Abstract
Natural selection pushes microbes towards maximal reproductive rates. This requires optimal tuning of metabolism, within biophysical bounds. A metabolic network can be decomposed into independent pathways, called Elementary Flux Modes (EFMs). Although billions of EFMs exist in a metabolic network, experiments suggest that few are simultaneously used. We present an extremum principle: metabolic simplicity is a consequence of rate maximisation. The number of used EFMs is determined only by the number of constraints that limit enzyme concentrations, not by the size, kinetics or topology of the network. Since the biochemical basis and biophysical constraints are similar across unicellulars, our theory explains why microorganisms show common metabolic behaviours, such as overflow metabolism. We present the extremum principle in a graphical framework, which also provides guidelines for experimental characterization of the growth-limiting constraints. This work provides a practical theory, rooted in biochemistry, that describes a fundamental limit of evolution and phenotypic adaptation.