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 Coccidians, Toxoplasma gondii and Neospora caninum also possess the genes for non-mevalonate pathway enzymes. The enzymes of mevalonate pathway are absent in T. gondii and N. caninum. Most of the proteins of this pathway are either validated or predicted to be localised to apicoplast in T. gondii. 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].

 

Enzyme EC Number Gene id
1-deoxy-D-xylulose-5-phosphate reductoisomerase 1.1.1.267 NCLIV_051900
4-hydroxy-3-methylbut-2-enyl diphosphate reductase 1.17.1.2 NCLIV_045740
4-hydroxy-3-methylbut-2-en-1-yl diphosphate synthase 1.17.7.1 NCLIV_025400
Ferredoxine reductase 1.18.1.2 NCLIV_009490
1-deoxy-D-xylulose 5-phosphate synthase 2.2.1.7 NCLIV_003330
4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol kinase 2.7.1.148 NCLIV_044740
Pyruvate kinase 2.7.1.40 NCLIV_009420
2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase 2.7.7.60 NCLIV_044490
2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase 4.6.1.12 NCLIV_029230
Triose phosphate isomerase 5.3.1.1 NCLIV_033270
Triose phosphate transporter; PEP/Pi translocator none NCLIV_026210
Ferredoxin none NCLIV_052080

 

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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