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Metabolic states with maximal specific rate carry flux through an elementary flux mode

Specific product formation rates and cellular growth rates are important maximization targets in biotechnology and microbial evolution. Maximization of a specific rate (i.e. a rate expressed per unit biomass amount) requires the expression of particular metabolic pathways at optimal enzyme concentrations. In contrast to the prediction of maximal product yields, any prediction of optimal specific rates at the genome scale is currently computationally intractable, even if the kinetic properties of all enzymes are available. In the present study, we characterize maximal‐specific‐rate states of metabolic networks of arbitrary size and complexity, including genome‐scale kinetic models. We report that optimal states are elementary flux modes, which are minimal metabolic networks operating at a thermodynamically‐feasible steady state with one independent flux. Remarkably, elementary flux modes rely only on reaction stoichiometry, yet they function as the optimal states of mathematical models incorporating enzyme kinetics. Our results pave the way for the optimization of genome‐scale kinetic models because they offer huge simplifications to overcome the concomitant computational problems.