Distribution of phytol in the malaria parasite

One of the most promising targets for malaria drug design is isoprenoid metabolism. Isoprenoid biosynthesis depends on the methyl erythritol 4-phosphate (MEP) pathway, located in a modified plastid called the apicoplast. Isoprenoids produced by this pathway are used for isoprenylation of various metabolites and proteins. Previous observations by the group demonstrated the plasmodial biosynthesis of phytylpyrophosphate (PPP) from geranylgeranyl pyrophosphate (GGPP) and their respective alcohols, phytol (POH) from geranylgeraniol (GGOH). We also characterized the parasitic biosynthesis of phytylated and geranylgeranylated naphthoquinones. Furthermore, exogenous POH and PPP can be covalently linked to protein clusters. These results add phytylation as a new post-translational modification of proteins. Proteomic and bioinformatic approaches revealed that phytylated proteins are involved in the intracellular trafficking of parasites. The antiplasmodial activity of the specific inhibitor of the MEP pathway, fosmidomycin, and the ribosomal inhibitor, tetracycline, is attenuated by exogenous POH. Previously, similar rescue effects were observed for various unsaturated isoprenoid precursors such as isoprene and various unsaturated oligoprenyl pyrophosphates and isoprenoid alcohols. Despite the effects seen in vitro, it is unlikely to occur in vivo, as these metabolites are not readily available in host plasma. However, POH is naturally present in the blood, therefore, exogenous plasma incorporation may be a plausible resistance mechanism to fosmidomycin. Despite evidence of incorporation of exogenous POH into malaria parasites, the mechanism of interconversion of POH into its active form, PPP, is still unknown.

Project details

Basic Science
Drug-based Strategies

Feb 2022 — Feb 2023

Brazil