Glycosphingolipids in Plasmodium falciparum

Abstract

Malaria remains a major health problem especially in tropical and subtropical regions of the world, and therefore developing new antimalarial drugs constitutes an urgent challenge. Lipid metabolism has been attracting a lot of attention as an application for malarial chemotherapeutic purposes in recent years. However, little is known about glycosphingolipid biosynthesis in Plasmodium falciparum. In this report we describe for the first time the presence of an active glucosylceramide synthase in the intraerythrocytic stages of the parasite. Two different experiments, using UDP-[ 14 C]glucose as donor with ceramides as acceptors, or UDP-glucose as donor and fluorescent ceramides as acceptors, were performed. In both cases, we found that the parasitic enzyme was able to glycosylate only dihydroceramide. The enzyme activity could be inhibited in vitro with low concentrations of D,L-threo-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP). In addition, de novo biosynthesis of glycosphingolipids was shown by metabolic incorporation of [ 14 C]palmitic acid and [ 14 C]glucose in the three intraerythrocytic stages of the parasite. The structure of the ceramide, monohexosylceramide, trihexosylceramide and tetrahexosylceramide fractions was analysed by UV-MALDI-TOF mass spectrometry. When PPMP was added to parasite cultures, a correlation between arrest of parasite growth and inhibition of glycosphingolipid biosynthesis was observed. The particular substrate specificity of the malarial glucosylceramide synthase must be added to the already known unique and amazing features of P. falciparum lipid metabolism; therefore this enzyme might represent a new attractive target for malarial chemotherapy.

Plasma metabolomics reveals membrane lipids, aspartate/asparagine and nucleotide metabolism pathway differences associated with chloroquine resistance in Plasmodium vivax malaria

“…Furthermore, previous studies have shown the involvement of transporter genes and membrane proteins that involved in the transport of drugs and lipids with antimalarial drug resistance [ 14 ]. Glycosphingolipids are important components of cellular membranes involved in various biological functions, and their biosynthesis was described in Plasmodium by an active malarial glucosylceramide synthase [ 91 , 92 ]. Marked lower levels of glycerophosphocholines in CQ-R compared to CQ-S and control groups and perturbation of the glycerophospholipid metabolism based on the pathway analysis indicates that there could be perturbed PLA2 activity in the CQ-R subjects before treatment.…”

Glycosphingolipid GM3 is localized in both exoplasmic and cytoplasmic leaflets of Plasmodium falciparum malaria parasite plasma membrane

“…GM1 and GM3 are monosialic glycosphingolipids synthesized from glucosylceramide. The intraerythrocytic stage of P. falciparum includes an active glucosylceramide synthase that catalyzes the transfer of glucose to ceramide from UDP-glucose 48 . However, a previous report showed that P. falciparum did not biosynthesize or utilizes sialic acid 49 .…”

Lipid transport proteins in malaria, from Plasmodium parasites to their hosts

“…Glycerophospholipids constitute the major lipid class detected in parasite fractions removed from the erythrocyte, with phosphatidylcholine (PC) and phosphatidylethanolamine (PE) together accounting for ~50% of total lipid content [22,24,55,89]. These structural membrane components primarily contain two saturated or monosaturated FA chains [22], consistent with parasites requiring an exogenous supply of oleic and palmitic acid to sustain growth [21,23,24].…”