Gupta M, Zhu C X, Tse-Dinh Y C
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla 10595.
J Biol Chem. 1992 Dec 5;267(34):24177-80.
Although highly homologous to the other eukaryotic type I DNA topoisomerases, vaccinia virus DNA topoisomerase I is distinct in its resistance to the anti-cancer drug camptothecin. After comparison of available sequences of sensitive and resistant type I topoisomerases, the aspartic acid at position 221 of vaccinia virus topoisomerase I is mutated to a valine. The resulting mutant protein is partially active. In contrast to the wild type enzyme, the relaxation of supercoiled DNA is inhibited by camptothecin. Its cleavage reaction with DNA is enhanced by camptothecin due to inhibition of religation of DNA. This demonstrates that even though the size of vaccinia virus is only about one-third that of the other camptothecin-sensitive topoisomerases, it has a potential interaction site for camptothecin.
尽管痘苗病毒DNA拓扑异构酶I与其他真核生物I型DNA拓扑异构酶高度同源，但它对抗癌药物喜树碱具有独特的抗性。在比较了敏感型和抗性I型拓扑异构酶的现有序列后，痘苗病毒拓扑异构酶I第221位的天冬氨酸突变为缬氨酸。产生的突变蛋白具有部分活性。与野生型酶相反，喜树碱抑制超螺旋DNA的松弛。由于DNA再连接受到抑制，喜树碱增强了其与DNA的切割反应。这表明，尽管痘苗病毒的大小仅约为其他对喜树碱敏感的拓扑异构酶的三分之一，但它具有喜树碱的潜在相互作用位点。
