Functional interrogation of Plasmodium genus metabolism identifies species- and stage-specific differences in nutrient essentiality and drug targeting
Fig 4
Stage-specific central metabolic flux patterns in malaria.
(a) Correlated reaction sets for iAM-Pf480 were used to define stage and model specific pathways, which were analyzed and compared across different stages. Modularity indices (see methods) were 0.023, 0.024, 0.026, 0.145, 0.022 for the T, Schizont, GII, GV, and Ook stages, respectively. In proliferative versus non-proliferative stages of malaria, there were changes in the patterns of central carbon metabolism, notably the non-oxidative PPP and glycolysis. (b) The direction of flux in the non-oxidative branch of PPP goes towards production of glycolytic intermediates in the Trophozoite, Schizont, GII, and GV stages but not the Ookinete stage. Reversal of non-oxidative pentose phosphate pathway fluxes in the Ook enables provision of ribose 5 phosphate (r5p) needed for the synthesis of nucleotide precursors of DNA. The non-oxidative branch in the schizont is colored in red indicating its coupling to growth rate in this stage (Table G in S1 Tables). Both the oxidative and non-oxidative PPP branches were correlated in GII. Glycolysis was split into upper and lower branches in all stages except GV where the non-oxidative PPP branch was correlated with inositol metabolism. Arrows are omitted from the schizont pathway map to account for reduced flux values relative the other 4 stages. (c) Predicted sampled flux distribution are shown in the non-oxidative branch of PPP (Transketolase; TKT1) and inositol metabolism (myo-inositol-3-phosphate lyase; MI3PS) across all the stages showing increased involvement of inositol metabolism in the GV stage (see supplementary material for discussion and S1 Fig for the high resolution version of the figure).