Pathway Thermodynamics Highlights Kinetic Obstacles in Central Metabolism
Figure 2
MDF analysis of oxidative pathways.
(A) Structure of the TCA cycle. The reaction marked in red is the only one with a positive shadow price at pH 7.5. Non-cofactor metabolites shaded in green show positive shadow prices. (B) MDF as function of pH, as calculated for the TCA cycle and several of its similar variants. Solid cyan line: default metabolite concentration range used throughout this study (1 µM–10 mM). Dashed and dotted cyan lines: oxaloacetate concentration (marked as ‘OA’) is allowed to attain lower values, 100 nM and 10 nM, respectively. Solid magenta line: oxaloacetate is channeled (‘channeling’) between malate dehydrogenase and citrate synthase. Semi-dashed green line: quinone (‘MQO’) serves as the electron acceptor in malate oxidation, instead of NAD. The Flux-Force Efficacy axis, on the right, refers to the reactions that dissipate the smallest amount of Gibbs energy, and hence equal to the pathway MDF. The light grey line marks the values corresponding to pH 7.5, the pH used in (C). (C) The MDF and ATP yield per glucose of the different oxidative pathways. ‘PEP-GLX’ corresponds to the PEP-Glyoxylate pathway, which was found to operate in E. coli under glucose starvation [64]. ‘P. fluorescens’ corresponds to the pathway used by Pseudomonas fluorescens under conditions of aluminum toxicity [81]. ‘OxPP’ corresponds to the oxidative pentose phosphate cycle, which can be used to fully oxidize sugars into CO2, providing NADPH for cellular activity. Reducing power was assumed to be converted to ATP via oxidative phosphorylation, where NADH or a pair of reduced ferredoxins give rise to 1.5 ATP molecules and reduced ubiquinone produces one ATP molecule. The structures of all pathways are given in Figure S1.