Functional decomposition of metabolism allows a system-level quantification of fluxes and protein allocation towards specific metabolic functions.

Quantifying the contribution of individual molecular components to complex cellular processes is a grand challenge in systems biology. Here we establish a general theoretical framework (Functional Decomposition of Metabolism, FDM) to quantify the contribution of every metabolic reaction to metabolic functions, e.g. the synthesis of biomass building blocks. FDM allowed for a detailed quantification of the energy and biosynthesis budget for growing Escherichia coli cells. Surprisingly, the ATP generated during the biosynthesis of building blocks from glucose almost balances the demand from protein synthesis, the largest energy expenditure known for growing cells. This leaves the bulk of the energy generated by fermentation and respiration unaccounted for, thus challenging the common notion that energy is a key growth-limiting resource. Moreover, FDM together with proteomics enables the quantification of enzymes contributing towards each metabolic function, allowing for a first-principle formulation of a coarse-grained model of global protein allocation based on the structure of the metabolic network.