Metabolic flux partitioning between the TCA cycle and glyoxylate shunt combined with a reversible methyl citrate cycle provide nutritional flexibility for Mycobacterium tuberculosis
Metabolic flux partitioning between the TCA cycle and glyoxylate shunt combined with a reversible methyl citrate cycle provide nutritional flexibility for Mycobacterium tuberculosis
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TCA 循环和乙醛酸分流之间的代谢通量分配与可逆柠檬酸甲酯循环相结合，为结核分枝杆菌提供了营养灵活性
DOI：
10.1101/2021.01.29.428863
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Borah K
中科院分区：
文献类型：
--
作者：
Borah K
结核分枝杆菌(Mtb)需要利用多种宿主来源的碳底物才能成功地维持结核感染，从而将Mtb特定的代谢途径和碳共代谢所需的酶确定为潜在的药物靶点。代谢通量代表了许多不同水平的细胞调节的最终综合结果，这些调节有助于代谢物在代谢网络中的流动。因此，我们对不同条件下代谢通量的重新连接有一个深入的了解是至关重要的。在这里，我们使用稳定同位素示踪剂(13C和2H)的13C代谢通量分析和脂类指纹图谱来研究在稳态恒化器中在生理相关碳源上缓慢生长的Mtb的代谢网络。我们证明，Mtb能够有效地协同代谢胆固醇或甘油的组合以及C2生成碳底物。Mtb在整个网络中对碳源的统一同化表明，在这些条件下没有代谢区划，但代谢通量存在底物特有的差异。这项工作发现，三氯乙酸循环和乙醛分流之间的通量分配与可逆的柠檬酸甲酯循环相结合是Mtb营养灵活性的关键代谢节点。这些发现为代谢结构提供了新的见解，使结核分枝杆菌对不同的碳底物具有适应性。重要每年有超过100万人死于结核病(TB)。更多的人被感染，但成功地诊断和治疗了抗生素，然而耐药结核病分离株正变得越来越普遍，因此迫切需要新的治疗方法来有效地杀死病原体。结核分枝杆菌特异性代谢途径已被确定为治疗结核病的重要药物靶点。然而，这种病原体明显的代谢可塑性是有效靶向Mtb特异性脆弱性的主要障碍，因此确定Mtb在不同条件下使用的代谢通量是至关重要的。在这里，我们使用~(13)C代谢通量分析来测量结核分枝杆菌在生长在潜在的活体营养素上时所使用的代谢通量。我们的分析确定了代谢网络的选择性使用，包括TCA循环、乙醛分流和柠檬酸甲酯循环。本研究中确定的代谢通量表型通过Mtb确定可逆的柠檬酸甲酯循环和乙醛分流作为Mtb营养灵活性的关键代谢节点，从而提高了我们对多个碳底物共代谢的理解。
The utilisation of multiple host-derived carbon substrates is required byMycobacterium tuberculosis(Mtb) to successfully sustain a tuberculosis infection thereby identifying the Mtb specific metabolic pathways and enzymes required for carbon co-metabolism as potential drug targets. Metabolic flux represents the final integrative outcome of many different levels of cellular regulation that contribute to the flow of metabolites through the metabolic network. It is therefore critical that we have an in-depth understanding of the rewiring of metabolic fluxes in different conditions. Here, we employed13C-metabolic flux analysis using stable isotope tracers (13C and2H) and lipid fingerprinting to investigate the metabolic network of Mtb growing slowly on physiologically relevant carbon sources in a steady state chemostat. We demonstrate that Mtb is able to efficiently co-metabolise combinations of either cholesterol or glycerol along with C2 generating carbon substrates. The uniform assimilation of the carbon sources by Mtb throughout the network indicated no compartmentalization of metabolism in these conditions however there were substrate specific differences in metabolic fluxes. This work identified that partitioning of flux between the TCA cycle and the glyoxylate shunt combined with a reversible methyl citrate cycle as the critical metabolic nodes which underlie the nutritional flexibility of Mtb. These findings provide new insights into the metabolic architecture that affords adaptability of Mtb to divergent carbon substrates.ImportanceEach year more than 1 million people die of tuberculosis (TB). Many more are infected but successfully diagnosed and treated with antibiotics, however antibiotic-resistant TB isolates are becoming ever more prevalent and so novel therapies are urgently needed that can effectively kill the causative agent. Mtb specific metabolic pathways have been identified as an important drug target in TB. However the apparent metabolic plasticity of this pathogen presents a major obstacle to efficient targeting of Mtb specific vulnerabilities and therefore it is critical to define the metabolic fluxes that Mtb utilises in different conditions. Here, we used13C-metabolic flux analysis to measure the metabolic fluxes that Mtb uses whilst growing on potentialin vivonutrients. Our analysis identified selective use of the metabolic network that included the TCA cycle, glyoxylate shunt and methyl citrate cycle. The metabolic flux phenotypes determined in this study improves our understanding about the co-metabolism of multiple carbon substrates by Mtb identifying a reversible methyl citrate cycle and the glyoxylate shunt as the critical metabolic nodes which underlie the nutritional flexibility of Mtb.
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GSMN-ML-人类专性病原体麻风分枝杆菌的基因组规模代谢网络重建
DOI：
10.1101/819508
发表时间：
2019
期刊：
--
影响因子：
--
作者：
Borah K
通讯作者：
Borah K
影响因子：
5.4
作者：
Jackson, Mary
通讯作者：
Jackson, Mary
13C 代谢通量分析确定了分枝杆菌中丙酮酸异化的不寻常途径，需要异柠檬酸裂解酶和二氧化碳固定
影响因子：
6.7
作者：
D. Beste;B. Bonde;Nathaniel D. Hawkins;J. Ward;M. H. Beale;S. Noack;Katharina Nö;N. Kruger;R. Ratcliffe;J. McFadden;Eric J. Rubin
通讯作者：
Eric J. Rubin
影响因子：
30.3
作者：
Russell DG;VanderVen BC;Lee W;Abramovitch RB;Kim MJ;Homolka S;Niemann S;Rohde KH
通讯作者：
Rohde KH
影响因子：
6.4
作者：
Crowe AM;Casabon I;Brown KL;Liu J;Lian J;Rogalski JC;Hurst TE;Snieckus V;Foster LJ;Eltis LD
通讯作者：
Eltis LD