Metabolomic profiling reveals developmentally regulated biosynthesis of polyprenols and dolichols in the malaria parasite

The cis-polyisoprenoid lipids namely polyprenols (POH), dolichols (DOH) and their derivatives are linear polymers of several isoprene units and have recently gained special attention due to several breakthroughs in the field including improvements in the analytical techniques for their analysis, partial identification of their enzymatic machinery, and the discovery of new biological functions beyond glycosylation. In eukaryotes, POH and DOH are synthesized as a mixture of four or more homologues of different length with one or two predominant species with sizes varying among organisms. Interestingly, POH are 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 protozoan parasite Plasmodium falciparum than previously postulated as we uncovered the active biosynthesis of medium-long POH and DOH (15 to 19 isoprene units). Moreover, a distinctive POH and DOH profile both within the intraerythrocytic asexual cycle and between asexual and gametocyte stages was observed. These results suggest that cis-polyisoprenoid biosynthesis is developmentally regulated. In addition, we confirmed that DOH biosynthesis occurs via reduction of the POH to DOH by an active polyprenol reductase (PfPPRD) and metabolomics analyses of a PfPPRD conditional mutant suggest that a salvage mechanism of DOH may exist.