Thymidylate synthase: structure, inhibition, and strained conformations during catalysis.
Thymidylate synthase: structure, inhibition, and strained conformations during catalysis.
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DOI：
10.1016/s0163-7258(97)00099-5
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发表时间：
1997-10
影响因子：
13.5
通讯作者：
W. Montfort;A. Weichsel
中科院分区：
文献类型：
--
作者：
W. Montfort;A. Weichsel
胸苷酸合成酶（TS）是一个长期的目标化疗药物，因为它在DNA合成的核心作用，它也是感兴趣的，因为它丰富的机制功能。TS催化的反应是dUMP的甲基化，转移的甲基由辅因子亚甲基四氢叶酸（CH 2 THF）提供。近年来，通过对TS的晶体结构测定和机理研究，人们对TS的反应机理有了更深入的了解，并探讨了构象变化在TS催化和抑制中的作用。这些结构包括TS与底物dUMP结合的复合物;辅因子CH 2 THF;核苷酸类似物5-氟-dUMP、5-硝基-dUMP和dGMP;以及有前景的抗叶酸剂BW 1843、ZD 1694和AG 337。从这些研究中，出现了一个图片TS配体诱导的构象变化在催化中发挥关键作用，通过应变反应过程中发生的硫醇加合物，通过保护高反应性的反应中间体，并通过提供一种手段，以稳定的高能量构象的辅因子后，初始绑定的低能量构象。TS的最佳抑制剂还诱导和稳定TS的构象变化。一种抑制剂，BW 1843，扭曲结合的活性位点，并插入蛋白质中两个移动的亚结构域之间的疏水补丁。还讨论了细胞生物学和真核TS的调节和使用基于结构的药物设计的抗叶酸剂目前在临床试验中用于治疗癌症的发展的最新进展。
Thymidylate synthase (TS) is a long-standing target for chemotherapeutic agents because of its central role in DNA synthesis, and it is also of interest because of its rich mechanistic features. The reaction catalyzed by TS is the methylation of dUMP, with the transferred methyl group provided by the cofactor methylenetetrahydrofolate (CH2THF). Recently, several crystal structure determinations and mechanistic studies have led to a deeper understanding of the TS reaction mechanism, and address the role of conformational change in TS catalysis and inhibition. Included among these structures are complexes of TS bound to substrate dUMP; cofactor CH2THF; the nucleotide analogs 5-fluoro-dUMP, 5-nitro-dUMP and dGMP; and the promising antifolates BW1843, ZD1694, and AG337. From these studies, a picture of TS emerges where ligand-induced conformational changes play key roles in catalysis by straining the thiol adduct that occurs during the reaction; by protecting the highly reactive reaction intermediates; and by providing a means to stabilize a high-energy conformer of the cofactor after initial binding of a low-energy conformer. The best inhibitors of TS also induce and stabilize a conformational change in TS. One inhibitor, BW1843, distorts the active site on binding, and intercalates into a hydrophobic patch between two mobile subdomains in the protein. Also discussed are recent developments in the cell biology and regulation of eukaryotic TS and the use of structure-based drug design in the development of the antifolates currently in clinical trial for the treatment of cancer.