Intracellular Mycobacterium tuberculosis Exploits Host-derived Fatty Acids to Limit Metabolic Stress
Intracellular Mycobacterium tuberculosis Exploits Host-derived Fatty Acids to Limit Metabolic Stress
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DOI：
10.1074/jbc.m112.445056
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发表时间：
2013-03-08
影响因子：
4.8
通讯作者：
Russell, David G.
中科院分区：
文献类型：
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作者：
Lee, Wonsik;VanderVen, Brian C.;Russell, David G.
最近的数据表明，结核分枝杆菌 (Mtb) 在其宿主细胞内可获得的营养物质的多样性受到限制。脂肪酸和胆固醇似乎更受青睐；然而，它们的降解可能会导致某些代谢应激。它们的分解会产生丙酰辅酶A，从而产生潜在有毒的中间体。丙酰辅酶A的解毒依赖于甲基柠檬酸循环、甲基丙二酰途径的活性，或丙酰辅酶A与细胞壁中甲基支链脂质的结合。目前的工作探索通过这些途径的碳通量，主要关注那些负责将丙酰辅酶A掺入毒力相关细胞壁脂质的途径。利用遗传和生化救援，我们证明了结核分枝杆菌在其宿主巨噬细胞内经历了这些代谢压力，并且细菌访问了宿主脂肪酸库。这些宿主脂质的代谢扩大了乙酰辅酶A库并减轻了丙酰辅酶A的压力。这些数据对于我们了解感染过程中结核分枝杆菌的中枢代谢具有重要意义。
Recent data indicate that the nutrients available to Mycobacterium tuberculosis (Mtb) inside its host cell are restricted in their diversity. Fatty acids and cholesterol appear more favored; however, their degradation can result in certain metabolic stresses. Their breakdown can generate propionyl-CoA, which gives rise to potentially toxic intermediates. Detoxification of propionyl-CoA relies on the activity of the methylcitrate cycle, the methylmalonyl pathway, or incorporation of the propionyl-CoA into methyl-branched lipids in the cell wall. The current work explores carbon flux through these pathways, focusing primarily on those pathways responsible for the incorporation of propionyl-CoA into virulence-associated cell wall lipids. Exploiting both genetic and biochemical rescue, we demonstrate that these metabolic pressures are experienced by Mtb inside its host macrophage and that the bacterium accesses host fatty acid stores. The metabolism of these host lipids expands the acetyl-CoA pool and alleviates the pressure from propionyl-CoA. These data have major implications for our appreciation of central metabolism of Mtb during the course of infection.