Hypothetical model of the contributions PEPC and adaptations of D10^Δ^<i>pepc</i> to compensate for lack of PEPC.

<p>The width of arrows is indicative of the fluxes through the pathways. Glucose used by wild type parasites is phosphorylated into glucose 6-phosphate, which is either catabolised in the glycolytic pathway to generate lactate or is used in the PPP to provide NADPH and 5 and 7-carbon sugars for downstream metabolic processes. During glycolysis, NAD⁺ reduction and NADH oxidation (blue boxes) are balanced in the complete glycolytic sequence itself, but some metabolites are used in other ways. Glycerol 3-phosphate dehydrogenase and especially MDH, converting OAA (the product of CO₂ fixation by PEPC) to malate, play roles in maintenance of redox balance in the cytoplasm (red boxes). Pyruvate is metabolised not only into lactate but is also transferred into the mitochondrion where it is oxidised into acetyl-CoA by a PDH-like dehydrogenase <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003876#ppat.1003876-MacRae1" target="_blank">[3]</a>, <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003876#ppat.1003876-Cobbold1" target="_blank">[6]</a>. Malate is transferred into the mitochondrion via a malate∶α-ketoglutarate (αKG) antiporter and enters TCA metabolism leading to OAA formation in the organelle, this oxidation transfers reducing equivalents into the mtETC (QH₂). OAA may leave the mitochondrion, thus completing a parasite-specific form of a malate shuttle, or be converted to citrate as part of canonical TCA metabolism. Deletion of <i>pepc</i> leads to an imbalance in redox metabolism in both cytosol and presumably also mitochondrion. D10^{Δ<i>pepc</i>} apparently adapted to this with increased generation of glycerol 3-phosphate with concomitant NADH oxidation, thus compensating partially for the loss of downstream generation of NAD⁺ through MDH. Increased flux through oxidative PPP is a mechanism for generating NADPH which may be compensating for the reduced flux through TCA metabolism and therefore a reduced generation of NADPH at the IDH step in D10^{Δ<i>pepc</i>}(purple boxes). The reduction in flux to lactate in D10^{Δ<i>pepc</i>} reflects the severely reduced growth phenotype of D10^{Δ<i>pepc</i>}. The flux from glutamine via glutamate to α-ketoglutarate and, within the mitochondrion, to succinate and, at an apparently lower flux, to fumarate and malate is shown, with α-ketoglutarate as an additional entry point into TCA metabolism. The flux through these metabolites is lower in D10^{Δ<i>pepc</i>} compared with D10, reflecting the general growth defect of D10^{Δ<i>pepc</i>} and also its reduced consumption of glutamine, although the pathway in which the carbon skeleton is incorporated is not dramatically affected.