Metabolomics profiling reveals new aspects of dolichol biosynthesis in Plasmodium falciparum

Abstract

The cis-polyisoprenoid lipids namely polyprenols, dolichols and their derivatives are linear polymers of several isoprene units. In eukaryotes, polyprenols and dolichols are synthesized as a mixture of four or more homologues of different length with one or two predominant species with sizes varying among organisms. Polyprenols have been hardly detectable in eukaryotic cells under normal conditions with the exception of plants and sporulating yeast. Our metabolomics studies revealed that cis-polyisoprenoids are more prevalent and diverse in the parasite Plasmodium falciparum than previously postulated as we uncovered active de novo biosynthesis and substantial levels of accumulation of polyprenols and dolichols of 15 to 19 isoprene units. A distinctive polyprenol and dolichol profile both within the intraerythrocytic asexual cycle and between asexual and gametocyte stages was also observed suggesting that cis-polyisoprenoid biosynthesis changes throughout parasites development. In addition, we confirmed the presence of an active cis-prenyltransferase (PfCPT) and that dolichol biosynthesis occurs via reduction of the polyprenol to dolichol by an active polyprenol reductase (PfPPRD) in the malaria parasite. Isotopic labeling and metabolomic analyses of a conditional mutant of PfCPT or PfPPRD suggest that polyprenols may be able to substitute dolichols in their biological functions when dolichol synthesis is impaired in Plasmodium.