Genome-Scale Metabolic Modeling of Actinomycetes for Secondary Metabolites Production

Actinomycetes are an important source for the discovery of medically useful secondary metabolites, such as anticancers and antibiotics. Major challenges of producing secondary metabolites include optimization of metabolic fluxes towards the biosynthesis of a target secondary metabolite and identification of an appropriate heterologous production host. Systems biology approaches including reconstruction of genome-scale metabolic models (GEMs) are increasingly applied to explore the dependencies between primary and secondary metabolism to predict gene manipulation targets for the overproduction of secondary metabolites. GMSM (Genome-scale metabolic Modeling with Secondary Metabolism) pipeline (unpublished) allows automatic reconstruction of GEMs with secondary metabolites biosynthetic pathways. . Here, we exemplify the strength of GMSM by reconstructing GEMs of important actinobacteria such as Streptomyces venezuelae and Streptomyces collinus. Growth prediction performance of GEMs under a variety of substrate conditions was compared with and fine-tuned using these two organisms’ phenotype microarray data. The resulting GEMs can provide an important tool for applying systems metabolic engineering strategies for the optimal production of secondary metabolites in various actinomycetes as a heterologous production host. In this regard, GMSM can serve as a useful platform to explore the potential of various actinomycetes by generating a collection of GEMs to produce diverse secondary metabolites.