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.

Toxoplasma gondii apicoplast-resident ferredoxin is an essential electron transfer protein for the MEP isoprenoid-biosynthetic pathway

“…It therefore does not come as a surprise that infection with tachyzoites of human and mouse cells leads to increased transcription of some of the MVA pathway genes ( 74 , 75 , 76 ), presumably resulting in increased isoprenoid synthesis. This is in contrast to blood stages of P. falciparum because erythrocytes contain minimal amounts of functional MVA pathway enzymes, and IPP levels of uninfected red blood cells are also low ( 8 , 77 ). Our finding of an observable contribution of the host MVA pathway to a dampened iΔFd phenotype is in agreement with previous studies.…”

Recent metabolomic developments for antimalarial drug discovery

“…The difference in labeling between uninfected and iRBC successfully discerned the extensiveness and rate of metabolic fluxes of the TCA cycle (MacRae et al 2013). More recently, Cobbold et al performed an untargeted LC-MS metabolomic assay with unsupervised isotopologue grouping to describe the metabolic capacity of the P. falciparum trophozoite-infected RBC and RBC (Cobbold et al 2021). The basis for the study was that significant protein and metabolic-encoding P. falciparum genes are still unannotated, thus failing to shed light on enzyme promiscuity and ambiguous metabolites (Cobbold et al 2021).…”

Lipid transport proteins in malaria, from Plasmodium parasites to their hosts

“…Investigating these and other outstanding questions will be greatly aided by advances in research technologies to manipulate Plasmodium parasites [61,102,107,108,133,134,135,136]. Inducible gene deletion, protein disruption and mRNA stability techniques have already proven to be indispensable to the investigation of many essential proteins and will undoubtedly be of great use in furthering our understanding of the proteins involved in the transfer of lipids in the parasite and in the host cell.…”