Bridging substrate intake kinetics and bacterial growth phenotypes with flux balance analysis incorporating proteome allocation

Empirical kinetic models such as the Monod equation have been widely applied to relate the cell growth with substrate availability. The Monod equation shares a similar form with the mechanistically-based Michaelis-Menten kinetics for enzymatic processes, which has provoked long-standing and un-concluded conjectures on their relationship. In this work, we integrated proteome allocation principles into a Flux Balance Analysis (FBA) model of Escherichia coli, which quantitatively revealed potential mechanisms that underpin the phenomenological Monod parameters: the maximum specific growth rate could be dictated by the abundance of growth-controlling proteome and growth-pertinent proteome cost; more importantly, the Monod constant (K(s)) was shown to relate to the Michaelis constant for substrate transport (K(m,g)), with the link being dependent on the cell’s metabolic strategy. Besides, the proposed model was able to predict glucose uptake rate at given external glucose concentration through the size of available proteome resource for substrate transport and its enzymatic cost, while growth rate and acetate overflow were accurately simulated for two E. coli strains. Bridging the enzymatic kinetics of substrate intake and overall growth phenotypes, this work offers a mechanistic interpretation to the empirical Monod law, and demonstrates the potential of coupling local and global cellular constrains in predictive modelling.