Active isoprenoid pathway in the intra-erythrocytic stages of Plasmodium falciparum: presence of dolichols of 11 and 12 isoprene units.
N-glycosylation of proteins is required for the intra-erythrocytic schizogony of Plasmodium falciparum. In eukaryotic cells, this process involves the transfer of oligosaccharides from a dolichyl pyrophosphate derivative to asparagine residues. We have identified dolichol, dolichyl phosphate and dolichyl pyrophosphate species of 11 and 12 isoprenoid residues by metabolic labelling with [(3)H]farnesyl pyrophosphate, [(3)H]geranylgeranyl pyrophosphate and [(14)C]acetate in the different intra-erythrocytic stages of P. falciparum. This is the first demonstration of short-chain dolichols in the phylum Apicomplexa. The results demonstrate the presence of an active isoprenoid pathway in the intra-erythrocytic stages of P. falciparum. Parasites treated with mevastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, show depressed biosynthesis of dolichol, dolichyl phosphate and isoprenoid pyrophosphate. This effect is observed in all intra-erythrocytic stages of the parasite life cycle, but is most pronounced in the ring stage. N-linked glycosylation of proteins was inhibited in the ring and young-trophozoite stages after mevastatin treatment of parasite cultures. Therefore the isoprenoid pathway may represent a different approach to the development of new anti-malarial drugs.
CIHIDECAR, Departamento de Qu approximately ímica Orgánica, Pabellón II, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428, Argentina.
A S
AS
Couto
E A
EA
Kimura
V J
VJ
Peres
M L
ML
Uhrig
A M
AM
Katzin
D000818:Animals; D004286:Dolichols / Q000031:analogs & derivatives / Q000378:metabolism*; D004912:Erythrocytes / Q000469:parasitology*; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*
D004286:Dolichols; D006023:Glycoproteins; C012258:mevastatin; D008148:Lovastatin