Diadenosine tetraphosphate (Ap4A) - an E-coli alarmone or a damage metabolite?
Diadenosine tetraphosphate (Ap4A) - an E-coli alarmone or a damage metabolite?
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DOI：
10.1111/febs.14113
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发表时间：
2017-07-01
期刊：
影响因子：
5.4
通讯作者：
Tawfik, Dan S.
中科院分区：
文献类型：
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作者：
Despotovic, Dragana;Brandis, Alexander;Tawfik, Dan S.
在压力下，新陈代谢正在发生变化：蛋白质和代谢物的特定上调或下调以及副作用发生。区分特定的应激信号代谢物（alarmones）和副产物（damage metabolites）并不容易。一个例子是二腺苷四磷酸（Ap 4A）-一种在生命的所有领域中发现的氨酰-tRNA合成酶的副产物。最早的观察表明Ap 4A在大肠杆菌中作为热应激的警报因子。然而，尽管经过50年的研究，与Ap 4A相关的信号传导机制仍然未知。我们定义了一套标准，用于区分alarmones损伤代谢物系统分类Ap 4A。简而言之，没有发现由Ap 4A触发的信号级联反应的迹象;相反，我们发现Ap 4A以组成性的非调节方式有效地去除。Ap 4A浓度的几倍扰动没有影响，但由于锌稳态的干扰，在非常高的水平下的积累是有毒的，还因为Ap 4A与ATP的结构重叠可导致假结合和ATP结合蛋白的失活。总体而言，Ap 4A符合损伤代谢物的所有标准。虽然我们不排除在信号传导中的任何作用，但我们的结果表明，在检查Ap 4A和其他代谢物（其水平在应激时发生变化）时，应将损伤代谢物选项视为零假设。
Under stress, metabolism is changing: specific up- or down-regulation of proteins and metabolites occurs as well as side effects. Distinguishing specific stress-signaling metabolites (alarmones) from side products (damage metabolites) is not trivial. One example is diadenosine tetraphosphate (Ap4A) - a side product of aminoacyl-tRNA synthetases found in all domains of life. The earliest observations suggested that Ap4A serves as an alarmone for heat stress in Escherichia coli. However, despite 50 years of research, the signaling mechanisms associated with Ap4A remain unknown. We defined a set of criteria for distinguishing alarmones from damage metabolites to systematically classify Ap4A. In a nutshell, no indications for a signaling cascade that is triggered by Ap4A were found; rather, we found that Ap4A is efficiently removed in a constitutive, nonregulated manner. Several fold perturbations in Ap4A concentrations have no effect, yet accumulation at very high levels is toxic due to disturbance of zinc homeostasis, and also because Ap4A's structural overlap with ATP can result in spurious binding and inactivation of ATP-binding proteins. Overall, Ap4A met all criteria for a damage metabolite. While we do not exclude any role in signaling, our results indicate that the damage metabolite option should be considered as the null hypothesis when examining Ap4A and other metabolites whose levels change upon stress.