Pan-reactome analysis of Streptomyces strains reveals association and disconnection between primary and secondary metabolism.

Secondary metabolites have crucial medicinal and industrial applications, but their alignment with primary metabolism remains unclear. As secondary metabolism depends on primary metabolism for precursor supply, we present a pan-reactome analysis of 242 Streptomyces strains to investigate their association and disconnection. This analysis includes phylogenetic grouping of the strains using genome data, and uniform manifold approximation and projection (UMAP) analysis of their genome-scale metabolic models (GEMs) and biosynthetic gene cluster (BGC) data, which represent biochemical reactions in primary and secondary metabolism. Subsequent correlation analysis of the preprocessed GEM and BGC data showed a Pearson correlation coefficient of 0.54, revealing both metabolic association and disconnection. In particular, among 47 precursors of polyketides, nonribosomal peptides, and hybrids, nine precursors required by these BGCs were predicted to be non-producible due to missing genes in primary metabolism or BGCs. The pan-reactome analysis facilitates the identification of precursor availability and metabolic gaps, providing insights into secondary metabolite biosynthesis.