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

Many biosynthetic gene clusters (BGCs) in the genomes of environmental microorganisms require heterologous expression in order to realize their genetic potential, including cryptic and metagenomic BGCs. Streptomyces coelicolor M1152 is a widely used host strain for the heterologous expression of BGCs, as it has been genetically engineered for this purpose via the deletion of four of its native biosynthetic gene clusters (BGCs) and the introduction of a point mutation in the rpoB gene that encodes the beta subunit of RNA polymerase. This latter mutation was shown to have a strong positive impact on antibiotic biosynthesis via processes that remain poorly understood. Therefore, a systemic understanding of the consequences on cellular metabolism of the genomic changes of M1152 could greatly contribute to this understanding. Here we carried out a comparative analysis of M1152 and its ancestor strain M145, connecting observed phenotypic differences to changes in transcript and protein abundance. Measured protein abundance was used to constrain an amended genome-scale model (GEM) and to predict metabolic fluxes. This approach connects observed differences in growth rate and glucose consumption to changes in central carbon metabolism, accompanied by differential expression of important regulons. Our results suggest that precursor availability is not limiting the biosynthesis of secondary metabolites. This implies that alternative strategies could be beneficial for further development of S. coelicolor for heterologous production of novel compounds.