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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Promotion of purine nucleotide binding to thymidylate synthase by a potent folate analogue inhibitor, 1843U89.
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Promotion of purine nucleotide binding to thymidylate synthase by a potent folate analogue inhibitor, 1843U89.

机译：通过有效的叶酸类似物抑制剂1843U89促进嘌呤核苷酸与胸苷酸合酶的结合。

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摘要

A folate analogue, 1843U89 (U89), with potential as a chemotherapeutic agent due to its potent and specific inhibition of thymidylate synthase (TS; EC 2.1.1.45), greatly enhances not only the binding of 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and dUMP to Escherichia coli TS but also that of dGMP, GMP, dIMP, and IMP. Guanine nucleotide binding was first detected by CD analysis, which revealed a unique spectrum for the TS-dGMP-U89 ternary complex. The quantitative binding of dGMP relative to GMP, FdUMP, and dUMP was determined in the presence and absence of U89 by ultrafiltration analysis, which revealed that although the binding of GMP and dGMP could not be detected in the absence of U89 both were bound in its presence. The Kd for dGMP was about the same as that for dUMP and FdUMP, with binding of the latter two nucleotides being increased by two orders of magnitude by U89. An explanation for the binding of dGMP was provided by x-ray diffraction studies that revealed an extensive stacking interaction between the guanine of dGMP and the benzoquinazoline ring of U89 and hydrogen bonds similar to those involved in dUMP binding. In addition, binding energy was provided through a water molecule that formed hydrogen bonds to both N7 of dGMP and the hydroxyl of Tyr-94. Accommodation of the larger dGMP molecule was accomplished through a distortion of the active site and a shift of the deoxyribose moiety to a new position. These rearrangements also enabled the binding of GMP to occur by creating a pocket for the ribose 2' hydroxyl group, overcoming the normal TS discrimination against nucleotides containing the 2' hydroxyl.
机译：叶酸类似物1843U89（U89）由于对胸苷酸合酶（TS; EC 2.1.1.45）的强效和特异性抑制作用而具有作为化学治疗剂的潜力，不仅增强了5-氟-2'-脱氧尿苷5的结合， -单磷酸酯（FdUMP）和dUMP到大肠杆菌TS，还有dGMP，GMP，dIMP和IMP。鸟嘌呤核苷酸结合首先通过CD分析检测到，揭示了TS-dGMP-U89三元复合物的独特光谱。通过超滤分析确定了在存在和不存在U89的情况下dGMP相对于GMP，FdUMP和dUMP的定量结合，这表明，尽管在不存在U89的情况下也无法检测到GMP和dGMP的结合，存在。 dGMP的Kd与dUMP和FdUMP的Kd大致相同，后两个核苷酸的结合通过U89增加了两个数量级。 X射线衍射研究提供了dGMP结合的解释，该研究揭示了dGMP的鸟嘌呤和U89的苯并喹唑啉环之间的广泛堆积相互作用以及类似于dUMP结合的氢键。另外，通过水分子提供结合能，所述水分子与dGMP的N7和Tyr-94的羟基均形成氢键。较大的dGMP分子的调节是通过活性位点的扭曲和脱氧核糖部分向新位置的转移来实现的。这些重排还使得能够通过为核糖2'羟基形成一个口袋来克服与含有2'羟基的核苷酸的正常TS区分，从而实现GMP的结合。

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