Design of metabolic regulatory structures for enhanced lysine synthesis flux using (log)linearized kinetic models

Abstract

The problem of finding the optimal regulatory structures was formulated as a mixed-integer linear programming problem for lysine synthetic pathway using (log)linear models obtained from nonlinear kinetic models developed previously by us. Optimal structures were obtained from a set of postulated regulatory structures. This method of metabolic design allowed the identification of the type and the strength of the necessary regulations, the activities of the corresponding enzymes and the intermediate metabolite levels in the lysine pathway. The calculated results indicate that >20% increase of the internal lysine flux can be obtained when only the inhibitory regulation was allowed, and eight optimal structures with one regulatory loop were adopted. When the regulation due to enzyme activation was allowed, the internal lysine flux can be increased by >70%. Changes of the participating precursor and cofactor concentrations may not improve the lysine flux significantly in this system.