Carbon Metabolism of<i>Plasmodium falciparum</i>

Biddau, Marco; Müller, Sylke

doi:10.1002/9783527694082.ch16

Cited by 2 publications

(1 citation statement)

References 142 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, we included the requirement for cellular export of lactate and hemozoin. Lactate is measured in extracellular in vitro metabolomics and in vivo via blood acidosis; it is the terminal product of glycolysis, the sole energy production pathway used by the blood-stage parasite [59-62]. By requiring lactate export, we force the model to utilize glycolytic energy metabolism.…”

Section: Resultsmentioning

confidence: 99%

NovelPlasmodium falciparummetabolic network reconstruction identifies shifts associated with clinical antimalarial resistance

Carey

Papin

Guler

2017

Preprint

View full text Add to dashboard Cite

BACKGROUND Malaria remains a major public health burden and resistance has emerged to every antimalarial on the market, including the frontline drug artemisinin. Our limited understanding of Plasmodium biology hinders the elucidation of resistance mechanisms. In this regard, systems biology approaches can facilitate the integration of existing experimental knowledge and further understanding of these mechanisms. RESULTS Here, we developed a novel genome-scale metabolic network reconstruction, iPfal17, of the asexual blood-stage P. falciparum parasite to expand our understanding of metabolic changes that support resistance. We identified 11 metabolic tasks to evaluate iPfal17 performance. Flux balance analysis and simulation of gene knockouts and enzyme inhibition predict candidate drug targets unique to resistant parasites. Moreover, integration of clinical parasite transcriptomes into the iPfal17 reconstruction reveals patterns associated with antimalarial resistance. These results predict that artemisinin sensitive and resistant parasites differentially utilize scavenging and biosynthetic pathways for multiple essential metabolites including folate and polyamines, and others within the mitochondria. Our findings are consistent with experimental literature, while generating novel hypotheses about artemisinin resistance and parasite biology. We detect evidence that resistance parasites maintain greater metabolic flexibility, perhaps representing an incomplete transition to the metabolic state most appropriate for nutrient-rich blood.

show abstract

Section: Resultsmentioning

confidence: 99%

NovelPlasmodium falciparummetabolic network reconstruction identifies shifts associated with clinical antimalarial resistance

Carey

Papin

Guler

2017

Preprint

View full text Add to dashboard Cite

show abstract

Novel Plasmodium falciparum metabolic network reconstruction identifies shifts associated with clinical antimalarial resistance

2017

View full text Add to dashboard Cite

BackgroundMalaria remains a major public health burden and resistance has emerged to every antimalarial on the market, including the frontline drug, artemisinin. Our limited understanding of Plasmodium biology hinders the elucidation of resistance mechanisms. In this regard, systems biology approaches can facilitate the integration of existing experimental knowledge and further understanding of these mechanisms.ResultsHere, we developed a novel genome-scale metabolic network reconstruction, iPfal17, of the asexual blood-stage P. falciparum parasite to expand our understanding of metabolic changes that support resistance. We identified 11 metabolic tasks to evaluate iPfal17 performance. Flux balance analysis and simulation of gene knockouts and enzyme inhibition predict candidate drug targets unique to resistant parasites. Moreover, integration of clinical parasite transcriptomes into the iPfal17 reconstruction reveals patterns associated with antimalarial resistance. These results predict that artemisinin sensitive and resistant parasites differentially utilize scavenging and biosynthetic pathways for multiple essential metabolites, including folate and polyamines. Our findings are consistent with experimental literature, while generating novel hypotheses about artemisinin resistance and parasite biology. We detect evidence that resistant parasites maintain greater metabolic flexibility, perhaps representing an incomplete transition to the metabolic state most appropriate for nutrient-rich blood.ConclusionUsing this systems biology approach, we identify metabolic shifts that arise with or in support of the resistant phenotype. This perspective allows us to more productively analyze and interpret clinical expression data for the identification of candidate drug targets for the treatment of resistant parasites.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3905-1) contains supplementary material, which is available to authorized users.

show abstract

Carbon Metabolism ofPlasmodium falciparum

Cited by 2 publications

References 142 publications

NovelPlasmodium falciparummetabolic network reconstruction identifies shifts associated with clinical antimalarial resistance

NovelPlasmodium falciparummetabolic network reconstruction identifies shifts associated with clinical antimalarial resistance

Novel Plasmodium falciparum metabolic network reconstruction identifies shifts associated with clinical antimalarial resistance

Contact Info

Product

Resources

About