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首页> 外文期刊>Biochimica et Biophysica Acta. Protein Structure and Molecular Enzymology >Crystal structures of 5-fluoro-dUrd and its 2 and/or 4-thio analogues: models of substituted dUMP pyrimidine ring interacting with thymidylate synthase
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Crystal structures of 5-fluoro-dUrd and its 2 and/or 4-thio analogues: models of substituted dUMP pyrimidine ring interacting with thymidylate synthase

机译：5-氟-dUrd及其2和/或4-硫代类似物的晶体结构：取代dUMP嘧啶环与胸苷酸合酶相互作用的模型

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摘要

In order to understand the influence on thymidylate synthase interactions with dUMP analogues of the pyrimidine ring 2- and/or 4-thio, and 5-fluoro substitutions, X-ray diffractions by crystals of 5-fluoro-dUrd and its 2- and 4-thio, and 2,4-dithio analogues were measured, the four structures solved and refined. The following conclusions were suggested by results of comparative analyses of structural parameters (bond lengths, valence angles), followed by theoretical considerations based on calculated resonance structure distributions and aromaticity indices of the uracil, thiouracil, fluorouracil and fluorothiouracil rings. The effect of 4-thio substitution of FdUMP, altering specificity of inactivation of thymidylate synthases from various sources, is probably due to weaker proton acceptor power of the 4-thio substituent and increasing acidity (enhanced proton-donor power) of the N(3)-H moiety, resulting in an impaired fitness into the network of hydrogen bonds in the enzyme active center cleft. 2,4-Dithio substitution results in (i) impaired pyrimidine ring recognition by the enzyme active center, due to the 4-thio substituent (ii) increased pyrimidine ring aromaticity in dUMP, leading to resistance of C(6) to nucleophilic attack by the enzyme active center cysteine and (iii) altered planarity of the pyrimidine ring and deflections, with respect to the ring plane, of substituent at C(2), C(4) and C(5). 5-Fluoro substitution apparently activates the pyrimidine ring towards the interaction with thymidylate synthase by producing local strain, which results in an increased reactivity as predicted by the Walsh-Bent rule.
机译：为了了解与嘧啶环2和/或4-硫基的dUMP类似物以及5-氟取代对胸苷酸合酶相互作用的影响，5-氟-dUrd及其2-和4晶体的X射线衍射测量了-硫代和2,4-二硫代类似物，解析并纯化了四个结构。结构参数（键长，化合价角）的比较分析结果提出了以下结论，然后根据尿嘧啶，硫尿嘧啶，氟尿嘧啶和氟硫尿嘧啶环的共振结构分布和芳香指数对理论进行了考虑。 FdUMP的4-硫基取代作用改变了各种来源的胸苷酸合酶失活的特异性，这可能是由于4-硫基取代基的质子受体能力较弱以及N（3的酸度（增强的质子给体功率）增加）所致。 ）-H部分，导致酶活性中心裂口中氢键网络的适应性受损。 2,4-二硫代取代导致（i）酶活性中心对嘧啶环的识别受损，这是由于4-硫取代基（ii）dUMP中嘧啶环的芳香性增加，导致C（6）受到亲核攻击的抵抗酶的活性中心半胱氨酸和（iii）改变了嘧啶环的平面性，并改变了相对于环平面的C（2），C（4）和C（5）取代基。 5-氟取代显然通过产生局部菌株而使嘧啶环朝着与胸苷酸合酶的相互作用活化，这导致了沃尔什-本特定律所预测的增加的反应性。

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