Mutalik Vivek K, Venkatesh K V
Department of Chemical Engineering, School of Biosciences and Bioengineering, Indian Institute of Technology at Bombay, Powai, Mumbai 400 076, India.
Biosystems. 2007 Jul-Aug;90(1):1-19. doi: 10.1016/j.biosystems.2006.06.003. Epub 2006 Jun 23.
The nitrogen starvation response in Escherichia coli is characterized by the enhanced expression of Ntr regulon, comprising hundreds of genes including the one coding for nitrogen-assimilating glutamine synthetase (GS) enzyme. The biosynthesis and activity of GS is regulated mainly by nitrogen and carbon levels in the cell and monitored by three functionally separable interconnected modules. Here, we present the steady-state modular analysis of this intricate network made up of a GS bicyclic closed-loop cascade, a NRII-NRI two-component system, and an autoregulated glnALG operon encoding genes for GS, NRII, and NRI. Our simulation results indicate that the transcriptional output of glnALG operon is discrete and switch-like, whereas the activation of transcription factor NRI is graded, and the inactivation of GS is moderately ultrasensitive to input stimulus glutamine. The autoregulation of the NRII-NRI two-component system was found to be essential for the all-or-none induction of the glnALG operon. Furthermore, we show that the autoregulated two-component system modulates the total active GS by delineating the GS activity from its biosynthetic regulation. Our analysis indicates that the exclusive relationship between GS activity and its synthesis is brought about by the autoregulated two-component system. The modularity of the network endows the system to respond differently to nitrogen depending on the carbon status of the cell. Through a system-level quantification, we conclude that the discrete switch-like transcriptional response of the E. coli glnALG operon to nutrient starvation prevents the premature initiation of transcription and may represent the desperate attempt by the cell to survive in limiting conditions.
大肠杆菌中的氮饥饿反应的特征是Ntr调节子的表达增强，该调节子包含数百个基因，其中包括一个编码氮同化谷氨酰胺合成酶（GS）的基因。GS的生物合成和活性主要受细胞中氮和碳水平的调节，并由三个功能上可分离的相互连接的模块监控。在此，我们展示了对这个复杂网络的稳态模块化分析，该网络由一个GS双环闭环级联、一个NRII-NRI双组分系统以及一个自我调节的glnALG操纵子组成，后者编码GS、NRII和NRI的基因。我们的模拟结果表明，glnALG操纵子的转录输出是离散的且类似开关的，而转录因子NRI的激活是分级的，并且GS的失活对输入刺激谷氨酰胺具有适度的超敏感性。发现NRII-NRI双组分系统的自我调节对于glnALG操纵子的全或无诱导至关重要。此外，我们表明自我调节的双组分系统通过将GS活性与其生物合成调节区分开来调节总活性GS。我们的分析表明，GS活性与其合成之间的排他关系是由自我调节的双组分系统导致的。网络的模块化使系统能够根据细胞的碳状态对氮做出不同反应。通过系统水平的量化，我们得出结论，大肠杆菌glnALG操纵子对营养饥饿的离散开关样转录反应可防止转录过早启动，这可能代表细胞在限制条件下生存的绝望尝试。
