Fig. 2

Applications of GEMs for the production of chemicals and materials, drug targeting in pathogens, the prediction of enzyme functions, and pan-reactome analysis. a. Flux-response analysis using the Escherichia coli GEM iJO1366 [20] has been used to identify gene manipulation targets for the enhanced production of a monomer of an aromatic polymer d-phenyllactic acid in E. coli [122]. The final strain has two additional genes (tyrB and aspC) knocked out from an E. coli base strain XB201T that expresses AroG^fbr, PheA^fbr, and FldH. The final strain produced 1.62 g/L of d-phenyllactic acid, much more than the 0.55 g/L produced by the base strain. b Reconstruction of the Yarrowia lipolytica GEM iYLI647 and its application for the prediction of reaction engineering targets using four different in silico strain-design strategies [123]. c Identification of stage-specific antimalarial drug targets for Plasmodium falciparum using stage-specific GEMs that represent five different life cycle stages [124]. d Reconstruction of a GEM for Acinetobacter baumannii using several databases and its application for the prediction of condition-specific drug targets to combat antibiotic-resistant A. baumannii [125]. e Discovery of new isozyme functions for genes that have been shown to be nonessential in experiments but that were predicted to be essential in a gene essentiality simulation of the E. coli iJO1366 GEM (i.e., false-negative prediction for the aspC gene) [126]. It was found that tyrosine aminotransferase, which is encoded by tyrB (red line), can compensate for the loss of aspartate aminotransferase, encoded by aspC, which catalyzes the conversion of l-aspartate (l-Asp) and α-ketoglutarate (Akg) to oxaloacetate (Oaa) and l-glutamate (l-Glu). gDCW/L grams dry cell weight per liter. f The PROmiscuity PrEdictoR (PROPER) method identifies promiscuous enzymes at a genome-scale in a target organism [127]. Promiscuous functions for all of the genes in the target organism (E. coli) were predicted using the PROPER method and an E. coli GEM from the Model SEED, which identified 98 alternative routes for the biosynthesis of various metabolites. For example, the product of the thiG gene in E. coli was newly found to biosynthesize pyridoxal 5′-phosphate, which is also known to be biosynthesized by the product of the pdxB gene. g Analysis of the pan-reactome and accessory reactome of 410 Salmonella strains spanning 64 serovars using their respective GEMs [128]. Simulation of the GEMs under various nutrient conditions revealed the different catabolic capabilities of the different strains as well as their preferred growth environments. h Analysis of the pan-reactome and accessory reactome of 24 Penicillium species by using their respective GEMs [129]. Hierarchical clustering of the 24 GEMs revealed additional insights into the biosynthetic pathways of secondary metabolites, which successfully differentiated the metabolic clades