Molecular Biology and Biotechnology, University of Sheffield, Sheffield, S10 2TN, UK.
Leicester Tuberculosis Research Group, Department of Respiratory Sciences, University of Leicester, Maurice Shock Medical Sciences Building, University Road, Leicester, LE1 9HN, UK.
Cell Rep. 2020 Sep 29;32(13):108209. doi: 10.1016/j.celrep.2020.108209.
Mycobacterium tuberculosis causes human tuberculosis, and a better understanding of its biology is required to identify vulnerabilities that might be exploited in developing new therapeutics. The iron-sulfur cluster of the essential M. tuberculosis central metabolic enzyme, aconitase (AcnA), disassembles when exposed to oxidative/nitrosative stress or iron chelators. The catalytically inactive apo-AcnA interacts with a sequence resembling an iron-responsive element (IRE) located within the transcript of another essential protein, CwlM, a regulator of peptidoglycan synthesis. A Mycobacterium smegmatis cwlM conditional mutant complemented with M. tuberculosis cwlM with a disrupted IRE is unable to recover from combinations of oxidative, nitrosative, and iron starvation stresses. An equivalent M. tuberculosis cwlM conditional mutant complemented with the cwlM gene lacking a functional IRE exhibits a growth defect in THP-1 macrophages. It appears that AcnA acts to couple peptidoglycan synthesis and central metabolism, and disruption of this coupling potentially leaves mycobacteria vulnerable to attack by macrophages.
结核分枝杆菌引起人类结核病，为了确定可能用于开发新疗法的弱点，需要更好地了解其生物学特性。必需的结核分枝杆菌中心代谢酶， aconitase（AcnA）的铁硫簇在暴露于氧化/硝化应激或铁螯合剂时会解体。无催化活性的 apo-AcnA 与位于另一种必需蛋白 CwlM 转录本内的序列相互作用，该序列类似于铁反应元件（IRE），CwlM 是肽聚糖合成的调节剂。用破坏 IRE 的结核分枝杆菌 cwlM 基因补充的 cwlM 条件突变的耻垢分枝杆菌无法从氧化、硝化和铁饥饿应激的组合中恢复。用缺乏功能性 IRE 的 cwlM 基因补充的等效结核分枝杆菌 cwlM 条件突变体在 THP-1 巨噬细胞中表现出生长缺陷。似乎 AcnA 作用是将肽聚糖合成和中心代谢偶联，而这种偶联的破坏可能使分枝杆菌容易受到巨噬细胞的攻击。
