Isoprenoids metabolism

Isoprenes are the 5-C functional units (monomer) of a variety of naturally occurring compounds termed as terpenoids or isoprenoids. Terpenoids are used as precursors for production of sterols and steroids in animals. Some proteins have terpenoid moieties attached to them in order to boost their attachment to membranes.

 

There are two different metabolic pathways exist in various organisms for the synthesis of isoprene units isopentenyl diphosphate and its isomer dimethylallyl diphosphate. They are mevalonate pathway and non-mevalonate (DOXP/MEP) pathway. The mevalonate pathway utilises acetyl-CoA as substrate and produces HMG-CoA and mevalonate as intermediates in the pathway. This pathway takes place in animals, plants and yeast. The non-mevalonate pathway utilises glyceraldehydes-3-phosphate and pyruvate as substrates. In addition to possessing mevalonate pathway, plants also possess chloroplast based non-mevalonate pathway.

 

The mevalonate pathway is experimentally proven to be absent in Plasmodium falciparum. In addition, the experiments with DOXP-dependent non-mevalonate pathway inhibitors such as fosmidomycin demonstrated the presence of this non-mevalonate pathway. This pathway has also been validated as an effective drug target. As in plants, this pathway also localises to the plastid, apicoplast [1]. The genes for the enzymes of mevalonate pathway are also absent in the genome, whereas the enzymes of non-mevalonate pathway are present and metabolic pathway was reconstructed in MPMP (isoprenoids metabolism).

 

The Toxoplasma gondii genome also possesses the genes for non-mevalonate pathway enzymes. The enzymes of mevalonate pathway are absent in T. gondii. Most of the proteins of this pathway are either validated or predicted to be localised to apicoplast. Although, the enzymes of the pathway are present, the experimental studies with fosmidomycin showed absence of any effect in the growth of T. gondii and Eimeria tenella questioning the role of this pathway in viability of these Coccidian parasites [2, 3]. Nair et al then demonstrated that this resistance to fosmidomycin is governed by uptake into the cell  by carrying out heterologous expression of bacterial transporter in T. gondii. They also suggested that some hypothetical transporter must import fosmidomycin into the cell in P. falciparum [4].

 

Protein EC Number Gene id Protein localisation Localisation data source
1-deoxy-D-xylulose-5-phosphate reductoisomerase 1.1.1.267 TGME49_214850    
4-hydroxy-3-methylbut-2-enyl diphosphate reductase 1.17.1.2 TGME49_227420 Apicoplast Previous publication; Orthology transformation from P. falciparum
4-hydroxy-3-methylbut-2-en-1-yl diphosphate synthase 1.17.7.1 TGME49_262430 Apicoplast Previous publication; Orthology transformation from P. falciparum
Ferredoxine reductase 1.18.1.2 TGME49_298990 Apicoplast Apiloc
1-deoxy-D-xylulose 5-phosphate synthase 2.2.1.7 TGME49_208820    
4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol kinase 2.7.1.148 TGME49_306550    
Pyruvate kinase 2.7.1.40 TGME49_299070 Apicoplast Apiloc; Previous publication; Orthology transformation from P. falciparum
2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase 2.7.7.60 TGME49_306260    
2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase 4.6.1.12 TGME49_255690 Apicoplast Orthology transformation from P. falciparum
Triose phosphate isomerase 5.3.1.1 TGME49_233500 Apicoplast Apiloc
Ferredoxin none TGME49_215070 Apicoplast Apiloc; Orthology transformation from P. falciparum
Triose phosphate transporter; PEP/Pi translocator none TGME49_261070 Membrane; Apicoplast GO annotation; Apiloc

 

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Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Phosphoenolpyruvate Glycolysis Isopentenyl-PP Terpenoid metabolism, N-glycan biosynthesis
Glycerone-P Glycolysis Dimethylallyl-PP Terpenoid metabolism