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首页> 外文期刊>Chemical biology and drug design >Interdomain twists of human thymidine phosphorylase and its active-inactive conformations: Binding of 5-FU and its analogues to human thymidine phosphorylase versus dihydropyrimidine dehydrogenase
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Interdomain twists of human thymidine phosphorylase and its active-inactive conformations: Binding of 5-FU and its analogues to human thymidine phosphorylase versus dihydropyrimidine dehydrogenase

机译：人胸苷磷酸化酶及其活性无活性构象：5-FU及其类似物与人胸苷磷酸化酶与二氢嘧啶脱氢酶的结合

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摘要

5-fluorouracil (5-FU) is an anticancer drug, which inhibits human thymidine phosphorylase (hTP) and plays a key role in maintaining the process of DNA replication and repair. It is involved in regulating pyrimidine nucleotide production, by which it inhibits the mechanism of cell proliferation and cancerous tumor growth. However, up to 80% of the administered drug is metabolized by dihydropyrimidine dehydrogenase (DPD). This work compares binding of 5-FU and its analogues to hTP and DPD, and suggests strategies to reduce drug binding to DPD to decrease the required dose of 5-FU. An important feature between the proteins studied here was the difference of charge distribution in their binding sites, which can be exploited for designing drugs to selectively bind to the hTP. The 5-FU presence was thought to be required for a closed conformation. Comparison of the calculation results pertaining to unliganded and liganded protein showed that hTP could still undergo open-closed conformations in the absence of the ligand; however, the presence of a positively charged ligand better stabilizes the closed conformation and rigidifies the core region of the protein more than unliganded or neutral liganded system. The study has also shown that one of the three hinge segments linking the two major alpha and alpha/beta domains of the hTP is an important contributing factor to the enzyme's open-close conformational twist during its inactivation-activation process. In addition, the angle between the alpha/beta-domain and the alpha-domain has shown to undergo wide rotations over the course of MD simulation in the absence of a phosphate, suggesting that it contributes to the stabilization of the closed conformation of the hTP.
机译：5-氟尿嘧啶（5-FU）是一种抗癌药物，其抑制人胸苷磷酸化酶（HTP），并在维持DNA复制和修复过程中发挥关键作用。它参与调节嘧啶核苷酸产生，其抑制细胞增殖和癌性肿瘤生长的机制。然而，通过二氢嘧啶脱氢酶（DPD）来代谢至多80％的给药药物。这项工作比较了5-FU及其类似物与HTP和DPD的结合，并表明减少对DPD的药物结合以降低5-FU所需剂量的策略。这里研究的蛋白质之间的一个重要特征是其结合位点中的电荷分布的差异，这可以利用用于设计药物以选择性地结合HTP。被认为是闭合构象所要求的5-FU存在。与未结合和配体蛋白有关的计算结果的比较表明，HTP在没有配体的情况下仍然可以经历开孔;然而，具有带正电荷的配体的存在更好地稳定闭合构象并符合蛋白质的核心区域，而不是预粘的或中性配合体系。该研究还表明，连接HTP的两个主要α和α/β结构域的三个铰链段中的一种是酶在其失活激活过程中的开闭构象扭曲的重要因素。另外，α/β-结构域和α-结构域之间的角度显示在没有磷酸盐的情况下在MD模拟过程中经历宽旋转，这表明它有助于稳定HTP的闭合构象。

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