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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >An unusual type IB topoisomerase from African trypanosomes
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An unusual type IB topoisomerase from African trypanosomes

机译：来自非洲锥虫的不寻常的IB型拓扑异构酶

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African trypanosomes are ancient eukaryotes that cause lethal disease in humans and cattle. Available drugs are inadequate and the need for new therapeutic targets is great. Trypanosoma brucei and related pathogens differ strikingly from higher eukaryotes in many aspects of nucleic acid structure and metabolism. We find yet another example of this in their unusual DNA topoisomerase IB. Type IB topoisomerases relieve the supercoils that accumulate during DNA and RNA synthesis, and are of considerable importance as the target for antitumor camptothecins. Dozens of type IB topoisomerases sequenced from eukaryotes, bacteria, and pox viruses are all encoded by a single gene that predictably contains a highly conserved DNA binding domain and C-terminal catalytic domain, linked by a nonconserved hydrophilic region. We find that topoisomerase IB in T. brucei is encoded by two genes: one for the DNA-binding domain and a second for the C-terminal catalytic domain. In keeping with this, highly purified fractions of native T. brucei topoisomerase IB catalytic activity contain two proteins, of 90 and 36 kDa. The native enzyme is conventional in its Mg2+-independence, ability to relax positive and negative supercoils, and inhibition by camptothecin. Camptothecin promotes the formation of a covalent complex between P-32-labeled substrate DNA and the small subunit. This unusual structural organization may provide a missing link in the evolution of type IB enzymes, which are thought to have arisen over time from the fusion of two independent domains. It also provides another basis for the design of selectively toxic drug candidates. [References: 32]
机译：非洲锥虫是古老的真核生物，可导致人类和牛的致死性疾病。现有药物不足，对新治疗靶标的需求很大。布氏锥虫和相关病原体在核酸结构和代谢的许多方面与高级真核生物显着不同。我们在其不寻常的DNA拓扑异构酶IB中找到了另一个例子。 IB型拓扑异构酶可缓解在DNA和RNA合成过程中积累的超螺旋，并且作为抗肿瘤喜树碱的靶标具有相当重要的意义。从真核生物，细菌和痘病毒中测序的数十种IB型拓扑异构酶均由单个基因编码，该基因可预测地包含高度保守的DNA结合结构域和C端催化结构域，并通过非保守的亲水性区域连接。我们发现布氏锥虫中的拓扑异构酶IB由两个基因编码：一个基因用于DNA结合结构域，另一个基因用于C末端催化结构域。因此，天然布鲁氏菌拓扑异构酶IB催化活性的高度纯化的级分包含两种蛋白，分别为90和36kDa。天然酶在其Mg2 +独立性，放松正负超螺旋的能力以及喜树碱的抑制作用方面是常规的。喜树碱促进P-32标记的底物DNA与小亚基之间共价复合物的形成。这种不寻常的结构组织可能在IB型酶的进化中提供了缺失的环节，据认为这种酶是随着时间的流逝由两个独立域的融合而产生的。它还为设计选择性毒性候选药物提供了另一个基础。 [参考：32]

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