TY - JOUR T1 - Genome-scale Model Constrained by Proteomics Reveals Metabolic Rearrangements in the Heterologous Host <em>Streptomyces coelicolor</em> JF - bioRxiv DO - 10.1101/796722 SP - 796722 AU - Snorre Sulheim AU - TjaĊĦa Kumelj AU - Dino van Dissel AU - Ali Salehzadeh-Yazdi AU - Chao Du AU - Kay Nieselt AU - Eivind Almaas AU - Alexander Wentzel AU - Eduard Kerkhoven Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/11/29/796722.abstract N2 - Streptomyces coelicolor M1152 is a widely used host strain for the heterologous production of novel small molecule natural products, genetically engineered for this purpose through e.g. deletion of four of its native biosynthetic gene clusters (BGCs) for improved precursor supply. Regardless of its potential, a systems understanding of its tight regulatory network and the effects of the significant genomic changes in M1152 is missing. In this study, we compare M1152 to its ancestor M145, thereby connecting observed phenotypic differences to changes on transcription and translation. Measured protein levels are connected to predicted metabolic fluxes, facilitated by an enzyme-constrained genome-scale model (GEM), that by itself is a consensus result of a community effort. This approach connects observed differences in growth rate and glucose consumption to changes in central carbon metabolism, accompanied by differential expression of important regulons. Results suggest that precursors supply is not limiting secondary metabolism, informing that alternative strategies will be beneficial for further development of S. coelicolor for heterologous production of novel compounds.Importance This study provides the first systems description of S. coelicolor M1152, an engineered heterologous expression host widely used for the production and discovery of natural products. By combining time-series proteomics and transcriptomics, batch fermentation data and genome-scale modelling we can connect observed phenotypes to known genetic modifications and find extensive metabolic rearrangements in the M1152 strain compared to the wild-type stain M145. We furthermore found that the rational strategy of enhancing precursor supply will surprisingly only have limited impact.Instrumental to this study has been the genome-scale model that has allowed us to contextualize the transcriptional changes. To consolidate recent efforts in this field we reconstructed the consensus model Sco-GEM in an open-science framework. This approach facilitates further development by the research community in an organized manner, including version control, continuous integration and quality control and tracking of individual contributions. ER -