Glucosylceramide synthase , a key enzyme in the glycosphingolipid pathway of Plasmodium falciparum.

M. LANDONI,; V. DUSCHAK,; V. PERES,; A. M. KATZIN; A. S. COUTO.

Pinamar, Buenos Aires, Argentina.

Congreso; 41th Reunion Annual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular, 20th Reunion Annual de la Sociedad Argentina de Neuroquímica and 10th Congress of the Panamerican Association for Biochemistry and Molecular Biology; 2005

Malaria is the most serious and widespread parasitic disease in humans. Glycosphingolipids (GSLs) are membrane lipids in most eukaryotic organisms and in a few bacteria, however little is known in parasites. The core structure of the GSLs, glucosylceramide, is synthesized by a UDP glucose: ceramide glucosyltransferase (GCS). Recently, we have shown the presence of this active enzyme in the intraerythrocytic stages of P. falciparum. In the present work, a metabolic incorporation of NBD ceramide and NBD-DHceramide was performed showing 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 sphingomyelin. At difference with the mammalian cells, these pathways seem not to be interrelated. When PPMP, a GCS inhibitor, was used,  GSL synthesis was abolished. Taking into account that this key enzyme uses dihydroceramide as the lipidic substrate at variance with mammals, we began the study of this parasitic enzyme. We have purified by two different methods a 60 kDa protein that was recognized by a polyclonal anti-human GCS; by confocal microscopy  we found it co-localized with Golgi markers. In addition, preliminar assays show it is a glycoprotein. On going studies are being carried out to determine whether  GCS may constitute a new target for antimalaric  drugs.