Redirector: Designing Cell Factories by Reconstructing the Metabolic Objective
A. Here are the novel aspects of the Redirector algorithm brought together to depict the algorithmic flow. An iterative local search alternates between a bilevel optimization using objective control and the progressive target discovery. Objective control produces enzyme genetic alterations (+targets) and the associated metabolite production level, while the progressive target discovery increases the progressive growth parameter, or γ (+growth), based on the enzyme optimization targets and metabolite production level, from the previous iteration. B. The objective control method involves an FBA objective that includes the biomass (growth) flux as well as a selected set of enzyme associated reaction fluxes, which are up- or down-regulated. An optimized set of enzymes is included in the objective to drive the production of the metabolite of interest. The dotted lines show that an enzyme appearing in the objective incentivizes changes in the associated reaction fluxes. C. The progressive target discovery method adjusts a coefficient on the biomass term, used in objective control, after each iteration of the optimization. Here we show a decision tree for the adjustment of the progressive growth parameter based on the discovery of new targets, and the metabolite production level from the previous iteration.