Isoprenoid biosynthesis in Plasmodium falciparum

Abstract

Malaria 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.

FIG 1

Life cycle of Plasmodium falciparum. Infection begins with the injection of sporozoites into the host bloodstream by the bite of an Anopheles mosquito. Parasites multiply in the liver and are released back into the host bloodstream as merozoites, where they begin the intraerythrocytic developmental cycle (RBCs, red blood cells). Inside the erythrocyte, parasites grow into large trophozoites. They eventually divide to become multinucleate schizonts, which erupt from the host cell and reenter the blood as merozoites. A proportion of these blood-stage parasites become gametocytes and are taken up by the mosquito vector, where they complete sexual replication.

FIG 2

Synthesis of isoprenoid products in P. falciparum. (A) Electron micrograph of P. falciparum cell, with labels showing the red blood cell (RBC), nucleus (N), food vacuole (FV), and apicoplast (Ap). Scale bar represents 500 nm. (B) The P. falciparum apicoplast is the site of isoprenoid synthesis by the MEP pathway. It is surrounded by four membranes, indicative of secondary endosymbiotic origins. Scale bar represents 100 nm. (C) Isoprenoid products produced by P. falciparum. Abbreviations used: phosphoenol pyruvate (PEP), dihydroxyacetone phosophate (DHAP), pyruvate kinase (PK), triose phosphate isomerase (TPI), 1-deoxy-d-xylulose 5-phosphate synthase (DXS), 1-deoxy-d-xylulose 5-phosphate (DOXP), DOXP reductoisomerase (DXR), fosmidomycin (FSM), 2-C-methyl-d-erythriol 4-phosphate (MEP), MEP cytidyltransferase (IspD), 4-diphosphocytidyl-2-C-methylerythritol (CDP-ME), CDP-ME kinase (IspE), 4-diphosphocytidyl-2-C-methylerythritol 2-phosphate (CDP-MEP), 2-C-methyl-d-erythritol 2,4-cyclopyrophosphate (MEcPP), MEcPP synthase (IspF), (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), HMB-PP synthase (IspG), HMB-PP reductase (IspH), dimethylallyl pyrophosphate (DMAPP), isopentenyl pyrophosphate (IPP), isopentenyl pyrophosphate isomerase (IPPI), tRNA isopentenyltransferase (TIPT), tRNA methylthiolase (TMT), farnesyl pyrophosphate synthase (FPPS), bisphosphate (BisP), geranyl pyrophosphate (GPP), polyprenol reductase (PPR), farnesyl pyrophosphate (FPP), octaprenyl pyrophosphate synthase (OPPS), nerolidol (NER), farnesyl transferase (FTase), prenyltransferase inhibitors (PTI), geranylgeranyl transferase (GGTase), geranylgeranyl pyrophosphate (GGPP), phytoene synthase (PS), phytoene desaturase (PD), norflurazon (NOR), dolichyl pyrophosphate (dolichyl-PP), 2-methyl-6-phytyl-1,4-benzoquinol (MPBQ), and usnic acid (UA).