LpxC is a deacetylase that catalyzes the first committed step of lipid A biosynthesis in Escherichia coli. LpxC competes for a common precursor, R-3-hydroxymyristoyl-UDP-GlcNAc, with FabZ, whose dehydratase activity catalyzes the first committed step of phospholipid biosynthesis. To maintain the optimum flow of the common precursor to these two competing pathways, the LpxC level is controlled by FtsH/YciM-mediated proteolysis. It is not known whether this complex or another protein senses the status of lipid A synthesis to control LpxC proteolysis. The work carried out in this study began with a novel mutation, yejM1163, which causes hypersensitivity to large antibiotics such as vancomycin and erythromycin. Isolates resistant to these antibiotics carried suppressor mutations in the ftsH and yciM genes. Western blot analysis showed a dramatically reduced LpxC level in the yejM1163 background, while the presence of ftsH or yciM suppressor mutations restored LpxC levels to different degrees. Based on these observations, it is proposed that YejM is a sensor of lipid A synthesis and controls LpxC levels by modulating the activity of the FtsH/YciM complex. The truncation of the periplasmic domain in the YejM1163 protein causes unregulated proteolysis of LpxC, thus diverting a greater pool of R-3-hydroxymyristoyl-UDP-GlcNAc toward phospholipid synthesis. This imbalance in lipid synthesis perturbs the outer membrane permeability barrier, causing hypersensitivity toward vancomycin and erythromycin. yejM1163 suppressor mutations in ftsH and yciM lower the proteolytic activity toward LpxC, thus restoring lipid homeostasis and the outer membrane permeability barrier.

中文翻译：

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YejM通过调节大肠杆菌FtsH / YciM复合物的蛋白酶活性来控制LpxC水平。

LpxC是一种脱乙酰基酶，可催化大肠杆菌中脂质A生物合成的第一个重要步骤。LpxC与FabZ竞争一种常见的前体R -3-羟基肉豆蔻酰基UDP-GlcNAc，FabZ的脱水酶活性催化着磷脂生物合成的第一步。为了维持这两种竞争途径的共同前体的最佳流动，LpxC水平受FtsH / YciM介导的蛋白水解作用的控制。尚不清楚这种复合物还是另一种蛋白质是否感觉到脂质A合成的状态以控制LpxC蛋白水解。这项研究中进行的工作始于一个新的突变yejM1163会引起对大型抗生素（如万古霉素和红霉素）的超敏反应。对这些抗生素具有抗性的分离株在ftsH和yciM基因中带有抑制突变。蛋白质印迹分析显示，yejM1163背景中的LpxC水平显着降低，而ftsH或yciM抑制子突变的存在将LpxC水平恢复到不同程度。基于这些观察结果，提出YejM是脂质A合成的传感器，并通过调节FtsH / YciM复合物的活性来控制LpxC水平。YejM1163蛋白中周质结构域的截断会导致LpxC的蛋白水解失控，从而转移了更多的R-3-羟基肉豆蔻酰基-UDP-GlcNAc对磷脂的合成。脂质合成的这种不平衡扰乱了外膜通透性屏障，导致对万古霉素和红霉素过敏。yejM1163在抑制性突变FTSH和yciM降低朝向LpxC蛋白水解活性，从而恢复脂质稳态和外膜渗透屏障。