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首页> 外文期刊>Journal of Molecular Biology >Pyruvate Kinase Regulates the Pentose-Phosphate Pathway in Response to Hypoxia in Mycobacterium tuberculosis
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Pyruvate Kinase Regulates the Pentose-Phosphate Pathway in Response to Hypoxia in Mycobacterium tuberculosis

机译：丙酮酸激酶响应结核分枝杆菌的缺氧来调节磷酸磷酸盐途径

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摘要

In response to the stress of infection, Mycobacterium tuberculosis (Mtb) reprograms its metabolism to accommodate nutrient and energetic demands in a changing environment. Pyruvate kinase (PYK) is an essential glycolytic enzyme in the phosphoenolpyruvate-pyruvate-oxaloacetate node that is a central switch point for carbon flux distribution. Here we show that the competitive binding of pentose monophosphate inhibitors or the activator glucose 6 -phosphate (G6P) to MtbPYK tightly regulates the metabolic flux. Intriguingly, pentose monophosphates were found to share the same binding site with G6P. The determination of a crystal structure of MtbPYK with bound ribose 5 -phosphate (R5P), combined with biochemical analyses and molecular dynamic simulations, revealed that the allosteric inhibitor pentose monophosphate increases PYK structural dynamics, weakens the structural network communication, and impairs substrate binding. G6P, on the other hand, primes and activates the tetramer by decreasing protein flexibility and strengthening allosteric coupling. Therefore, we propose that MtbPYK uses these differences in conformational dynamics to up- and down-regulate enzymic activity. Importantly, metabolome profiling in mycobacteria reveals a significant increase in the levels of pentose monophosphate during hypoxia, which provides insights into how PYK uses dynamics of the tetramer as a competitive allosteric mechanism to retard glycolysis and facilitate metabolic reprogramming toward the pentose-phosphate pathway for achieving redox balance and an anticipatory metabolic response in Mtb. (C) 2019 Elsevier Ltd. All rights reserved.
机译：为了应对感染的应力，结核分枝杆菌（MTB）重新编程其新陈代谢，以适应不断变化的环境中的营养和能量需求。丙酮酸激酶（PyK）是磷酸丙酯 - 丙酮酸丙酯 - 乙酸盐节点中的必需甘油酶，其是用于碳通量分布的中央开关点。在这里，我们表明戊糖单磷酸盐抑制剂或活化剂葡萄糖6-磷酸（G6P）至MTBPYK的竞争结合严格调节代谢通量。发现戊糖单磷酸盐与G6P共享相同的结合位点。用结合核糖5-磷酸（R5P）的MTBPYK晶体结构的测定与生物化学分析和分子动态模拟相结合，揭示了颠覆性抑制剂戊糖单磷酸盐，削弱了结构网络通信，削弱了底物粘合。另一方面，G6P，通过降低蛋白质柔性和强化渐变偶联来引用并激活四聚体。因此，我们建议MTBPYK使用这些差异构象动态到上调和下调酶活性。重要的是，分枝杆菌的代谢物质概况揭示了缺氧期间的戊糖单磷酸盐水平的显着增加，这提供了对Pyk如何使用Teltamer的动态作为竞争性的变构机制来延迟糖酵解，并促进代谢重新编程为实现磷酸磷酸术路径氧化还原平衡与MTB中的预期代谢反应。 （c）2019 Elsevier Ltd.保留所有权利。

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  • 来源
    《Journal of Molecular Biology》 |2019年第19期|共16页
  • 作者

    Zhong Wenhe; Guo Jingjing; Cui Liang; Chionh Yok Hian; Li Kuohan; El Sahili Abbas; Cai Qixu; Yuan Meng; Michels Paul A. M.; Fothergill-Gilmore Linda A.; Walkinshaw Malcolm D.; Mu Yuguang; Lescar Julien; Dedon Peter C.;

  • 作者单位

    Singapore MIT Alliance Res &

    Technol Antimicrobial Resistance Interdisciplinary Res Gr 1 CREATE;

    Nanyang Technol Univ Singapore Ctr Environm Sci Engn SCELSE 60 Nanyang Dr Singapore 637551;

    Singapore MIT Alliance Res &

    Technol Antimicrobial Resistance Interdisciplinary Res Gr 1 CREATE;

    Singapore MIT Alliance Res &

    Technol Antimicrobial Resistance Interdisciplinary Res Gr 1 CREATE;

    Nanyang Technol Univ NTU Inst Struct Biol Singapore 636921 Singapore;

    Nanyang Technol Univ NTU Inst Struct Biol Singapore 636921 Singapore;

    Hong Kong Univ Sci &

    Technol State Key Lab Mol Neurosci Div Life Sci Kowloon Clear Water Bay;

    Univ Edinburgh Inst Quantitat Biol Biochem &

    Biotechnol Kings Bldg Edinburgh EH9 38F Midlothian;

    Univ Edinburgh Inst Quantitat Biol Biochem &

    Biotechnol Kings Bldg Edinburgh EH9 38F Midlothian;

    Univ Edinburgh Inst Quantitat Biol Biochem &

    Biotechnol Kings Bldg Edinburgh EH9 38F Midlothian;

    Univ Edinburgh Inst Quantitat Biol Biochem &

    Biotechnol Kings Bldg Edinburgh EH9 38F Midlothian;

    Nanyang Technol Univ Sch Biol Sci 60 Nanyang Dr Singapore 637551 Singapore;

    Nanyang Technol Univ NTU Inst Struct Biol Singapore 636921 Singapore;

    Singapore MIT Alliance Res &

    Technol Antimicrobial Resistance Interdisciplinary Res Gr 1 CREATE;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子生物学;
  • 关键词

    allosteric regulation; structural dynamics; metabolic reprogramming; stress response;

    机译：变构规则;结构动力学;代谢重编程;压力反应;

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