Abstract
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.
Highlights
Modifications made during metabolic engineering for overproduction of chemicals have network-wide effects on cellular function due to ubiquitous metabolic interactions
This means in perfect orthogonal networks (i) the product pathway shares no enzymatic steps with cellular pathways that are responsible for the production of precursors required for biomass and, (ii) only a single metabolite serves as a branch point from which product and biomass pathways diverge
In contrast to the prevalent approach of growthcoupled designs, we suggest that orthogonal pathway design coupled with dynamic metabolic engineering (DME) might be effective for de novo strain design
Summary
Modifications made during metabolic engineering for overproduction of chemicals have network-wide effects on cellular function due to ubiquitous metabolic interactions. In one recent study, the structure of the central metabolism was described as a ‘minimal walk’ between the input substrate and the 12 requisite precursors for biomass[9] Based on this minimal-walk description, the natural structure of metabolism is not optimal for the production of a desired chemical. We argue that to optimally convert the input substrate to the target chemical, one has to analogously generate a biosynthetic network that is largely independent of the natural metabolism but still capable of synthesizing biomass We define such pathways as orthogonal pathways and examine the orthogonal properties of natural and synthetic metabolic networks that are designed for chemical production. A metric for optimality that we developed helps to identify pathways that are optimal in the context of a set of minimal cellular interactions
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