Overflow metabolism in Escherichia coli results from efficient proteome allocation

Abstract

Overflow metabolism refers to the seemingly wasteful strategy in which cells use fermentation instead of the more efficient respiration to generate energy, despite the availability of oxygen. Known as Warburg effect in the context of cancer growth, this phenomenon occurs ubiquitously for fast growing cells, including bacteria, fungi, and mammalian cells, but its origin has remained mysterious despite decades of research. Here we study metabolic overflow in E. coli and show that it is a global physiological response used to cope with changing proteomic demands of energy biogenesis and biomass synthesis under different growth conditions. A simple model of proteomic resource allocation can quantitatively account for all of the observed behaviors and accurately predict responses to novel perturbations. The key hypothesis of the model, that the proteome cost of energy biogenesis by respiration exceeds that by fermentation, is quantitatively confirmed by direct measurement of protein abundances via quantitative mass spectrometry.

pH determines the energetic efficiency of the cyanobacterial CO 2 concentrating mechanism

“…We validate this prediction by measuring the intracellular pH in live cyanobacterial cells (Synechococcus elongatus PCC 7942). Thus, the CCM offers another example where the properties of complex systems central to bacterial growth are well-explained by the principle of energetic cost minimization (24)(25)(26), in this case explaining the remodeling of cytosolic pH and transport modalities to minimize the cost of Ci accumulation for the CCM.…”

A yield-cost tradeoff governs Escherichia coli's decision between fermentation and respiration in carbon-limited growth

“…the fermentation phenotype with α = 0) when w C is above (resp. below) thecorresponding to a growth rate µ ac 0.7/h, in quantitative agreement (within 10%) with the experimentally determined onset of the acetate switch [13].Such a two-state scenario inspires a minimal coarse-grained mathematical model of E. coli's metabolism in which the cell can use either respiration or fermentation to produce energy subject to a global constraint on proteome composition (see Supporting Text). The model predicts that, at optimality, a transition between the fermentation phenotype (fast growth) and the respiration phenotype (slow growth) occurs when the cost of intaking carbon matches the extra protein cost required by respiration, at which point one phenotype outperforms the other in terms of maximum achievable growth rate (see Fig.…”

“…This specific aspect makes it in principle possible to describe strains with different "acetate overflow lines" (e.g. mutants [37,38] or "acetate feeding" strains obtained in evolution experiments [39,40]), which correspond to feasible -albeit suboptimalcellular states that would be harder to describe by the model of [13]. On the other hand, the latter characterizes, in a sense, The respiration phenotype has a large yield (small q) and large specific protein costs, while the fermentation phenotype carries lower yields (higher q) and a smaller cost.…”

“…By slightly extending the model of [13], Vazquez and Oltvai [36] have recently linked overflow metabolism to a macromolecular crowding constraint, along the lines of [41,42].…”

“…coli's 'acetate switch' [13,29], whereby bacteria cross over from a predominantly fermentative to a predominantly respiratory metabolism upon carbon limitation, is an example of the latter strategy. Indeed respiration, while more costly in terms of enzymes with respect to fermentation, has a larger ATP yield (ca.…”