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首页> 外文期刊>Chemistry: A European journal >Study of the Phosphoryl-Transfer Mechanism of Shikimate Kinase by NMR Spectroscopy
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Study of the Phosphoryl-Transfer Mechanism of Shikimate Kinase by NMR Spectroscopy

机译：ki酸酯激酶磷酸转移机理的NMR光谱研究

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摘要

The phosphoryl-transfer mechanism of shikimate kinase from Mycobacterium tuberculosis and Helicobacter pylori, which is an attractive target for antibiotic drug discovery, has been studied by 1D H-1 and (PNMR)-P-31 spectroscopy. Metaphosphoric acid proved to be a good mimetic of the metaphosphate intermediate and facilitated the ready and rapid evaluation by NMR spectroscopic analysis of a dissociative mechanism. The required closed form of the active site for catalysis was achieved by the use of ADP (product) or two synthetic ADP analogues (AMPNP, AMPCP). Molecular dynamics simulation studies reported here also revealed that the essential arginine (Arg116/Arg117 in H. pylori and M. tuberculosis, respectively), which activates the -phosphate group of ATP for catalysis and triggers the release of the product for turnover, would also be involved in the stabilisation of the metaphosphate intermediate during catalysis. We believe that the studies reported here will be helpful for future structure-based design of inhibitors of this attractive target. The approach is also expected be useful for studies on the possible dissociative mechanism of other kinase enzymes.
机译：通过1D H-1和（PNMR）-P-31光谱研究了结核分枝杆菌和幽门螺杆菌的sh草酸激酶的磷酸化转移机制，这是发现抗生素药物的诱人靶标。偏磷酸证明是偏磷酸酯中间体的良好模拟物，并通过离解机理的NMR光谱分析促进了快速简便的评估。通过使用ADP（产品）或两种合成的ADP类似物（AMPNP，AMPCP），可以实现催化活性位点所需的封闭形式。此处报道的分子动力学模拟研究还表明，必需精氨酸（分别在幽门螺杆菌和结核分枝杆菌中的Arg116 / Arg117）也可以激活ATP的-磷酸基团进行催化并触发产物的释放以实现周转。在催化过程中参与偏磷酸酯中间体的稳定化。我们相信，这里报道的研究将有助于该有吸引力的靶标抑制剂的未来基于结构的设计。该方法也有望用于研究其他激酶可能的解离机理。

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