The non-protein amino acid meta-Tyrosine (m-Tyr) is produced in cells under conditions of oxidative stress, and m-Tyr has been shown to be toxic to a broad range of biological systems. However, the mechanism by which m-Tyr damages cells is unclear. In E. coli, the quality control (QC) function of phenyalanyl-tRNA synthetase (PheRS) is required for resistantce to m-Tyr. To determine the mechanism of m-Tyr toxicity, we utilitized a strain of E. coli that expresses a QC-defective PheRS. The global responses of E. coli cells to m-Tyr were assessed by RNA-seq, and >500 genes were differentially expressed after the addition of m-Tyr. The most strongly up-regulated genes are involved in unfolded-protein stress response, and cells exposed to m-Tyr contained large, electron-dense protein aggregates, indicating that m-Tyr destabilized a large fraction of the proteome. Additionally, we observed that amino acid biosynthesis and transport regulons, controlled by ArgR, TrpR, and TyrR, and the stringent-response regulon, controlled by DksA/ppGpp, were differentially expressed. m-Tyr resistant mutants were isolated and found to have altered a promoter to increase expression of the enzymes for Phe production or to have altered transporters, which likely result in less uptake or increased efflux of m-Tyr. These findings indicate that when m-Tyr has passed the QC checkpoint by the PheRS, this toxicity of m-Tyr may result from interfering with amino acid metabolism, destabalizing a large number of proteins, and the formation of protein aggregates.

非蛋白质氨基酸间酪氨酸（m- Tyr）是在氧化应激条件下在细胞中产生的，并且m- Tyr已显示出对多种生物系统的毒性。但是，间-Tyr损伤细胞的机制尚不清楚。在大肠杆菌中，质量控制phenyalanyl -tRNA合成酶（PheRS的）的（QC）功能所需的resistantce到米-Tyr。为了确定m -Tyr毒性的机制，我们利用了一种表达QC缺陷型PheRS的大肠杆菌菌株。的全球应对大肠杆菌细胞间通过RNA-seq评估Tyr，加入m -Tyr后差异表达500多个基因。最强烈上调的基因与未折叠的蛋白质应激反应有关，暴露于m -Tyr的细胞含有大量的电子致密蛋白聚集体，表明m -Tyr使大部分蛋白质组不稳定。此外，我们观察到，由ArgR，TrpR和TyrR控制的氨基酸生物合成和运输调节子，以及由DksA / ppGpp控制的严格响应调节子。米-Tyr抗性突变体中分离，并发现具有改变的启动子，以增加酶的Phe生产的表达或以具有改变的转运蛋白，其有可能导致较少的摄取或增加的流出米-Tyr。这些结果表明，当间-酪氨酸已由PheRS的通过了检查点QC，这种毒性的间-酪氨酸可能导致从与氨基酸代谢干扰，destabalizing大量的蛋白，和蛋白聚集体的形成。