Metabolic impact assessment for heterologous protein production in Streptomyces lividans based on genome-scale metabolic network modeling

• Wild-type genome-scale metabolic network model is extended with heterologous protein reactions.
• Intrinsic properties of the model are examined using stoichiometric network analysis.
• Geometric flux balance analysis reveals a widely-distributed impact on metabolism of S. lividans.
• Data-based robustness analysis is used to account for cell heterogeneity.

The metabolic impact exerted on a microorganism due to heterologous protein production is still poorly understood in Streptomyces lividans. In this present paper, based on exometabolomic data, a proposed genome-scale metabolic network model is used to assess this metabolic impact in S. lividans. Constraint-based modeling results obtained in this work revealed that the metabolic impact due to heterologous protein production is widely distributed in the genome of S. lividans, causing both slow substrate assimilation and a shift in active pathways. Exchange fluxes that are critical for model performance have been identified for metabolites of mouse tumor necrosis factor, histidine, valine and lysine, as well as biomass. Our results unravel the interaction of heterologous protein production with intracellular metabolism of S. lividans, thus, a possible basis for further studies in relieving the metabolic burden via metabolic or bioprocess engineering.