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A Lysine Acetyltransferase Contributes to the Metabolic Adaptation to Hypoxia in Mycobacterium tuberculosis.
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2018-10-11 , DOI: 10.1016/j.chembiol.2018.09.009 Emily S C Rittershaus 1 , Seung-Hun Baek 2 , Inna V Krieger 3 , Samantha J Nelson 1 , Yu-Shan Cheng 3 , Subhalaxmi Nambi 1 , Richard E Baker 1 , John D Leszyk 4 , Scott A Shaffer 4 , James C Sacchettini 3 , Christopher M Sassetti 1
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2018-10-11 , DOI: 10.1016/j.chembiol.2018.09.009 Emily S C Rittershaus 1 , Seung-Hun Baek 2 , Inna V Krieger 3 , Samantha J Nelson 1 , Yu-Shan Cheng 3 , Subhalaxmi Nambi 1 , Richard E Baker 1 , John D Leszyk 4 , Scott A Shaffer 4 , James C Sacchettini 3 , Christopher M Sassetti 1
Affiliation
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Upon inhibition of respiration, which occurs in hypoxic or nitric oxide-containing host microenvironments, Mycobacterium tuberculosis (Mtb) adopts a non-replicating "quiescent" state and becomes relatively unresponsive to antibiotic treatment. We used comprehensive mutant fitness analysis to identify regulatory and metabolic pathways that are essential for the survival of quiescent Mtb. This genetic study identified a protein acetyltransferase (Mt-Pat/Rv0998) that promoted survival and altered the flux of carbon from oxidative to reductive tricarboxylic acid (TCA) reactions. Reductive TCA requires malate dehydrogenase (MDH) and maintains the redox state of the NAD+/NADH pool. Genetic or chemical inhibition of MDH resulted in rapid cell death in both hypoxic cultures and in murine lung. These phenotypic data, in conjunction with significant structural differences between human and mycobacterial MDH enzymes that could be exploited for drug development, suggest a new strategy for eradicating quiescent bacteria.
中文翻译：
赖氨酸乙酰转移酶有助于结核分枝杆菌对缺氧的代谢适应。
在缺氧或含一氧化氮的宿主微环境中呼吸受到抑制后，结核分枝杆菌 (Mtb) 会采取非复制的“静止”状态，并且对抗生素治疗变得相对无反应。我们使用全面的突变适应性分析来确定对静止 Mtb 的生存至关重要的调节和代谢途径。这项遗传学研究确定了一种蛋白质乙酰转移酶 (Mt-Pat/Rv0998)，它可以促进存活并改变从氧化反应到还原三羧酸 (TCA) 反应的碳通量。还原性 TCA 需要苹果酸脱氢酶 (MDH) 并维持 NAD+/NADH 池的氧化还原状态。MDH 的遗传或化学抑制导致缺氧培养物和小鼠肺中的细胞快速死亡。这些表型数据，
更新日期：2018-10-12
中文翻译：
赖氨酸乙酰转移酶有助于结核分枝杆菌对缺氧的代谢适应。
在缺氧或含一氧化氮的宿主微环境中呼吸受到抑制后，结核分枝杆菌 (Mtb) 会采取非复制的“静止”状态，并且对抗生素治疗变得相对无反应。我们使用全面的突变适应性分析来确定对静止 Mtb 的生存至关重要的调节和代谢途径。这项遗传学研究确定了一种蛋白质乙酰转移酶 (Mt-Pat/Rv0998)，它可以促进存活并改变从氧化反应到还原三羧酸 (TCA) 反应的碳通量。还原性 TCA 需要苹果酸脱氢酶 (MDH) 并维持 NAD+/NADH 池的氧化还原状态。MDH 的遗传或化学抑制导致缺氧培养物和小鼠肺中的细胞快速死亡。这些表型数据，
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