Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis
Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis
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DOI：
10.1073/pnas.1109958109
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发表时间：
2012-01-24
影响因子：
11.1
通讯作者：
Moody, D. Branch
中科院分区：
文献类型：
--
作者：
Madigan, Cressida A.;Cheng, Tan-Yun;Moody, D. Branch
为了测量病原体适应背后的分子变化，我们生成了一个超过12,000个质谱学事件的可搜索数据集，对应于构成结核分枝杆菌脂体的脂类和小分子。铁是结核分枝杆菌生存所必需的，这种有机体通过分枝菌素和羧基分枝杆菌铁载体输入这种金属。检测到一种意想不到的铁载体变异和铁清除基因的缺失，导致了修订的mycobactin生物合成模型。在整个生物体范围内搜索结核分枝杆菌数据库，寻找该模型预测的假想化合物，发现了两个以前未知的脂类家族，分别命名为单脱氧粘菌素和单脱氧羧基粘菌素。这些分子提出了一个修正的生物合成模型，该模型通过mycobactin生物合成途径改变底物和酶的作用顺序。我们通过解决结核分枝杆菌铁依赖调节因子(IDER)、mycobactin合成酶B(MbtB)或mycobactin合成酶G(MbtG)缺失后的脂质体，对这一模型进行了遗传学测试。这些研究表明，在铁饥饿期间，脱氧粘菌素受到积极的调节，并确定了MbtG在将脱氧粘菌素转化为分枝杆菌蛋白和促进结核分枝杆菌生长方面的重要作用。因此，脂质组学是一种有效的发现工具，可以告知遗传关系，导致修订的一般模型，这些毒力赋予铁载体的生物合成。
To measure molecular changes underlying pathogen adaptation, we generated a searchable dataset of more than 12,000 mass spectrometry events, corresponding to lipids and small molecules that constitute a lipidome for Mycobacterium tuberculosis. Iron is essential for M. tuberculosis survival, and the organism imports this metal using mycobactin and carboxymycobactin siderophores. Detection of an unexpected siderophore variant and deletions of genes for iron scavenging has led to a revised mycobactin biosynthesis model. An organism-wide search of the M. tuberculosis database for hypothetical compounds predicted by this model led to the discovery of two families of previously unknown lipids, designated monodeoxymycobactins and monodeoxycarboxymycobactins. These molecules suggest a revised biosynthetic model that alters the substrates and order of action of enzymes through the mycobactin biosynthetic pathway. We tested this model genetically by solving M. tuberculosis lipidomes after deletion of the iron-dependent regulator (ideR), mycobactin synthase B (mbtB), or mycobactin synthase G (mbtG). These studies show that deoxymycobactins are actively regulated during iron starvation, and also define essential roles of MbtG in converting deoxymycobactins to mycobactin and in promoting M. tuberculosis growth. Thus, lipidomics is an efficient discovery tool that informs genetic relationships, leading to a revised general model for the biosynthesis of these virulence-conferring siderophores.