13C-flux spectral analysis of host-pathogen metabolism reveals a mixed diet for intracellular Mycobacterium tuberculosis.
13C-flux spectral analysis of host-pathogen metabolism reveals a mixed diet for intracellular Mycobacterium tuberculosis.
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DOI：
10.1016/j.chembiol.2013.06.012
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发表时间：
2013-08-22
影响因子：
--
通讯作者：
McFadden J
中科院分区：
文献类型：
--
作者：
Beste DJ;Nöh K;Niedenführ S;Mendum TA;Hawkins ND;Ward JL;Beale MH;Wiechert W;McFadden J
尽管细胞内碳代谢已经成为一个有吸引力的药物靶点，但细胞内复制病原体的碳源，如结核杆菌结核分枝杆菌，它导致世界三分之一人口的长期感染，仍然是未知的。我们使用了一种基于系统的方法-13 C-通量光谱分析（FSA）与人工分析相结合-来测量结核分枝杆菌及其巨噬细胞宿主细胞之间的代谢相互作用。实验数据的13 C-FSA分析表明，结核分枝杆菌从其宿主细胞获得氨基酸、C1和C2底物的混合物。实验证实C1底物来源于CO2。对磷酸烯醇式丙酮酸羧激酶突变体进行的13 C标记实验表明，细胞内结核分枝杆菌可以接触糖酵解C3底物。这些发现为开发新的化疗药物提供了限制。直接测量结核分枝杆菌的细胞内代谢开发了用于分析宿主和病原体之间代谢相互作用的工具氨基酸C1、C2和C3是结核分枝杆菌的细胞内底物CO2被鉴定为结核分枝杆菌的细胞内碳源尽管是潜在的药物靶标，结核分枝杆菌（Mtb）的细胞内代谢是宿主病原体生物学中了解最少的方面之一。Beste等人探测直接生长在巨噬细胞内的病原体的代谢，并观察结核分枝杆菌是否能够获得多种饮食和营养。
Whereas intracellular carbon metabolism has emerged as an attractive drug target, the carbon sources of intracellularly replicating pathogens, such as the tuberculosis bacillus Mycobacterium tuberculosis, which causes long-term infections in one-third of the world’s population, remain mostly unknown. We used a systems-based approach—13C-flux spectral analysis (FSA) complemented with manual analysis—to measure the metabolic interaction between M. tuberculosis and its macrophage host cell. 13C-FSA analysis of experimental data showed that M. tuberculosis obtains a mixture of amino acids, C1 and C2 substrates from its host cell. We experimentally confirmed that the C1 substrate was derived from CO2. 13C labeling experiments performed on a phosphoenolpyruvate carboxykinase mutant revealed that intracellular M. tuberculosis has access to glycolytic C3 substrates. These findings provide constraints for developing novel chemotherapeutics. The intracellular metabolism of Mycobacterium tuberculosis was directly measured A tool for analyzing metabolic interactions between host and pathogen was developed Amino acids C1, C2, and C3 are intracellular substrates for M. tuberculosis CO2 was identified as an intracellular carbon source for M. tuberculosis Despite being a potential drug target, intracellular metabolism of Mycobacterium tuberculosis (Mtb) is one of the least understood aspects of host pathogen biology. Beste et al. probe the metabolism of the pathogen directly growing inside the macrophage and see that Mtb has access to a diverse diet and nutrients.
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