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Phospo enol pyruvate carboxylase (PEPC) is absent from humans but encoded in the  Plasmodium falciparum  genome, suggesting that PEPC has a parasite-specific function. To investigate its importance in  P. falciparum , we generated a  pepc  null mutant (D10 Δ pepc  ), which was only achievable when malate, a reduction product of oxaloacetate, was added to the growth medium. D10 Δ pepc   had a severe growth defect  in vitro , which was partially reversed by addition of malate or fumarate, suggesting that  pepc  may be essential  in vivo . Targeted metabolomics using  13 C-U-D-glucose and  13 C-bicarbonate showed that the conversion of glycolytically-derived PEP into malate, fumarate, aspartate and citrate was abolished in D10 Δ pepc   and that pentose phosphate pathway metabolites and glycerol 3-phosphate were present at increased levels. In contrast, metabolism of the carbon skeleton of  13 C, 15 N-U-glutamine was similar in both parasite lines, although the flux was lower in D10 Δ pepc  ; it also confirmed the operation of a complete forward TCA cycle in the wild type parasite. Overall, these data confirm the CO 2  fixing activity of PEPC and suggest that it provides metabolites essential for TCA cycle anaplerosis and the maintenance of cytosolic and mitochondrial redox balance. Moreover, these findings imply that PEPC may be an exploitable target for future drug discovery.

Phosphoenolpyruvate Carboxylase Identified as a Key Enzyme in Erythrocytic Plasmodium falciparum Carbon Metabolism