Limonene arrests parasite development and inhibits isoprenylation of proteins in Plasmodium falciparum.
Isoprenylation is an essential protein modification in eukaryotic cells. Herein, we report that in Plasmodium falciparum, a number of proteins were labeled upon incubation of intraerythrocytic forms with either [(3)H]farnesyl pyrophosphate or [(3)H]geranylgeranyl pyrophosphate. By thin-layer chromatography, we showed that attached isoprenoids are partially modified to dolichol and other, uncharacterized, residues, confirming active isoprenoid metabolism in this parasite. Incubation of blood-stage P. falciparum treated with the isoprenylation inhibitor limonene significantly decreased the parasites' progression from the ring stage to the trophozoite stage and at 1.22 mM, 50% of the parasites died after the first cycle. Using Ras- and Rap-specific monoclonal antibodies, putative Rap and Ras proteins of P. falciparum were immunoprecipitated. Upon treatment with 0.5 mM limonene, isoprenylation of these proteins was significantly decreased, possibly explaining the observed arrest of parasite development.
Moura
I C
IC
Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
Wunderlich
G
G
Uhrig
M L
ML
Couto
A S
AS
Peres
V J
VJ
Katzin
A M
AM
Kimura
E A
EA
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002070:Butadienes / Q000378:metabolism; D002855:Chromatography, Thin Layer; D053138:Cyclohexenes; D045782:Hemiterpenes; D006801:Humans; D000077222:Limonene; D021261:Parasitic Sensitivity Tests; D010420:Pentanes; D010766:Phosphorylation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D011233:Precipitin Tests; D017368:Protein Prenylation / Q000187:drug effects*; D015800:Protozoan Proteins / Q000378:metabolism*; D013729:Terpenes / Q000494:pharmacology*; D014316:Tritium; D018631:ras Proteins / Q000378:metabolism
D000962:Antimalarials; D002070:Butadienes; D053138:Cyclohexenes; D045782:Hemiterpenes; D010420:Pentanes; D015800:Protozoan Proteins; D013729:Terpenes; C005059:isoprene; D014316:Tritium; D000077222:Limonene; D018631:ras Proteins