An Upper Limit in Gibbs Energy Dissipation Governs Cellular Metabolism

The principles governing cellular metabolic operation are still poorly understood. Because very diverse organisms show relatively comparable physiologies, we hypothesized that a fundamental thermodynamic constraint might govern cellular metabolism. To investigate this, we developed a novel constraint-based model for Saccharomyces cerevisiae with a comprehensive description of the biochemical thermodynamics and including a Gibbs energy balance. Nonlinear regression analyses of metabolome and physiology data revealed the existence of an upper rate limit for the cellular Gibbs energy dissipation. Applying this limit in flux balance analyses using growth maximization as objective, the model correctly predicted physiologies, intracellular metabolic fluxes, as well as even some metabolite levels, for different glucose uptake rates. Our work indicates that cells arrange their metabolic fluxes such that with increasing substrate uptake rates, an optimal growth rate is accomplished, but the critical rate limit in Gibbs energy dissipation is never exceeded. Once all possibilities for further intracellular flux redistribution towards ‘saving’ Gibbs energy dissipation are exhausted, cells reach their maximal growth rate. We found that this principle also holds for Escherichia coli and on different carbon sources. Our work suggests that metabolic reaction stoichiometry, a limit in the cellular Gibbs energy dissipation rate, and the growth maximization objective might shape metabolism across different organisms and conditions.