The glycosphingolipidic pathway: a new target for antiparasitic drugs.

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

Hamburgo- Alemania

Congreso; Molecular Life Sciences 2007; 2007

GBM

THE GLYCOSPHINGOLIPIDIC PATHWAY: A NEW TARGET FOR ANTIPARASITIC DRUGS.   Malena Landoni a, Vilma G. Duschak b, Alejandro M. Katzin c and Alicia S. Couto a.   1CIHIDECAR-Depto Q.Orgánica, FCEyN, UBA. 2Inst. Nac. de Parasitología, Dr. M. Fatala Chabén, ANLIS-Malbrán, Min. de Salud y Ambiente; Buenos Aires, Argentina. 3Depto.Parasitologia, Inst.Cs.Biomédicas, USP, Brazil.   Glycosphingolipids (GSLs) are membrane lipids in most eukaryotic organisms and in a few bacteria, however little is known about them, in parasites. The core structure of the majority of GSLs, glucosylceramide, is synthesized by an UDP-glucose:ceramide glucosyltransferase (GCS) which was originally found in animal tissues. We have shown for the first time the presence of this active enzyme in the intraerythrocytic stages of P. falciparum and at variance with mammals, it uses dihydroceramide as the lipidic substrate. In the present work, a metabolic incorporation of NBD ceramide and NBD-DHceramide was performed. Analysis of the labeled lipids showed that NBD-ceramide is very fast metabolized as well as a big amount of sphingomyeline was obtained. By contrast, when NBD-DHceramide was used as substrate, its levels remained almost unchanged. Glucosylceramide and lactosylceramide were shown, although practically no sphingomyelin was detected. 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 interrelated. We have already shown that when PPMP, a GCS inhibitor, was used in cultures, parasites failed to develop and GSLs synthesis was abolished. On going studies are being carried out on the purification and localization of the malarial enzyme to determine whether it may constitute a new target for antimalarial drugs.