The Glycosphingolipid Pathway as Target for New Antimalaric Drugs

MALENA LANDONI; VILMA G. DUSCHAK; ALEJANDRO M. KATZIN; ALICIA S. COUTO

Nairobi-Kenia

Conferencia; MIM 5TH PanAfrican Malarial Conference; 2009

Multilateral Initiative on Malaria(MIM)

THE GLYCOSPHINGOLIPID PATHWAY AS TARGET FOR NEW ANTIMALARIAL DRUGS   Malena Landoni1, Vilma G. Duschak2,   Alejandro M. Katzin3 y Alicia  S. Couto1   1CIHIDECAR, Depto de Química Orgánica, FCEN-UBA;  2 Inst. Nac.de Parasitología, Dr. Mario Fatala Chabén, Min.de Salud y Ambiente, Buenos Aires-Argentina;  3Depto. de Parasitologia, Inst. de Cs. Biomédicas, USP, Brazil.    acouto@qo.fcen.uba.ar   Alicia S. Couto Phone : 54-11-45415218 Meeting Code:    Although the biochemical pathways of glycosphingolipid biosynthesis are relatively well understood in mammalian cells, little is known about them in parasites. In a previous report, we have shown the presence of an active glucosyl ceramide synthase in Plasmodium falciparum with a particular substrate specificity. The fact that at variance with mammals, this key enzyme uses dihydroceramide  as the lipidic substrate led us to perform a metabolic incorporation by using NBD-ceramide and NBD-DHceramide as substrates. Analysis of the labeled lipids showed that NBD-ceramide is very fast metabolized as well as a big amount of sphingomyelin was obtained. By contrast, when NBD-DHceramide was used as substrate, its levels remained almost unchanged and although practically no sphingomyelin was detected, glucosylceramide and lactosylceramide were shown. In addition, when NBD-sphingomyelin was metabolically incorporated, no glucosyl or lactosylceramides were detected. Altogether, the results obtained indicate that P. falciparum has two different sphingolipid pathways: one of them, the de novo biosynthetic pathway for the synthesis of GSLs and another one using ceramide from the host cell to synthesize the parasite sphingomyeline. At difference with the mammalian cells, these pathways seem not to be connected, highlighting the malarial enzyme as a putative new target for antimalarial drugs.