Fig 1.
Graphical abstract of the workflow of FBA-based metabolic modeling for secondary metabolism.
Orange circle: secondary metabolite; pink circle: primary metabolite. FBA, flux balance analysis; smGSMM, genome-scale metabolic model with secondary metabolic pathway.
Table 1.
Automated pathway reconstruction tools for microbial secondary metabolism.
Table 2.
Summary of different modeling techniques to predict secondary metabolite production.
Fig 2.
Quantitative assessment of existing FBA-based modeling techniques for predicting secondary metabolite production.
(A) Comparison of predicted and observed growth rates and ACT production fluxes at different observed growth rates in Alam and colleagues [87]. (B) Comparison of 4 different objective functions used in FBA to predict both primary metabolism and clavulanic acid production flux [89]. Correlation scores are computed for predicted and observed fluxes. P-lim: limited phosphorus content. (C) Comparison of predicted and observed production fluxes of ACT and RED in Kim and colleagues [97]. ACT, actinorhodin; FBA, flux balance analysis.
Fig 3.
An illustrative example of pH-induced EPS production in lactic acid bacteria, used to explain the constrained proteome allocation model for both primary and secondary metabolism.
(A) The metabolic network of lactic acid bacteria for both primary metabolism (C, R, T sectors) and secondary metabolism (U sector). (B) Simulated metabolic response to pH: the increase of acidity inhibits the growth rate and induces EPS production. (C) Simulated proteome allocation in response to pH: the increase of acidity activates secondary metabolism, and more proteome resources get allocated to the U sector. Note: this “toy” model is for illustration only. EPS, exopolysaccharide.
Fig 4.
Schematic diagram of the combination of metabolic and GRNs to predict the secondary metabolite production.
The stress signal stimulates the expression of RF, resulting in the activation of enzymes catalyzing reactions for secondary metabolite biosynthesis. Orange circle: secondary metabolite; pink circle: primary metabolite. Enz, enzyme; GRN, gene regulatory network; RF, regulatory factor.