Isoprenoid Biosynthesis in Plasmodium falciparum

Abstract

bMalaria kills nearly 1 million people each year, and the protozoan parasite Plasmodium falciparum has become increasingly resistant to current therapies. Isoprenoid synthesis via the methylerythritol phosphate (MEP) pathway represents an attractive target for the development of new antimalarials. The phosphonic acid antibiotic fosmidomycin is a specific inhibitor of isoprenoid synthesis and has been a helpful tool to outline the essential functions of isoprenoid biosynthesis in P. falciparum. Isoprenoids are a large, diverse class of hydrocarbons that function in a variety of essential cellular processes in eukaryotes. In P. falciparum, isoprenoids are used for tRNA isopentenylation and protein prenylation, as well as the synthesis of vitamin E, carotenoids, ubiquinone, and dolichols. Recently, isoprenoid synthesis in P. falciparum has been shown to be regulated by a sugar phosphatase. We outline what is known about isoprenoid function and the regulation of isoprenoid synthesis in P. falciparum, in order to identify valuable directions for future research.

The metabolic repair enzyme phosphoglycolate phosphatase regulates central carbon metabolism and fosmidomycin sensitivity inPlasmodium falciparum

“…a) DHAP and phosphoenolpyruvate, derived from glycolysis, are imported into the apicoplast for synthesis of isoprenoids via the 1-deoxy-D-xylulose 5-phosphate/ 2- C -methyl-D-erythritol 4-phosphate pathway. Fosmidomycin acts as a competitive inhibitor of the first committed enzyme in this pathway and its efficacy is decreased when glycolytic flux is increased (44). b) Synchronised WT- and Δ Pf PGP-infected RBC were treated with different doses of fosmidomycin for 72 hours and the growth percentage was determined by flow cytometry following SYTO 61 labelling.…”

The apicoplast: now you see it, now you don’t

“…As it turns out, malaria parasites do not make appreciable amounts of fatty acids during their blood stage (the stage analysed biochemically) and the machinery becomes active only in later life cycle phases (see below). An apicoplast pathway to synthesise isopentenyl diphosphate (IPP) – a precursor of isoprenoids for prenylation of proteins, ubiquinone side chains, dolichols and modification of tRNAs (Ralph et al, 2004) – was also identified from the genome data (Jomaa et al, 1999; Guggisberg et al, 2014a; Imlay and Odom, 2014; Armstrong et al, 2015; Imlay et al, 2015). Subsequent data mining revealed that the apicoplast of malaria parasites makes iron sulphur complexes (Seeber, 2002, 2003; Ralph et al, 2004) and cooperates with the mitochondrion in the synthesis of haem (Ralph et al, 2004; Sato et al, 2004; van Dooren et al, 2006; Nagaraj et al, 2008, 2009a,b; Shanmugam et al, 2010).…”

Sterol Composition and Biosynthetic Genes of Vitrella brassicaformis, a Recently Discovered Chromerid: Comparison to Chromera velia and Phylogenetic Relationship with Apicomplexan Parasites

“…A direct comparison of sterol composition cannot be made between apicomplexans and chromerids because apicomplexans do not synthesize sterols de novo (Coppens ), although they do possess the ability to synthesize other isoprenoid compounds (Guggisberg et al. ) and to convert cholesterol to cholesteryl esters (Botté et al. ; Nishikawa et al.…”

“…Although chromerids and apicomplexans are closely related to each other (Janou skovec et al 2010; Moore et al 2008), they have adopted vastly different modes of life, with the former being photosynthetic and the latter being obligately pathogenic. A direct comparison of sterol composition cannot be made between apicomplexans and chromerids because apicomplexans do not synthesize sterols de novo (Coppens 2006), although they do possess the ability to synthesize other isoprenoid compounds (Guggisberg et al 2014) and to convert cholesterol to cholesteryl esters (Bott e et al 2013;Nishikawa et al 2005). Dinoflagellates, a closely related group to both chromerids and apicomplexans as based on ultrastructural and phylogenetic features (Janou skovec et al 2010; Moore et al 2008;Oborn ık et al 2012), however, synthesize a wide variety of sterols de novo (Patterson 1971(Patterson , 1991, which does not generally include those produced by C. velia and V. brassicaformis (see discussion by Leblond et al 2012).…”