Isoprenoid alcohols utilization by malaria parasites

Area of Science:

• * Molecular Parasitology
• * Biochemistry
• * Drug Discovery

Background:

• * Malaria, caused by *Plasmodium falciparum*, remains a major global health challenge, exacerbated by widespread drug resistance.
• * Fosmidomycin, an inhibitor of the methylerythritol 4-phosphate (MEP) pathway, shows promise but has faced clinical limitations.
• * Isoprene units are vital for synthesizing essential molecules like ubiquinone and dolichyl phosphate, and for protein isoprenylation.

Purpose of the Study:

• * To investigate the mechanism by which isoprenoid alcohols rescue *P. falciparum* from fosmidomycin.
• * To characterize the transport, metabolism, and incorporation of exogenous isoprenoid alcohols in the parasite.
• * To identify parasite enzymes involved in isoprenoid metabolism and protein prenylation.

Main Methods:

• * Drug-rescue assays with fosmidomycin and various isoprenoid alcohols (farnesol, geranylgeraniol, phytol).
• * Proteomic and radiolabelling approaches to analyze protein prenylation and isoprenoid incorporation.
• * Characterization of isoprenoid alcohol transport and phosphorylation within the parasite.

Main Results:

• * Farnesol, geranylgeraniol, and phytol, but not dolichols or nonaprenol, rescued parasites from fosmidomycin.
• * Incorporated isoprenoid alcohols were phosphorylated, elongated, and integrated into proteins and dolichyl phosphates.
• * Proteomic analysis revealed parasite proteins naturally prenylated with isoprenoids, with exogenous phytol enhancing this.
• * Evidence suggests at least two promiscuous protein prenyltransferases in *P. falciparum*.

Conclusions:

• * Exogenous isoprenoid alcohols can bypass MEP pathway inhibition, restoring essential isoprenoid-derived molecule synthesis.
• * This study uncovers a novel post-translational modification involving protein prenylation with diverse isoprenoids.
• * The findings provide insights into the apicoplast-targeting mechanism of fosmidomycin and identify potential new targets for antimalarial drug development.