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首页> 外文期刊>Journal of Molecular Biology >Fluoroquinolone-dependent DNA supercoiling by vaccinia topoisomerase I
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Fluoroquinolone-dependent DNA supercoiling by vaccinia topoisomerase I

机译：牛痘拓扑异构酶I对氟喹诺酮依赖性DNA超螺旋

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摘要

Vaccinia topoisomerase I is a site-specific DNA strand transferase that acts through a DNA-(3'-phosphotyrosyl)-enzyme intermediate, resulting in relaxation of supercoiled DNA. Although Vaccinia topoisomerase I is not an essential enzyme, its role in early transcription makes it a potential antiviral target. We describe the interaction of Vaccinia topoisomerase I with fluoroquinolone antibiotics otherwise known to target DNA gyrase and topoisomerase IV in bacterial cells. The fluoroquinolone enrofloxacin inhibits DNA relaxation by Vaccinia topoisomerase I at concentrations similar to those required for inhibition by the coumarin drugs coumermycin and novobiocin. When Vaccinia topoisomerase I is presented with relaxed DNA in the presence of enrofloxacin, it executes the reverse reaction, supercoiling the DNA. Further characterization indicates that enrofloxacin does not interfere with the initial strand scission by Vaccinia topoisomerase I. The structurally related fluoroquinolones moxifloxacin and lomefloxacin have no effect on the topoisomerase at the concentrations at which enrofloxacin mediates DNA supercoiling. The mechanism with which Vaccinia topoisomerase I supercoils relaxed DNA, an energetically unfavorable, yet ATP-independent process, must entail protein-DNA contacts downstream of the cleavage site, as opposed to the free rotation mechanism proposed for DNA relaxation; as proposed for fluoroquinolone-mediated inhibition of gyrase, the drug may target a preformed topoisomerase I-DNA complex to induce conformational changes in the enzyme that permit such contacts. (C) 2004 Elsevier Ltd. All rights reserved.
机译：牛痘拓扑异构酶I是一种位点特异性DNA链转移酶，它通过DNA-（3'-磷酸酪氨酰基）-酶中间体起作用，导致超螺旋DNA松弛。尽管痘苗拓扑异构酶I不是必需的酶，但它在早期转录中的作用使其成为潜在的抗病毒靶标。我们描述了痘苗拓扑异构酶I与氟喹诺酮类抗生素的相互作用，否则该抗菌素已知可靶向细菌细胞中的DNA促旋酶和拓扑异构酶IV。氟喹诺酮恩诺沙星以类似于香豆素药物香豆霉素和新霉素的抑制浓度，通过牛痘拓扑异构酶I抑制DNA松弛。在恩诺沙星的存在下，当痘苗病毒拓扑异构酶I与松弛的DNA一起出现时，它会执行逆反应，使DNA超螺旋。进一步的特征表明，恩诺沙星不会干扰痘苗病毒拓扑异构酶I对链的最初分裂。与结构相关的氟喹诺酮类莫西沙星和洛美沙星在恩诺沙星介导DNA超螺旋的浓度下对拓扑异构酶没有影响。 Vaccinia拓扑异构酶I超螺旋松弛DNA的机制，在能量上是不利的，但与ATP无关，必须使蛋白质-DNA接触切割位点的下游，这与DNA松弛所建议的自由旋转机制相反;如提出用于氟喹诺酮介导的回旋酶抑制，该药物可靶向预先形成的拓扑异构酶I-DNA复合物，以诱导允许这种接触的酶构象变化。 （C）2004 Elsevier Ltd.保留所有权利。

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