An Upper Limit on Gibbs Energy Dissipation Governs Cellular Metabolism

The principles governing cellular metabolic operation are poorly understood. Because diverse organisms show similar metabolic flux patterns, we hypothesized that a fundamental thermodynamic constraint might shape cellular metabolism. Here, we develop a constraint-based model for Saccharomyces cerevisiae with a comprehensive description of biochemical thermodynamics including a Gibbs energy balance. Non-linear regression analyses of quantitative metabolome and physiology data reveal the existence of an upper rate limit for cellular Gibbs energy dissipation. By applying this limit in flux balance analyses with growth maximization as the objective function, our model correctly predicts the physiology and intracellular metabolic fluxes for different glucose uptake rates as well as the maximal growth rate. We find that cells arrange their intracellular metabolic fluxes in such a way that, with increasing glucose uptake rates, they can accomplish optimal growth rates but stay below the critical rate limit on Gibbs energy dissipation. Once all possibilities for intracellular flux redistribution are exhausted, cells reach their maximal growth rate. This principle also holds for Escherichia coli and different carbon sources. Our work proposes that metabolic reaction stoichiometry, a limit on the cellular Gibbs energy dissipation rate, and the objective of growth maximization shape metabolism across organisms and conditions.