Development and validation of an updated computational model of Streptomyces coelicolor primary and secondary metabolism

Abstract

BackgroundStreptomyces species produce a vast diversity of secondary metabolites of clinical and biotechnological importance, in particular antibiotics. Recent developments in metabolic engineering, synthetic and systems biology have opened new opportunities to exploit Streptomyces secondary metabolism, but achieving industry-level production without time-consuming optimization has remained challenging. Genome-scale metabolic modelling has been shown to be a powerful tool to guide metabolic engineering strategies for accelerated strain optimization, and several generations of models of Streptomyces metabolism have been developed for this purpose.ResultsHere, we present the most recent update of a genome-scale stoichiometric constraint-based model of the metabolism of Streptomyces coelicolor, the major model organism for the production of antibiotics in the genus. We show that the updated model enables better metabolic flux and biomass predictions and facilitates the integrative analysis of multi-omics data such as transcriptomics, proteomics and metabolomics.ConclusionsThe updated model presented here provides an enhanced basis for the next generation of metabolic engineering attempts in Streptomyces.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4905-5) contains supplementary material, which is available to authorized users.

Genome‐Scale Metabolic Reconstruction of Actinomycetes for Antibiotics Production

“…Among all the GEMs of twelve actinomycetes reconstructed so far, GEMs of nine species have been released since 2017, which stresses the increasing industrial or medical importance of actinomycetes (Table ). In particular, GEMs of several representative species have been reconstructed multiple times over the years, including Streptomyces coelicolor , Streptomyces clavuligerus , Saccharopolyspora erythraea , Streptomyces lividans , and Streptomyces tsukubaensis . Recently, two different versions of GEMs have been released for S. coelicolor , namely Sco4 and iAA1259 .…”

“…In particular, GEMs of several representative species have been reconstructed multiple times over the years, including Streptomyces coelicolor , Streptomyces clavuligerus , Saccharopolyspora erythraea , Streptomyces lividans , and Streptomyces tsukubaensis . Recently, two different versions of GEMs have been released for S. coelicolor , namely Sco4 and iAA1259 . For Sco4, GEM reconstruction was carried out by implementing the software program RAVEN Toolbox 2 where three different GEMs, each reconstructed using KEGG, MetaCyc, and a previous S. coelicolor GEM iMK1208 as a reference, respectively, were merged together, and manually curated to give an upgraded GEM Sco4.…”

“…Sco4 includes description on biosynthetic pathways of a total of eleven secondary metabolites, such as flaviolin, geosmin, albaflavenone, 2‐methylisoborneol, hopane, and desferrioxamine; the previous version iMK1208 covers five secondary metabolites . Reconstruction of iAA1259, based on iMK1208, includes updates in biosynthetic pathways and model annotations by incorporating identifiers from multiple databases of genes, metabolites, and reactions, which enabled integrative analysis of multi‐omics data . iAA1259 covered an additional biosynthetic pathway of coelimycin P1 in comparison with the iMK1208 .…”

“…[22,23] Recently, two different versions of GEMs have been released for S. coelicolor, namely Sco4 [14] and iAA1259. [15] For Sco4, GEM reconstruction was carried out by implementing the software program RAVEN Toolbox 2 [14] where three different GEMs, each reconstructed using KEGG, MetaCyc, and a previous S. coelicolor GEM iMK1208 [13] as a reference, respectively, were merged together, and manually curated to give an upgraded GEM Sco4. Sco4 includes description on biosynthetic pathways of a total of eleven secondary metabolites, such as flaviolin, geosmin, albaflavenone, 2-methylisoborneol, hopane, and desferrioxamine; [14] the previous version iMK1208 covers five secondary metabolites.…”

“…[15] iAA1259 covered an additional biosynthetic pathway of coelimycin P1 in comparison with the iMK1208. [15] In general, some of the commonly observed upgrades in actinomycetes' GEMs include incorporating information from updated metabolic databases, improving gene-protein-reaction associations, resolution of metabolic gaps, updates in biomass compositions, and more extensive description of biosynthetic pathways of secondary metabolites ( Figure 1). [14,17,23] A challenge with the GEM reconstruction of secondary metabolite-producing microorganisms is to describe BGCs that are often unknown at metabolic level ( Figure 1).…”