Isoprenoid metabolism in apicomplexan parasites

Abstract

Apicomplexan parasites include some of the most prevalent and deadly human pathogens. Novel antiparasitic drugs are urgently needed. Synthesis and metabolism of isoprenoids may present multiple targets for therapeutic intervention. The apicoplast-localized methylerythritol phosphate (MEP) pathway for isoprenoid precursor biosynthesis is distinct from the mevalonate (MVA) pathway used by the mammalian host, and this pathway is apparently essential in most Apicomplexa. In this review, we discuss the current field of research on production and metabolic fates of isoprenoids in apicomplexan parasites, including the acquisition of host isoprenoid precursors and downstream products. We describe recent work identifying the first MEP pathway regulator in apicomplexan parasites, and introduce several promising areas for ongoing research into this well-validated antiparasitic target.

Keywords: Apicomplexa; Plasmodium; fosmidomycin; isoprenoid; metabolism; methylerythritol phosphate (MEP) pathway.

Figure 1. Isoprenoid metabolism in apicomplexan parasites

Some enzymes and processes are not conserved in all Apicomplexa; see text and Table 1. In Plasmodium and Toxo-plasma spp., FPP and GGPP are synthesized by a single bifunctional enzyme; in Cryptosporidium spp., NPPPS (nonspecific polyprenyl pyrophosphate synthase) synthesizes products with a wide range of chain lengths ([44,57,60]). Abbreviations: G3P, glyceraldehyde-3-phosphate; DXP, 1-deoxy-D-xylulose-5-phosphate; MEP, 2-C-methyl-D-erythritol-4-phosphate; CDPME, 4-diphosphocytidyl-2-C-methyl-D-erythritol; CDP-MEP, 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate; MEcPP, 2-C-methyl-D-erythritol 2,4-cyclodiphosphate; HMBPP, 1-hydroxy-2-methyl-2-buten-4-yl 4-diphosphate; IPP, isopentenyl pyrophosphate; DMAPP, dimethylallyl pyrophosphate; GPP, geranyl pyrophosphate; FPP, farnesyl pyrophosphate; GGPP, geranylgeranyl pyrophosphate; FPPS, farnesyl pyrophosphate synthase; GGPPS, geranylgeranyl pyrophosphate synthase; FT, protein farnesyltransferase; GGT1, type I protein geranylgeranyltransferase; GGT2, type II (Rab) protein geranylgeranyltransferase; OPP, octaprenyl pyrophosphate; OPPS, octaprenyl pyro-phosphate synthase; Q8, ubiqinone-8; cis-IPTase, cis-isopentenyltransferase; dol-P, dolichol phosphate; DPM1, dolichol phosphate mannosyltransferase; dol-P mannose, dolichol phosphate mannose; dol-PP-GlcNAc, dolichol pyrophosphate N-acetylglucosamine; OST, oligosaccharyltransferase; dol-PP, dolichol pyrophosphate.