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    

 

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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