Plasmodium falciparum glycosphingolipid pathway: a new target for antimalarial drugs

LANDONI M; DUSCHAK VG; PERES V; KATZIN AM; COUTO AS

Heidelberg, Germany,

Conferencia; Second Annual BIOMALPAR. Conference on the Biology and Pathology of the Malaria Parasite.; 2006

EMBL

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 the action of a UDP-glucose:ceramide glucosyltransferase (GCS, glucosylceramide synthase EC 2.4.1.80) 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 (Couto et al., 2004). Taking into account that, at variance with mammals, this key enzyme uses dihydroceramide as the lipidic substrate, we began a study of this interesting pathway. 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.