Design of optimally constructed metabolic networks of minimal functionality

Abstract

Background: Metabolic engineering aims to design microorganisms that will generate a product of interest at high yield. Thus, a variety of in silico modeling strategies has been applied successfully, including the concepts of elementary flux modes (EFMs) and constrained minimal cut sets (cMCSs). The EFMs (minimal, steady state pathways through the system) can be calculated given a metabolic model. cMCSs are sets of reaction deletions in such a network that will allow desired pathways to survive and disable undesired ones (e.g., those with low product secretion or low growth rates). Grouping the modes into desired and undesired categories had to be done manually until now.

On the feasibility of growth-coupled product synthesis in microbial strains

“…Enforcing obligate coupling of growth with product synthesis has become a key principle for the targeted modification of microorganisms [2,3,6,7,10,13,16,21,22,23,25,27,28,29,31,32,38,39,40,41]. The goal is to delete some reactions such that the host organism can only grow if it synthesizes a desired compound as a mandatory by-product.…”

“…One key advantage of growth-coupled product synthesis is that adaptive evolution can be used to further optimize the production rate [4,6]. Stoichiometric and constraint-based modeling techniques provide excellent tools to calculate intervention strategies enforcing growth-coupled product synthesis [2,9,10,13,15,21,25,29,31,33,36,39,41]. However, coupling biomass formation with synthesis of a metabolite may not be feasible for all compounds in a metabolic network.…”