Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis.
Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis.
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DOI：
10.15252/msb.202110280
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发表时间：
2021-05
影响因子：
9.9
通讯作者：
Beste DJV
中科院分区：
文献类型：
--
作者：
Borah K;Mendum TA;Hawkins ND;Ward JL;Beale MH;Larrouy-Maumus G;Bhatt A;Moulin M;Haertlein M;Strohmeier G;Pichler H;Forsyth VT;Noack S;Goulding CW;McFadden J;Beste DJV
结核分枝杆菌（Mtb）需要多种宿主来源的碳底物的共催化才能成功维持结核感染。然而，这种病原体的代谢可塑性和代谢网络的复杂性，在确定那些节点最适合治疗干预提出了一个主要障碍。因此，我们确定不同条件下结核分枝杆菌的代谢表型至关重要。我们使用稳定同位素和脂质指纹进行代谢通量分析，以研究在稳态恒化器系统中缓慢生长的Mtb的代谢网络。我们证明，结核分枝杆菌有效地共代谢胆固醇或甘油，与二碳生成底物结合，而没有任何代谢区室化。我们发现，TCA循环和乙醛酸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的营养灵活性的基础的关键代谢节点。这些研究结果提供了新的见解的代谢结构，提供适应性的细菌不同的碳底物和扩大我们的基本知识柠檬酸甲酯循环和乙醛酸分流。应用稳定同位素定量代谢分析、脂质指纹分析和数学建模研究了稳态恒化器系统中缓慢生长的结核分枝杆菌的代谢网络。
The co‐catabolism of multiple host‐derived carbon substrates is required by Mycobacterium tuberculosis (Mtb) to successfully sustain a tuberculosis infection. However, the metabolic plasticity of this pathogen and the complexity of the metabolic networks present a major obstacle in identifying those nodes most amenable to therapeutic interventions. It is therefore critical that we define the metabolic phenotypes of Mtb in different conditions. We applied metabolic flux analysis using stable isotopes and lipid fingerprinting to investigate the metabolic network of Mtb growing slowly in our steady‐state chemostat system. We demonstrate that Mtb efficiently co‐metabolises either cholesterol or glycerol, in combination with two‐carbon generating substrates without any compartmentalisation of metabolism. We discovered that partitioning of flux between the TCA cycle and the glyoxylate shunt combined with a reversible methyl citrate cycle is the critical metabolic nodes which underlie the nutritional flexibility of Mtb. These findings provide novel insights into the metabolic architecture that affords adaptability of bacteria to divergent carbon substrates and expand our fundamental knowledge about the methyl citrate cycle and the glyoxylate shunt. Quantitative metabolic analysis using stable isotopes, lipid fingerprinting, and mathematical modelling are applied to investigate the metabolic network of Mycobacterium tuberculosis growing slowly in a steady state chemostat system.
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影响因子：
--
作者：
Beste DJ;Nöh K;Niedenführ S;Mendum TA;Hawkins ND;Ward JL;Beale MH;Wiechert W;McFadden J
通讯作者：
McFadden J
影响因子：
14.8
作者：
Liu L;Shah S;Fan J;Park JO;Wellen KE;Rabinowitz JD
通讯作者：
Rabinowitz JD
影响因子：
--
作者：
de Carvalho, Luiz Pedro S.;Fischer, Steven M.;Rhee, Kyu Y.
通讯作者：
Rhee, Kyu Y.
影响因子：
3.2
作者：
Beste, D. J. V.;Laing, E.;McFadden, J. J.
通讯作者：
McFadden, J. J.
影响因子：
4.8
作者：
Contreras, Heidi;Joens, Matthew S.;Goulding, Celia W.
通讯作者：
Goulding, Celia W.