Abstract
Microbes may maximize the number of daughter cells per time or per amount of nutrients consumed. These two strategies correspond, respectively, to the use of enzyme-efficient or substrate-efficient metabolic pathways. In reality, fast growth is often associated with wasteful, yield-inefficient metabolism, and a general thermodynamic trade-off between growth rate and biomass yield has been proposed to explain this. We studied growth rate/yield trade-offs by using a novel modeling framework, Enzyme-Flux Cost Minimization (EFCM) and by assuming that the growth rate depends directly on the enzyme investment per rate of biomass production. In a comprehensive mathematical model of core metabolism in E. coli, we screened all elementary flux modes leading to cell synthesis, characterized them by the growth rates and yields they provide, and studied the shape of the resulting rate/yield Pareto front. By varying the model parameters, we found that the rate/yield trade-off is not universal, but depends on metabolic kinetics and environmental conditions. A prominent trade-off emerges under oxygen-limited growth, where yield-inefficient pathways support a 2-to-3 times higher growth rate than yield-efficient pathways. EFCM can be widely used to predict optimal metabolic states and growth rates under varying nutrient levels, perturbations of enzyme parameters, and single or multiple gene knockouts.
Highlights
This puts a selection pressure on biomass yield rather than on growth rate
To predict optimal metabolic fluxes and cell growth rates, we developed Enzyme-Flux Cost Minimization (EFCM), a method for computing flux modes that realize a linear flux objective at a minimal enzyme cost
EFCM, in contrast, computes enzyme cost based on a given kinetic model
Summary
In well-mixed, nutrient-rich environments, fastgrowing bacteria are favored by natural selection. Such environments are commonly studied in laboratory settings, but natural environments are more diverse. In isolated ecological niches with limited resources, it is the total number of offspring cells, rather than fast growth, that determines evolutionary success. This puts a selection pressure on biomass yield (biomass produced per amount of the limiting nutrient, e.g. glucose) rather than on growth rate (biomass produced per time and per cell biomass). Pure respiratory growth would give rise to a higher biomass yield per mole of glucose, but to lower growth rates
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