A Systematic Modeling Approach to Elucidate the Triggering of the Stringent Response in Recombinant E. coli Systems

A hybrid modeling approach, combining a stoichiometric model of the E. coli metabolic network and kinetic-based descriptions for the production of recombinant protein, cell growth and ppGpp synthesis, was applied to describe metabolic bottlenecks associated with recombinant processes. The model represents the triggering of the stringent response upon the deprivation of amino acids caused by the additional drainage of biosynthetic precursors for the production of recombinant proteins. The equation for ppGpp synthesis allows to estimate the accumulation of this molecule above its basal levels once amino acid shortages occur. The capability to predict these stress-responsive events might be crucial in the design of optimal cultivation strategies.