enzyme, topoisomerase II is the target for some of the most successful anticancer drugs used to treat human malignancies. These agents are referred to as topoisomerase II poisons, because they transform the enzyme into a potent cellular toxin. Topoisomerase II poisons act by increasing the concentration of covalent enzyme-cleaved DNA complexes that normally are fleeting intermediates in the catalytic cycle of topoisomerase II. As a result of their action, these drugs generate high levels of enzyme-mediated breaks in the genetic material of treated cells and ultimately trigger cell death pathways. Topoisomerase II is also the target for a second category of drugs referred to as catalytic inhibitors. Compounds in this category prevent topoisomerase II from carrying out its required physiological functions. Drugs from both categories vary widely in their mechanisms of actions. This review focuses on topoisomerase II function and how drugs alter the catalytic cycle of this important enzyme.
拓扑异构酶II是一种必需的酶，几乎参与了细胞内的每一个DNA过程。该酶通过使一个核酸片段穿过在另一个片段中产生的瞬时双链断裂，来实现DNA不同拓扑形式的相互转换。凭借其双链DNA穿通反应，拓扑异构酶II能够调节DNA的过度缠绕和欠缠绕，并能解开遗传物质中的结和缠结。除了真核酶的关键生理功能外，拓扑异构酶II还是用于治疗人类恶性肿瘤的一些最成功抗癌药物的靶点。这些药物被称为拓扑异构酶II毒药，因为它们将该酶转化为一种强效的细胞毒素。拓扑异构酶II毒药通过增加共价酶切割的DNA复合物的浓度来发挥作用，这些复合物通常是拓扑异构酶II催化循环中的短暂中间体。由于它们的作用，这些药物在被处理细胞的遗传物质中产生高水平的酶介导的断裂，并最终触发细胞死亡途径。拓扑异构酶II也是另一类被称为催化抑制剂的药物的靶点。这类化合物会阻止拓扑异构酶II执行其必需的生理功能。这两类药物的作用机制差异很大。本综述聚焦于拓扑异构酶II的功能以及药物如何改变这种重要酶的催化循环。
