초록
<▼1><P>Modifications made during metabolic engineering for overproduction of chemicals have network-wide effects on cellular function due to ubiquitous metabolic interactions. These interactions, that make metabolic network structures robust and optimized for cell growth, act to constrain the capability of the cell factory. To overcome these challenges, we explore the idea of an orthogonal network structure that is designed to operate with minimal interaction between chemical production pathways and the components of the network that produce biomass. We show that this orthogonal pathway design approach has significant advantages over contemporary growth-coupled approaches using a case study on succinate production. We find that natural pathways, fundamentally linked to biomass synthesis, are less orthogonal in comparison to synthetic pathways. We suggest that the use of such orthogonal pathways can be highly amenable for dynamic control of metabolism and have other implications for metabolic engineering.</P></▼1><▼2><P>Growth-coupled designs for chemical production are limited by native metabolic networks' optimality for growth. Here, the authors introduce pathway orthogonality as a measure of the independence of biomass and chemical production pathways, identify metabolic valves that allow substrate utilization to be switched between the two, and demonstrate advantages of orthogonal designs.</P></▼2>