Predictions to Increase Lasso Peptide Production in the Heterologous Host Streptomyces coelicolor M1152

ABSTRACT Production of specialized metabolites are restricted to the metabolic capabilities of the organisms. Genome‐scale models (GEM)s are useful to study the whole metabolism and to find metabolic engineering targets to increase the yield of a target compound. In this work we use a modified model of Streptomyces coelicolor M145 to simulate the production of lagmysin A (LP4) and the novel lagmysin B (LP2) lasso peptide, in the heterologous host Streptomyces coelicolor M1152. Overexpression targets were identified using the flux scanning based on enforced objective flux (FSEOF) algorithm and flux variability analysis (FVA), considering growth in minimum and in complex medium. Thirteen reactions were found as candidate metabolic engineering targets for both lasso peptides considering both settings. We propose the overexpression of enzymes of the glycolysis pathway (GAPD, PGK, PGM and ENO) and leucine biosynthesis (IPPS, IPPMIb, IPPMIa, IPMD and OMCDC) to enhance the production of either lagmysin A or B.