Abstract
The antimalarial agent fosmidomycin is a validated inhibitor of the nonmevalonate isoprenoid biosynthesis (methylerythritol 4-phosphate [MEP]) pathway in the malaria parasite, Plasmodium falciparum. Since multiple classes of prenyltransferase inhibitors kill P. falciparum, we hypothesized that protein prenylation was one of the essential functions of this pathway. We found that MEP pathway inhibition with fosmidomycin reduces protein prenylation, confirming that de novo isoprenoid biosynthesis produces the isoprenyl substrates for protein prenylation. One important group of prenylated proteins is small GTPases, such as Rab family members, which mediate cellular vesicular trafficking. We have found that Rab5 proteins dramatically mislocalize upon fosmidomycin treatment, consistent with a loss of protein prenylation. Fosmidomycin treatment caused marked defects in food vacuolar morphology and integrity, consistent with a defect in Rab-mediated vesicular trafficking. These results provide insights to the biological functions of isoprenoids in malaria parasites and may assist the rational selection of secondary agents that will be useful in combination therapy with new isoprenoid biosynthesis inhibitors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstadienes / pharmacology
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Antimalarials / pharmacology
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Biosynthetic Pathways / drug effects
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Cells, Cultured
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Drug Resistance
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Electron Transport / drug effects
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Erythritol / analogs & derivatives
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Erythritol / metabolism
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Erythrocytes / parasitology
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Fosfomycin / analogs & derivatives
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Fosfomycin / pharmacology
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Humans
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Plasmodium falciparum / drug effects
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Plasmodium falciparum / growth & development
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Plasmodium falciparum / metabolism*
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Protein Prenylation
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Protein Transport / drug effects
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Protozoan Proteins / metabolism*
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Schizonts / drug effects
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Schizonts / growth & development
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Schizonts / metabolism
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Sugar Phosphates / metabolism
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Terpenes / metabolism*
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Transport Vesicles / metabolism
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Ubiquinone / metabolism
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Vacuoles / drug effects
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Vacuoles / metabolism
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Vacuoles / ultrastructure
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Wortmannin
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rab5 GTP-Binding Proteins / metabolism*
Substances
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2-C-methylerythritol 4-phosphate
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Androstadienes
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Antimalarials
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Phosphoinositide-3 Kinase Inhibitors
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Protozoan Proteins
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Sugar Phosphates
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Terpenes
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Ubiquinone
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Fosfomycin
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fosmidomycin
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rab5 GTP-Binding Proteins
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Erythritol
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Wortmannin