Metabolic division of labor in microbial systems

Significance If contained in a single population a complex metabolic pathway can impose a burden on the host, decreasing the system’s overall productivity. This limitation can be overcome by division of labor (DOL), where distinct populations perform different steps of the pathway, thus reducing the burden on each population. By compartmentalizing reactions, however, DOL reduces their efficiency by introducing a transport barrier for metabolites and enzymes. It remains unclear how the trade-off between reducing burden and decreasing reaction efficiency dictates the potential benefit of DOL. Through the analysis of different metabolic pathways we derive a general criterion establishing when DOL outperforms a single population. Our results can guide rational engineering of metabolic pathways and provide insights into operation of natural pathways. Metabolic pathways are often engineered in single microbial populations. However, the introduction of heterologous circuits into the host can create a substantial metabolic burden that limits the overall productivity of the system. This limitation could be overcome by metabolic division of labor (DOL), whereby distinct populations perform different steps in a metabolic pathway, reducing the burden each population will experience. While conceptually appealing, the conditions when DOL is advantageous have not been rigorously established. Here, we have analyzed 24 common architectures of metabolic pathways in which DOL can be implemented. Our analysis reveals general criteria defining the conditions that favor DOL, accounting for the burden or benefit of the pathway activity on the host populations as well as the transport and turnover of enzymes and intermediate metabolites. These criteria can help guide engineering of metabolic pathways and have implications for understanding evolution of natural microbial communities.