Modeling the role of covalent enzyme modification inEscherichia colinitrogen metabolism

Abstract

In the bacterium Escherichia coli, the enzyme glutamine synthetase (GS) converts ammonium into the amino acid glutamine. GS is principally active when the cell is experiencing nitrogen limitation, and its activity is regulated by a bicyclic covalent modification cascade. The advantages of this bicyclic-cascade architecture are poorly understood. We analyze a simple model of the GS cascade in comparison to other regulatory schemes and conclude that the bicyclic cascade is suboptimal for maintaining metabolic homeostasis of the free glutamine pool. Instead, we argue that the lag inherent in the covalent modification of GS slows the response to an ammonium shock and thereby allows GS to transiently detoxify the cell, while maintaining homeostasis over longer times.

GlnK Facilitates the Dynamic Regulation of Bacterial Nitrogen Assimilation

“…5 ), and thus, higher GS-A levels. Thus GlnK dampens the assimilatory response to ammonium upshift, perhaps to avoid excess ammonium uptake causing the depletion of the glutamate pool ( 4 , 5 ). The fact that sequestration is regulated by α -KG (a product of the carbon metabolism), suggests that nitrogen shock responses could also help to avoid untoward impacts on carbon status.…”

“…As a result, their regulatory requirements are different: homeostatic regulation of glutamate is essential to maintain growth rate, whereas glutamine levels must adjust rapidly to reflect cellular nitrogen status while at the same time remaining within physiologically acceptable bounds. In particular, when nutrient-rich conditions are suddenly restored after a period of starvation, the cell must be able to avoid glutamine shock ( 4 , 5 ).…”

Nitrogen Assimilation in Escherichia coli: Putting Molecular Data into a Systems Perspective

“…Another model of the GS cascade arrived at the conclusion that the bicyclic cascade is suboptimal for homeostatically controlling the glutamine pool (571). It was hypothesized that a slow inactivation of GS by adenylylation allows GS to transiently deal with ammonium toxicity imposed on cells by a sudden internal ammonium upshift from 0.1 to 100 mM.…”

GlnK facilitates the dynamic regulation of bacterial nitrogen assimilation

“…5) and thus higher GS-A levels. Thus GlnK dampens the assimilatory response to ammonium upshift, perhaps to avoid excess ammonium uptake causing the depletion of the glutamate pool (4,5). The fact that sequestration is regulated by α-KG (a product of the carbon metabolism), suggests that nitrogen shock responses could also help to avoid untoward impacts on carbon status.…”

“…As a result, their regulatory requirements are different: homeostatic regulation of glutamate is essential to maintain growth rate, whereas glutamine levels must adjust rapidly to reflect cellular nitrogen status while at the same time remaining within physiologically acceptable bounds. In particular, when nutrient-rich conditions are suddenly restored after a period of starvation, the cell must be able to avoid glutamine shock (4,5).…”