Isoprenoid biosynthesis inhibition disrupts Rab5 localization and food vacuolar integrity in Plasmodium falciparum.

TitleIsoprenoid biosynthesis inhibition disrupts Rab5 localization and food vacuolar integrity in Plasmodium falciparum.
Publication TypeJournal Article
Year of Publication2013
AuthorsHowe, R, Kelly, M, Jimah, J, Hodge, D, Odom, AR
JournalEukaryot Cell
Date Published2013 Feb
KeywordsAndrostadienes, Antimalarials, Biosynthetic Pathways, Cells, Cultured, Drug Resistance, Electron Transport, Erythritol, Erythrocytes, Fosfomycin, Humans, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Plasmodium falciparum, Protein Prenylation, Protein Transport, Protozoan Proteins, rab5 GTP-Binding Proteins, Schizonts, Sugar Phosphates, Terpenes, Transport Vesicles, Ubiquinone, Vacuoles, Wortmannin

<p>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.</p>

Alternate JournalEukaryot Cell
PubMed ID23223036
PubMed Central IDPMC3571303
Grant ListK08 AI079010 / AI / NIAID NIH HHS / United States
S10 RR026891 / RR / NCRR NIH HHS / United States