Resource allocation in biochemically structured metabolic networks

Microbes tune their metabolism to environmental challenges by changing protein expression levels, metabolite concentrations, and reaction rates simultaneously. Here, we establish an analytical model for microbial resource allocation that integrates heterogeneous enzyme kinetics and the global architecture of metabolic networks. We describe the production of protein biomass from external nutrients in pathways of Michaelis-Menten enzymes and compute the resource allocation that maximizes growth under constraints of mass conservation and metabolite dilution by cell growth. This model predicts generic patterns of growth-dependent microbial resource allocation to proteome and metabolome. In a nutrient-rich medium, optimal protein expression depends primarily on the kinetics of individual synthesis steps, while metabolite concentrations and fluxes decrease along successive reactions in a metabolic pathway. Under nutrient limitation, individual protein expression levels change linearly with growth rate, the direction of change depending again on the enzyme's kinetic properties. On average, metabolite levels and fluxes show a stronger, nonlinear decline with growth rate. We identify a simple, metabolite-based regulatory logic by which cells can be tuned to near-optimal growth. Finally, our model predicts evolutionary stable states of metabolic networks, including local kinetic parameters and the global metabolite mass fraction, in tune with empirical data.