Phosphoenolpyruvate carboxylase identified as a key enzyme in erythrocytic Plasmodium falciparum carbon metabolism
Storm, Janet and Sethia, Sonal and Blackburn, Gavin and Chokkathukalam, A and Watson, David and Breitling, R. and Coombs, Graham and Muller, S. (2014) Phosphoenolpyruvate carboxylase identified as a key enzyme in erythrocytic Plasmodium falciparum carbon metabolism. PLOS Pathogens, 10 (1). pp. 1-14. e1003876. ISSN 1553-7366 (https://doi.org/10.1371/journal.ppat.1003876)
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Abstract
Phospoenolpyruvate 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 (D10Δpepc), which was only achievable when malate, a reduction product of oxaloacetate, was added to the growth medium. D10Δpepc 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 13C-U-D-glucose and 13C-bicarbonate showed that the conversion of glycolytically-derived PEP into malate, fumarate, aspartate and citrate was abolished in D10Δpepc and that pentose phosphate pathway metabolites and glycerol 3-phosphate were present at increased levels. In contrast, metabolism of the carbon skeleton of 13C,15N-U-glutamine was similar in both parasite lines, although the flux was lower in D10Δpepc; it also confirmed the operation of a complete forward TCA cycle in the wild type parasite. Overall, these data confirm the CO2 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.
ORCID iDs
Storm, Janet, Sethia, Sonal, Blackburn, Gavin, Chokkathukalam, A, Watson, David ORCID: https://orcid.org/0000-0003-1094-7604, Breitling, R., Coombs, Graham and Muller, S.;-
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Item type: Article ID code: 46145 Dates: DateEvent16 January 2014PublishedSubjects: Medicine > Pharmacy and materia medica
Medicine > Therapeutics. PharmacologyDepartment: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences Depositing user: Pure Administrator Date deposited: 16 Dec 2013 14:38 Last modified: 03 Oct 2024 00:22 Related URLs: URI: https://strathprints.strath.ac.uk/id/eprint/46145