Leucine, isoleucine and valine metabolism
Toxoplasma gondii possesses the pathway for degradation of branched chain amino acids leucine, isoleucine and valine, a pathway present in both animals and plants. These amino acids are essential to all the apicomplexans including Toxoplasma and Plasmodium species. This amino acids degradation pathway may well provide a source of acetyl-CoA for the Krebs cycle in starving animals. The T. gondii genome possesses the genes for enzymes which catalyse the degradation of these branched chain amino acids into acetyl-CoA, (R)-methyl-malonyl-CoA and propionyl-CoA. The absence of mitochondrial pyruvate dehydrogenase complex suggests that this mitochondrial pathway may provide an alternative source of acetyl-CoA for the TCA cycle in Toxoplasma. Although propionyl-CoA, another product of this process is toxic, the 2-methylcitrate cycle can metabolise it to pyruvate.
The only enzyme missing in the T. gondii genome is methylglutaconyl-CoA hydratase (4.2.1.18). Although the pathway is complete in Toxoplasma, Plasmodium falciparum does not possess a complete pathway. The Leucine, isoleucine and valine metabolism pathway in P. falciparum has the enzymes that participate in the beginning of the pathway including branched chain alpha-keto acid dehydrogenase complex and branched chain amino acid transaminase. The enzymes Enoyl-CoA hydratase and 3-hydroxy isobutyryl dehydrogenase are also present in the genome. The acyl-CoA dehydrogenases such as isovaleryl-CoA dehydrogenase and the enzymes catalysing the downstream reactions involved in degradation of 3-hydroxyisovaleryl-CoA, 3-hydroxy-2-isobutyrate and (S)-hydroxy-2-methylbutyryl-CoA to acetyl-CoA, propionyl-CoA and methyl-malonyl-CoA are absent.
Enzyme | EC Number | Gene id | Protein localisation | Localisation data source |
---|---|---|---|---|
3-hydroxyisobutyrate dehydrogenase | 1.1.1.31 | TGME49_272410 | ||
3-hydroxyacyl-CoA dehydrogenase | 1.1.1.35 | TGME49_234570 | Apical (anterior vesicle); Cytosol; Posterior vesicle | Apiloc |
Methylmalonate-semialdehyde dehydrogenase | 1.2.1.27 | TGME49_311370 | ||
Aldehyde dehydrogenase | 1.2.1.3 | TGME49_264000 | ||
Aldehyde dehydrogenase | 1.2.1.3 | TGME49_288450 | ||
3-methyl-2-oxobutanoate dehydrogenase alpha subunit (part of branched chain keto-acid dehydrogenase complex) | 1.2.4.4 | TGME49_239490 | Mitochondrion | Previous publication |
3-methyl-2-oxobutanoate dehydrogenase alpha subunit (part of branched chain keto-acid dehydrogenase complex) | 1.2.4.4 | TGME49_292100 | ||
3-methyl-2-oxobutanoate dehydrogenase beta subunit (part of branched chain keto-acid dehydrogenase complex) | 1.2.4.4 | TGME49_314400 | Mitochondrion | Previous publication |
Isovaleryl-CoA dehydrogenase | 1.3.8.4 | TGME49_205430 | ||
Butyryl-CoA dehydrogenase | 1.3.99.2 | TGME49_266270 | ||
Dihydrolipoyl dehydrogenase (part of branched chain keto-acid dehydrogenase complex) | 1.8.1.4 | TGME49_206470 | Mitochondrion | Apiloc; Previous publication |
2-methyl-acetoacetyl-CoA thiolase | 2.3.1.16 | TGME49_273740 | ||
Dihydrolipoyl transacylase (part of branched chain keto-acid dehydrogenase complex) | 2.3.1.168 | TGME49_319920 | Mitochondrion | Previous publication |
Acetyl-CoA C-acetyltransferase | 2.3.1.9 | TGME49_301120 | Mitochondrion | Previous publication |
Leucyltransferase | 2.3.2.6 | TGME49_202590 | ||
Branched-chain-amino-acid transaminase | 2.6.1.42 | TGME49_281500 | ||
Branched-chain-amino-acid transaminase | 2.6.1.42 | TGME49_297850 | ||
3-hydroxyisobutyryl-CoA hydrolase | 3.1.2.4 | TGME49_224090 | Nucleus | Previous publication |
3-hydroxyisobutyryl-CoA hydrolase | 3.1.2.4 | TGME49_294190 | Mitochondrion | Previous publication |
Hydroxymethylglutaryl-CoA lyase | 4.1.3.4 | TGME49_204460 | ||
Enoyl-CoA hydratase | 4.2.1.17 | TGME49_202140 | ||
Enoyl-CoA hydratase | 4.2.1.17 | TGME49_242390 | ||
Enoyl-CoA hydratase | 4.2.1.17 | TGME49_310830 | ||
Enoyl-CoA hydratase | 4.2.1.17 | TGME49_317705 | ||
Methylglutaconyl-CoA hydratase | 4.2.1.18 | Missing in annotation | ||
Leucine-tRNA ligase | 6.1.1.4 | TGME49_266730 | Apicoplast | Apiloc |
Leucine-tRNA ligase | 6.1.1.4 | TGME49_292080 | Cytosol | Previous publication |
Isoleucine-tRNA ligase | 6.1.1.5 | TGME49_207640 | Cytosol | Previous publication |
Valine-tRNA ligase | 6.1.1.9 | TGME49_216500 | ||
Valine-tRNA ligase | 6.1.1.9 | TGME49_253290 | Cytosol | Previous publication |
Acetoacetate-CoA ligase | 6.2.1.16 | TGME49_219230 | ||
Methylcrotonoyl-CoA carboxylase | 6.4.1.4 | TGME49_269680 |
List of genes annotated as tRNA-Leu in T. gondii genome
TGME49_005310 | TGME49_021290 | TGME49_022680 | TGME49_022690 |
TGME49_036810 | TGME49_049485 | TGME49_070110 | TGME49_090320 |
TGME49_091360 | TGME49_091370 | TGME49_100646 | TGME49_113170 |
List of genes annotated as tRNA-Ile in T. gondii genome
TGME49_013500 | TGME49_014450 | TGME49_033880 | TGME49_062564 |
TGME49_062568 | TGME49_100642 | TGME49_100643 | TGME49_127550 |
List of genes annotated as tRNA-Val in T. gondii genome
TGME49_018380 | TGME49_034660 | TGME49_051700 | TGME49_068410 |
TGME49_068420 | TGME49_100648 | TGME49_108900 | TGME49_108910 |
TGME49_115650 | TGME49_121380 |
Sources and fates of metabolites
Substrate | Source pathways | Product | Fate pathways |
---|---|---|---|
L-Leucine | Host | 3-hydroxyisovaleryl-CoA | Host? |
L-Isoleucine | Host | (R)-methylmalonyl-CoA | Host? |
L-Valine | Host | Propanoyl-CoA | 2-methylcitrate cycle |
2-oxoglutarate | Pyruvate metabolism, Tricarboxylic acid (TCA) cycle | L-Glutamate | Glutamate metabolism |
Thiamine diphosphate | Thiamine salvage | Acetyl-CoA | Pyruvate metabolism, Tricarboxylic acid (TCA) cycle, Fatty acid elongation in the cytosol, Fatty acid elongation in the ER |
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