Antimalarial drug targets in Plasmodium falciparum predicted by stage-specific metabolic network analysis.
BACKGROUND
Despite enormous efforts to combat malaria the disease still afflicts up to half a billion people each year of which more than one million die. Currently no approved vaccine is available and resistances to antimalarials are widely spread. Hence, new antimalarial drugs are urgently needed.


RESULTS
Here, we present a computational analysis of the metabolism of Plasmodium falciparum, the deadliest malaria pathogen. We assembled a compartmentalized metabolic model and predicted life cycle stage specific metabolism with the help of a flux balance approach that integrates gene expression data. Predicted metabolite exchanges between parasite and host were found to be in good accordance with experimental findings when the parasite's metabolic network was embedded into that of its host (erythrocyte). Knock-out simulations identified 307 indispensable metabolic reactions within the parasite. 35 out of 57 experimentally demonstrated essential enzymes were recovered and another 16 enzymes, if additionally the assumption was made that nutrient uptake from the host cell is limited and all reactions catalyzed by the inhibited enzyme are blocked. This predicted set of putative drug targets, shown to be enriched with true targets by a factor of at least 2.75, was further analyzed with respect to homology to human enzymes, functional similarity to therapeutic targets in other organisms and their predicted potency for prophylaxis and disease treatment.


CONCLUSIONS
The results suggest that the set of essential enzymes predicted by our flux balance approach represents a promising starting point for further drug development.
Huthmacher
Carola
C
Institute of Biochemistry, Charité, Monbijoustrasse 2, 10117 Berlin, Germany. carola.huthmacher@charite.de
Hoppe
Andreas
A
Bulik
Sascha
S
Holzhütter
Hermann-Georg
HG
D000818:Animals; D000962:Antimalarials / Q000378:metabolism* / Q000494:pharmacology; D019295:Computational Biology / Q000379:methods*; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D008018:Life Cycle Stages / Q000235:genetics; D053858:Metabolic Networks and Pathways; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D015203:Reproducibility of Results
D000962:Antimalarials
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