Non‐canonical metabolic pathways in the malaria parasite detected by isotope‐tracing metabolomics

The malaria parasite, Plasmodium falciparum , proliferates rapidly in human erythrocytes by actively scavenging multiple carbon sources and essential nutrients from its host cell. However, a global overview of the metabolic capacity of intraerythrocytic stages is missing. Using multiplex 13 C‐labell...

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Published in:	Molecular systems biology Vol. 17; no. 4; pp. e10023 - n/a
Main Authors:	Cobbold, Simon A, V Tutor, Madel, Frasse, Philip, McHugh, Emma, Karnthaler, Markus, Creek, Darren J, Odom John, Audrey, Tilley, Leann, Ralph, Stuart A, McConville, Malcolm J
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-04-2021 EMBO Press John Wiley and Sons Inc Springer Nature
Subjects:	Animals Asexuality Biosynthesis Carbon Carbon sources Cell division Electron Transport EMBO21 EMBO23 Enzymes Erythrocytes Erythrocytes - parasitology Essential nutrients Genes Genomes Glucose Glycine Hydroxymethyltransferase - metabolism haloacid dehalogenase Hemoglobins - metabolism Homeostasis Humans Isotope Labeling Labeling Lipid metabolism Lipids Malaria Mass spectrometry Mass spectroscopy Metabolic Flux Analysis Metabolic Networks and Pathways Metabolic pathways Metabolism metabolite repair Metabolites Metabolome Metabolomics Mitochondria Mitochondria - metabolism Nutrients Parasites Parasites - growth & development Parasites - metabolism Phosphoprotein Phosphatases - metabolism Plasmodium Plasmodium falciparum Plasmodium falciparum - growth & development Plasmodium falciparum - metabolism Protozoan Proteins - metabolism Repair Scavenging Scientific imaging Serine - metabolism SHMT Terpenes - metabolism Trophozoites - metabolism Vector-borne diseases metabolite repair Plasmodium mass spectrometry SHMT haloacid dehalogenase
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Summary:	The malaria parasite, Plasmodium falciparum , proliferates rapidly in human erythrocytes by actively scavenging multiple carbon sources and essential nutrients from its host cell. However, a global overview of the metabolic capacity of intraerythrocytic stages is missing. Using multiplex 13 C‐labelling coupled with untargeted mass spectrometry and unsupervised isotopologue grouping, we have generated a draft metabolome of P. falciparum and its host erythrocyte consisting of 911 and 577 metabolites, respectively, corresponding to 41% of metabolites and over 70% of the metabolic reaction predicted from the parasite genome. An additional 89 metabolites and 92 reactions were identified that were not predicted from genomic reconstructions, with the largest group being associated with metabolite damage‐repair systems. Validation of the draft metabolome revealed four previously uncharacterised enzymes which impact isoprenoid biosynthesis, lipid homeostasis and mitochondrial metabolism and are necessary for parasite development and proliferation. This study defines the metabolic fate of multiple carbon sources in P. falciparum , and highlights the activity of metabolite repair pathways in these rapidly growing parasite stages, opening new avenues for drug discovery. Synopsis Multiplex stable‐isotope labelling defines the observable metabolome of red blood cell stages of the malaria parasite Plasmodium falciparum and indicates potential roles for metabolic enzymes of unknown function. A draft metabolome of P. falciparum and its host erythrocyte is presented, consisting of 911 and 577 metabolites respectively. The metabolome covers 70% of predicted metabolic reactions. 92 unpredicted reactions are identified, the largest group associated with metabolite damage repair. Mediators of isoprenoid biosynthesis, lipid homeostasis, and mitochondrial metabolism are identified. Graphical Abstract Multiplex stable‐isotope labelling defines the observable metabolome of red blood cell stages of the malaria parasite Plasmodium falciparum and indicates potential roles for metabolic enzymes of unknown function.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work
ISSN:	1744-4292 1744-4292
DOI:	10.15252/msb.202010023