Coordination of bacterial proteome with metabolism by cyclic AMP signalling

Abstract

Cyclic AMP (cAMP) dependent catabolite repression effect in E. coli is among the most intensely studied regulatory processes in biology. However, the physiological function(s) of cAMP signalling and its molecular triggers remain elusive. Here we use a quantitative physiological approach to show that cAMP signalling tightly coordinates the cell’s protein expression program with its metabolic needs during exponential cell growth: The expression of carbon catabolic genes increased linearly with decreasing growth rates upon limitation of carbon influx, but decreased linearly with decreasing growth rate upon limitation of nitrogen or sulfur influx. In contrast, the expression of biosynthetic genes exhibited the opposite linear growth-rate dependence as the catabolic genes. A coarse-grained mathematical model provides a quantitative framework for understanding and predicting gene expression responses to catabolic and anabolic limitations. A scheme of integral feedback control featuring the inhibition of cAMP signalling by metabolic precursors is proposed and validated. These results reveal a key physiological role of cAMP-dependent catabolite repression: to ensure that proteomic resources are spent on distinct metabolic sectors as needed in different nutrient environments. Our finding underscores the power of quantitative physiology in unravelling the underlying functions of complex molecular signalling networks.

E1 of α-ketoglutarate dehydrogenase defends Mycobacterium tuberculosis against glutamate anaplerosis and nitroxidative stress

“…In some bacteria, intracellular metabolites play a signaling role in carbon utilization. For example, in Escherichia coli, elevated α-KG inhibits enzyme I of the phosphotransferase system, blocking glucose uptake (19), and impairs cAMP synthesis, eliciting catabolite repression (48). Moreover, aldehydes acting as electrophiles can form transient adducts with select Lys residues to control enzyme activities and redirect CCM metabolism (49).…”

Global metabolic network reorganization by adaptive mutations allows fast growth of Escherichia coli on glycerol

“…The decrease in cAMP levels in glpK mutation containing strains therefore appears responsible for converting glycerol into the observed overflow metabolites. Another interesting possibility is that the glpK mutation, by affecting cAMP levels, may contribute to better optimizing proteomic resources to metabolic needs, as recently proposed 29 . This would suggest that these needs are poorly adjusted in WT E. coli resulting in slower than expected growth.…”

Novel regulatory roles of cAMP receptor proteins in fast-growing environmental mycobacteria

“…Crp1 in M. smegmatis had no effect on the pattern of carbon source utilization, pointing to other roles in mycobacterial physiology. You et al (2013) report that cAMP-CRP signalling mediates more than CCR and coordinates the expression of catabolic proteins with biosynthetic and ribosomal proteins in response to cellular metabolic demands, implying that CRP senses the anabolic demands of the cell and allocates resources appropriately in response to growth rate. The M. smegmatis Crp1 regulon and the growth rate (i.e.…”

“…The cAMP-CRP complex binds at promoters containing a specific DNA sequence (consensus 59-TGTGAN 6 TCACA-39) to regulate expression of the downstream genes (Berg & von Hippel, 1988). In addition to mediating CCR, a recent study demonstrated that cAMP-CRP signalling is involved in coordinating the expression of catabolic proteins with biosynthetic (anabolic) and ribosomal proteins in response to cellular metabolic demands (You et al, 2013). There are currently estimated to be between 378 and~500 E. coli genes under the control of cAMP-CRP, including those encoding the transporters and catabolism of glucose and the process of aerobic respiration, demonstrating that CRP is a global regulator of gene expression in E. coli (Perrenoud & Sauer, 2005;Shimada et al, 2011).…”