Figure 2. E. coli core metabolic network metabolite producibility.

(A) The E. coli core metabolic network is represented as a bipartite graph with metabolites shown as circles and reactions shown as squares. Reactions shown with a black border are irreversible in the model, those with no border are reversible. All intracellular metabolites are colored based on their PM value (low – blue, high – red). Reactions and metabolite nodes are sized based on their total node degree. Several key metabolites of interest are highlighted with their corresponding PM values shown. Central metabolites such as H⁺ and Pyruvate have high degree and high PM. Cofactors such as AMP/ADP/ATP and NAD⁺/NADH have high degree but low PM, as they cannot be synthesized in this network. Oxygen is an example of a PM=0 metabolite that cannot be produced from any other metabolites in this network. D-lactate is an example of a metabolite with low degree and high PM that is it is easily produced but not well-connected. (B) The lactate dehydrogenase reaction producing D-Lactate is shown as an example to illustrate that poorly connected metabolites can display a high PM, and how recycled cofactors have minimal impact on PM values. Lactate dehydrogenase produces D-lactate and NAD⁺ from pyruvate, H⁺ and NADH. The metabolite D-lactate has high PM despite being produced only by this one reaction in the metabolic network because it can be produced from the high PM metabolites pyruvate and H⁺, which are themselves produced from a large number of possible precursors. Although NADH is also used to produce D-lactate, and has a relatively low PM in this core model, it has minimal impact on the PM of D-lactate as NADH can be recycled from NAD⁺ by a large number of reactions (represented by the arrows at the bottom of the figure) and thus production of NADH is not necessary for the production of D-lactate.

Figure 2—figure supplement 1. Node degree and producibility metric do not correlate for E. coli core metabolic network intracellular metabolites.

Different forms of the node degree (ND) are plotted against the producibility metric (PM) for all intracellular metabolites in the E. coli core network. No correlation (Spearman’s rank correlation) is observed between the PM and any form of node degree. (A) The in node degree (ND in) is the sum of the number of reactions producing the metabolite. (B) The out node degree (ND out) is the sum of the number of reactions consuming the metabolite. (C) The total node degree (ND total) is the sum of the in and out node degrees. (D) The total degree without double counting reversible reactions (ND total no Rev) is the total node degree when counting reversible reactions only once.

Figure 2—figure supplement 2. Producibility analysis of the histidine biosynthetic pathway.

(A) A network representation of the histidine biosynthetic pathway is shown. Reactions are represented as squares, histidine is shown as a red circle, main intermediate metabolites are shown as black circles, cofactors metabolites are shown as gray circles. Different histidine auxotrophs were generated by removing reactions at increasing distance from histidine in the E. coli iJO1366 metabolic network. (B) The producibility metric (PM) for histidine was calculated for the different simulated E. coli auxotrophs (blue dots). The theoretical PM values, calculated using the formula from Figure 1—figure supplement 2C and assuming minimal precursor sets of size corresponding to the number of main intermediate metabolites that remain attached to histidine in a particular auxotroph are also plotted (black X’s). (C) The presence of the histidine biosynthetic pathway was measured across 456 different oral microbiome metabolic networks in two different ways: pathway sum – the total number of reactions from the pathway present in an organism’s metabolic network, and pathway length – the number of reactions in the pathway starting at histidine and counting until the first missing reaction. These two metrics were compared to the PM for histidine across oral microbiome organisms, both metrics were correlated with the PM for histidine with pathway length being more strongly correlated (pathway sum: spearman correlation = 0.79, p-value=8.5e-99; pathway length: spearman correlation = 0.88, p-value=3.6e-145).