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The Prenylated Proteome of Plasmodium falciparum Reveals Pathogen-specific Prenylation Activity and Drug Mechanism-of-action.

ABSTRACT: Plasmodium parasites contain several unique membrane compartments in which prenylated proteins may play important roles in pathogenesis. Protein prenylation has also been proposed as an antimalarial drug target because farnesyltransferase inhibitors cause potent growth inhibition of blood-stage Plasmodium However, the specific prenylated proteins that mediate antimalarial activity have yet to be identified. Given the potential for new parasite biology and elucidating drug mechanism-of-action, we performed a large-scale identification of the prenylated proteome in blood-stage P. falciparum parasites using an alkyne-labeled prenyl analog to specifically enrich parasite prenylated proteins. Twenty high-confidence candidates were identified, including several examples of pathogen-specific prenylation activity. One unique parasite prenylated protein was FYVE-containing coiled-coil protein (FCP), which is only conserved in Plasmodium and related Apicomplexan parasites and localizes to the parasite food vacuole. Targeting of FCP to this parasite-specific compartment was dependent on prenylation of its CaaX motif, as mutation of the prenylation site caused cytosolic mislocalization. We also showed that PfRab5b, which lacks C-terminal cysteines that are the only known site of Rab GTPase modification, is prenylated. Finally, we show that the THQ class of farnesyltransferase inhibitors abolishes FCP prenylation and causes its mislocalization, providing the first demonstration of a specific prenylated protein disrupted by antimalarial farnesyl transferase inhibitors. Altogether, these findings identify prenylated proteins that reveal unique parasite biology and are useful for evaluating prenyltransferase inhibitors for antimalarial drug development.

SUBMITTER: Gisselberg JE

PROVIDER: S-EPMC5393391 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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The Prenylated Proteome of Plasmodium falciparum Reveals Pathogen-specific Prenylation Activity and Drug Mechanism-of-action.

Gisselberg Jolyn E JE Zhang Lichao L Elias Joshua E JE Yeh Ellen E

Molecular & cellular proteomics : MCP 20161231 4 suppl 1

Plasmodium parasites contain several unique membrane compartments in which prenylated proteins may play important roles in pathogenesis. Protein prenylation has also been proposed as an antimalarial drug target because farnesyltransferase inhibitors cause potent growth inhibition of blood-stage Plasmodium However, the specific prenylated proteins that mediate antimalarial activity have yet to be identified. Given the potential for new parasite biology and elucidating drug mechanism ...[more]

PMID: 28040698

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Project description:Chloroquine, long the default first-line treatment against malaria, is now abandoned in large parts of the world because of widespread drug-resistance in Plasmodium falciparum. In spite of its importance as a cost-effective and efficient drug, a coherent understanding of the cellular mechanisms affected by chloroquine and how they influence the fitness and survival of the parasite remains elusive. Here, we used a systems biology approach to integrate genome-scale transcriptomics to map out the effects of chloroquine, identify targeted metabolic pathways, and translate these findings into mechanistic insights. Specifically, we first developed a method that integrates transcriptomic and metabolomic data, which we independently validated against a recently published set of such data for Krebs-cycle mutants of P. falciparum. We then used the method to calculate the effect of chloroquine treatment on the metabolic flux profiles of P. falciparum during the intraerythrocytic developmental cycle. The model predicted dose-dependent inhibition of DNA replication, in agreement with earlier experimental results for both drug-sensitive and drug-resistant P. falciparum strains. Our simulations also corroborated experimental findings that suggest differences in chloroquine sensitivity between ring- and schizont-stage P. falciparum. Our analysis also suggests that metabolic fluxes that govern reduced thioredoxin and phosphoenolpyruvate synthesis are significantly decreased and are pivotal to chloroquine-based inhibition of P. falciparum DNA replication. The consequences of impaired phosphoenolpyruvate synthesis and redox metabolism are reduced carbon fixation and increased oxidative stress, respectively, both of which eventually facilitate killing of the parasite. Our analysis suggests that a combination of chloroquine (or an analogue) and another drug, which inhibits carbon fixation and/or increases oxidative stress, should increase the clearance of P. falciparum from the host system.

Dataset Information

The Prenylated Proteome of Plasmodium falciparum Reveals Pathogen-specific Prenylation Activity and Drug Mechanism-of-action.

Publications

The Prenylated Proteome of <i>Plasmodium falciparum</i> Reveals Pathogen-specific Prenylation Activity and Drug Mechanism-of-action.

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