Structural Requirements for the Feasibility of Growth-Coupled Product Synthesis in Microbial Strains

Growth-coupled product synthesis has become a key principle for metabolic engineering and various constraint-based modeling techniques have been developed to calculate intervention strategies by which a microorganism can only grow if it co-synthesizes a desired by-product. However, growth-coupled synthesis is not feasible for all metabolites. Using geometric techniques we show which structural properties in a network are required such that biomass and product synthesis can be coupled at all [1]. In networks without flux bounds, coupling is feasible if and only if an elementary mode exists that leads to formation of both biomass and product. Setting flux boundaries leads to more complicated inhomogeneous problems. Making use of the concept of elementary flux vectors, a generalization of elementary modes, criteria for feasibility of coupling can also be derived for this situation. We applied our criteria to a metabolic model of E. coli and determined for each metabolite whether its net production can be coupled with growth and calculated the maximal (guaranteed) coupling yield. The somewhat surprising result is that coupling is indeed possible for all (almost all) carbon metabolites of the central metabolism under aerobic (anaerobic) conditions. Consideration of ATP maintenance requirements may increase or decrease the maximal coupling yields. Overall, our work (i) provides important insights for a central problem of computational strain design and (ii) emphasizes elementary flux vectors as a suitable tool for analyzing metabolic networks with inhomogeneous constraints.

[1] Klamt S and Mahadevan R (2015) On the feasibility of growth-coupled product synthesis in microbial strains. Metabolic Engineering, in press.