Genome-scale Model Constrained by Proteomics Reveals Metabolic Changes in Streptomyces coelicolor M1152 Compared to M145

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.