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

Abstract

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.

• Authors: Simon A Cobbold, Madel V Tutor, Philip Frasse, Emma McHugh, Markus Karnthaler, Darren J Creek, Audrey Odom John, Leann Tilley, Stuart A Ralph, Malcolm J McConville
• Journal: Molecular systems biology (Mol Syst Biol) Vol. 17 Issue 4 Pg. e10023 (04 2021) ISSN: 1744-4292 [Electronic] England
• PMID: 33821563 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Hemoglobins
• Protozoan Proteins
• Terpenes
• Serine
• Glycine Hydroxymethyltransferase
• Phosphoprotein Phosphatases

Topics

• Animals
• Electron Transport
• Erythrocytes (parasitology)
• Glycine Hydroxymethyltransferase (metabolism)
• Hemoglobins (metabolism)
• Humans
• Isotope Labeling
• Metabolic Flux Analysis
• Metabolic Networks and Pathways
• Metabolome
• Metabolomics
• Mitochondria (metabolism)
• Parasites (growth & development, metabolism)
• Phosphoprotein Phosphatases (metabolism)
• Plasmodium falciparum (growth & development, metabolism)
• Protozoan Proteins (metabolism)
• Serine (metabolism)
• Terpenes (metabolism)
• Trophozoites (metabolism)