DNA topoisomerase I inhibitors: chemistry, biology, and interfacial inhibition.
DNA topoisomerase I inhibitors: chemistry, biology, and interfacial inhibition.
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DOI：
10.1021/cr900097c
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发表时间：
2009-07
期刊：
影响因子：
62.1
通讯作者：
Pommier, Yves
中科院分区：
文献类型：
--
作者：
Pommier, Yves
DNA拓扑异构酶I和II （Top1和Top2）是公认的抗癌药物的分子靶点。1-5哺乳动物体细胞表达6种拓扑异构酶基因：2种TOP1 (TOP1和TOP1mt)， 2种TOP2 （TOP2R和），2种拓扑异构酶III （TOP3R和）6,7（图1A）。最近发现的真核生物拓扑异构酶是线粒体Top1 (Top1mt)，我们在2001年报道过。8,9拓扑异构酶的一个共同特征是它们的催化机制，在所有情况下都是由拓扑异构酶的催化酪氨酸残基对DNA磷酸二酯键的亲核攻击组成的。对于Top1酶（Top1和Top1mt），酪氨酸与DNA磷酸的共价附着要么在断裂DNA的3 ‘端，要么在其他拓扑异构酶的断裂DNA的5 ’端（图1）。因此，Top1酶是唯一与断裂DNA的3 ‘端形成共价键，同时在断裂的另一端产生5 ’ -羟基端的拓扑异构酶。在这方面，真核Top1酶属于原核生物和酵母中更广泛的位点特异性酪氨酸重组酶家族（例如，大肠杆菌的XerCD，噬菌体λ整合酶和Cre重组酶，以及酿酒酵母的Flp）。Top1酶的另一个独特特征是它们的DNA弛豫机制是通过“受控旋转”而不是“链通道”。换句话说，Top1酶通过让5 ' -羟基末端围绕完整链旋转来放松DNA。这个过程反应不需要ATP或二价金属结合，这与Top2酶的情况不同，Top2酶既需要ATP水解，也需要Mg2+。像其他IA型拓扑异构酶一样，Top3酶需要Mg2+（但不需要ATP）来催化，在放松DNA超卷曲方面不是很活跃。当DNA呈负向超卷曲（单链）时，它们可以一次一次地使DNA放松。此外，Top2和Top3酶都是通过链通道分配机制而不是通过Top1酶的过程控制旋转来改变DNA拓扑结构的。在Top2酶的情况下，一个完整的DNA双链[称为T（运输）链]通过酶同型二聚体造成的双链断裂5,16,17（图1A）。在Top3酶的情况下，单链通过单链断裂，14通常在双霍利迪结交叉。18 Top1的缺口闭合活性的显著效率使酶能够以相似的效率放松负和正超螺旋DNA（即使在0℃）19。这与Top2R相反，它更有效地放松正超卷曲。值得注意的是，Top2和Top1一样，同时放松了正、负超级线圈
DNA topoisomerases I and II (Top1 and Top2) are established molecular targets of anticancer drugs. 1-5 Mammalian somatic cells express six topoisomerase genes: two TOP1 (TOP1 and TOP1mt), two TOP2 (TOP2R and), and two topoisomerase III (TOP3R and) 6, 7 (Figure 1A). The most recently discovered eukaryotic topoisomerase is mitochondrial Top1 (Top1mt), which we reported in 2001. 8, 9 A common feature of topoisomerases is their catalytic mechanism, which in all cases consists in a nucleophilic attack of a DNA phosphodiester bond by a catalytic tyrosyl residue from the topoisomerase. The resulting covalent attachment of the tyrosine to the DNA phosphate is either at the 3′-end of the broken DNA in the case of Top1 enzymes (Top1 and Top1mt) or at the 5′-end of the broken DNA for the other topoisomerases (Figure 1). Thus, Top1 enzymes are the only topoisomerases that form a covalent link with the 3′-end of the broken DNA while generating a 5′-hydroxyl end at the other end of the break. In that respect, the eukaryotic Top1 enzymes belong to the broader family of site-specific tyrosine recombinases of prokaryotes and yeast (eg, XerCD of Escherichia coli, bacteriophage λ integrase and Cre recombinase, and Flp of Saccharomyces cereVisiae). Another unique feature of the Top1 enzymes is their DNA relaxation mechanism by “controlled rotation” rather than by “strand passage”. 10-12 In other words, Top1 enzymes relax DNA by letting the 5′-hydroxyl end swivel around the intact strand. This processive reaction does not require ATP or divalent metal binding, which is different from the case of Top2 enzymes, which require both ATP hydrolysis and Mg2+. 5, 13 Top3 enzymes, like other type IA topoisomerases require Mg2+(but no ATP) for catalysis, 14 are not very active in relaxing DNA supercoiling. They can relax DNA when it is very negatively supercoiled (single-stranded) one turn at a time. 15 Moreover, both Top2 and Top3 enzymes change DNA topology by a strand passage distributive mechanism rather than by the processive controlled rotation of the Top1 enzymes. In the case of the Top2 enzymes, a full DNA duplex [referred to as the T (transported) strand] goes through the double-strand break made by an enzyme homodimer5, 16, 17 (Figure 1A). In the case of the Top3 enzymes, a single strand goes through the single-stranded break, 14 typically at double-Holliday junction crossovers. 18 The remarkable efficiency of the nicking-closing activity of Top1 enables the enzyme to relax both negatively and positively supercoiled DNA (even at 0 C) 19 with similar efficiency. 12 This is in contrast with Top2R, which relaxes more efficiently positive supercoiling. 20 Of note, Top2, like Top1, relaxes both positive and negative supercoils simi-
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