Induction of a novel class of diacylglycerol acyltransferases and triacylglycerol accumulation in Mycobacterium tuberculosis as it goes into a dormancy-like state in culture
Induction of a novel class of diacylglycerol acyltransferases and triacylglycerol accumulation in Mycobacterium tuberculosis as it goes into a dormancy-like state in culture
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DOI：
10.1128/jb.186.15.5017-5030.2004
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发表时间：
2004-08-01
影响因子：
3.2
通讯作者：
Kolattukudy, PE
中科院分区：
文献类型：
--
作者：
Daniel, J;Deb, C;Kolattukudy, PE
结核分枝杆菌通过吸入感染性气溶胶进入宿主，并在肺泡巨噬细胞中复制，直到宿主的免疫防御导致细菌抑制，这导致病原体进入非复制性耐药休眠。休眠的病原体可以存活数十年，直到宿主的免疫系统被削弱，并发展为活动性结核病。尽管脂肪酸被认为是持续阶段所需的主要能量来源，但所用脂肪酸的来源尚不清楚。我们假设病原体使用三酰甘油（TG）作为脂肪酸的储存形式。关于M.结核我们发现，当在大肠杆菌中表达时，我们鉴定为推定的三酰甘油合成酶（tgs）的15个分支杆菌基因表现出TGS活性，并且我们报告了最活跃酶的一些基本催化特征。我们发现，当病原体进入非复制耐药状态引起的O-2缓慢撤出，也通过NO治疗，这是已知的诱导休眠相关基因时，诱导几个TGS基因。在大肠杆菌中表达TGS活性最高的基因Rv 3130 c。大肠杆菌显示最高的诱导缺氧和NO处理。生化证据表明，TG的合成和积累发生在这两种条件下。我们的结论是，TG可能是一种形式的能量储存在长期休眠期间使用。因此，TG合成可能是新型抗潜伏药物的合适靶点，可以防止生物体存活休眠，从而有助于控制结核病。
Mycobacterium tuberculosis enters the host by inhalation of an infectious aerosol and replicates in the alveolar macrophages until the host's immune defense causes bacteriostasis, which leads the pathogen to go into nonreplicative drug-resistant dormancy. The dormant pathogen can survive for decades till the host's immune system is weakened and active tuberculosis develops. Even though fatty acids are thought to be the major energy source required for the persistence phase, the source of fatty acids used is not known. We postulate that the pathogen uses triacylglycerol (TG) as a storage form of fatty acids. Little is known about the biosynthesis of TG in M. tuberculosis. We show that 15 mycobacterial genes that we identified as putative triacylglycerol synthase (tgs) when expressed in Escherichia coli showed TGS activity, and we report some basic catalytic characteristics of the most active enzymes. We show that several tgs genes are induced when the pathogen goes into the nonreplicative drug-resistant state caused by slow withdrawal of O-2 and also by NO treatment, which is known to induce dormancy-associated genes. The gene (Rv3130c) that shows the highest TGS activity when expressed in E. coli shows the highest induction by hypoxia and NO treatment. Biochemical evidence shows that TG synthesis and accumulation occur under both conditions. We conclude that TG may be a form of energy storage for use during long-term dormancy. Therefore, TG synthesis may be an appropriate target for novel antilatency drugs that can prevent the organism from surviving dormancy and thus assist in the control of tuberculosis.