Steady state analysis of biological regulatory networks: applied to Glutamine synthetase system of Escherichia coli

18 April 2005

Vivek Mutalik
Department of Chemical Engineering
Indian Institute of Technology, Bombay, India


Glutamine synthetase (GS) regulation in Escherichia coli is a prototype of signal transduction by enzyme cascades. This enzyme plays a crucial role in nitrogen assimilation under nitrogen starvation conditions. Because of its functional significance, GS biosynthesis and activity in the cell is highly regulated. The biosynthesis of GS is regulated by a two-component signaling system and an auto-regulatory genetic module, whereas, its activity is regulated through a closed loop bicyclic cascade. The GS regulatory network acts as a signal integration system for nitrogen and carbon sufficiency by sensing the intracellular concentration of glutamine and 2-ketoglutarate. Under nitrogen starvation conditions, glutamine synthetase synthesis and activity are amplified to assimilate nitrogen from available sources.

In this seminar, I would discuss our work on the steady state simulation of GS bicyclic cascade with transcription regulatory system comprising of NRII-NRI two-component signaling system and autoregulated glnALG operon coding for GS, NRII and NRI. The complete signaling network was simulated by analyzing the final output response in-terms of GS synthesis and activity with respect to the input levels of glutamine and 2-ketoglutarate. Simulation results reveal that the transcriptional output of glnALG operon is a discrete switch-like response, while GS inactivation is moderately ultrasensitive and the activation of transcriptional factor NRI is graded to input stimulus, glutamine. The significance of the autoregulatory two-component signaling system and its effect on the concentration of total active GS will also be discussed.


V K Mutalik, P Shah and K V Venkatesh, "Allosteric interactions and bifunctionality make the response of glutamine synthetase cascade system of Escherichia coli robust and ultrasensitive", JBC 278:26327-32 2003. PubMed