Functional Decomposition of Metabolism reveals gross imbalance in the energy budget of aerobically growing bacteria

Quantifying the contribution of individual molecular reactions to complex physiological functions in living cells is a grand challenge in quantitative biology. We established a general theoretical framework (Functional Decomposition of Metabolism, FDM) to quantify the contribution of every metabolic reaction to cellular metabolic functions, e.g., the synthesis of metabolic building blocks such as amino acids and the generation of bioenergy such as ATP. This allowed us to obtain a plethora of results for E. coli growing in a variety of conditions without supervised knowledge on curated metabolic pathways, including the quantification of allocated enzymes to each metabolic function. A quantitative analysis of the cellular energy budget using FDM revealed an outstanding puzzle: We found that the ATP generated as a by-product of metabolic building block synthesis is already sufficient to satisfy most of the known energy need of cells growing aerobically on glucose, without the need of much additional energy synthesis. Yet, the fermentation and respiration pathways are highly active, resulting in more than doubled ATP synthesis flux and costing about 30% of the total carbon intake, without identifiable physiological rationales. This excess in ATP generation disappears for anaerobic growth on glucose. Our results suggest that, unlike popular beliefs, energy is not a limiting resource for aerobically growing E. coli.