Leucine, isoleucine and valine metabolism

The amino acids leucine, isoleucine and valine are essential amino acids for all apicomplexans as for humans. Coccidians such as Toxoplasma and Neospora possesses the pathway for degradation of branched chain amino acids leucine, isoleucine and valine, a pathway present in both animals and plants. This amino acids degradation pathway may well provide a source for acetyl-CoA for Krebs cycle in starving animals. The genomes of Neospora caninum and Toxoplasma gondii possess 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 TCA cycle in Neospora and 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 N. caninum and T. gondii genomes is methylglutaconyl-CoA hydratase (4.2.1.18). Although the pathway is complete in Coccidia, Plasmodium species do not possess a complete pathway.

 

Enzyme EC Number Gene id
3-hydroxyisobutyrate dehydrogenase 1.1.1.31 NCLIV_034890
3-hydroxyacyl-CoA dehydrogenase 1.1.1.35 NCLIV_042220
Methylmalonate-semialdehyde dehydrogenase 1.2.1.27 NCLIV_055270
Aldehyde dehydrogenase 1.2.1.3 NCLIV_024060
Aldehyde dehydrogenase 1.2.1.3 NCLIV_040940
3-methyl-2-oxobutanoate dehydrogenase alpha chain (part of branched chain keto-acid dehydrogenase complex) 1.2.4.4 NCLIV_012850
3-methyl-2-oxobutanoate dehydrogenase alpha chain (part of branched chain keto-acid dehydrogenase complex) 1.2.4.4 NCLIV_016110
3-methyl-2-oxobutanoate dehydrogenase beta chain (part of branched chain keto-acid dehydrogenase complex) 1.2.4.4 NCLIV_057460
Isovaleryl-CoA dehydrogenase 1.3.8.4 NCLIV_020260
Butyryl-CoA dehydrogenase 1.3.99.2 NCLIV_048110
Dihydrolipoyl dehydrogenase (part of branched chain keto-acid dehydrogenase complex) 1.8.1.4 NCLIV_044200
2-methyl-acetoacetyl-CoA thiolase 2.3.1.16 NCLIV_033970
Dihydrolipoyl transacylase (part of branched chain keto-acid dehydrogenase complex) 2.3.1.168 NCLIV_010320
Acetyl-CoA C-acetyltransferase 2.3.1.9 NCLIV_069850
Leucyltransferase 2.3.2.6 NCLIV_022350
Branched-chain-amino-acid transaminase 2.6.1.42 NCLIV_006760
Branched-chain-amino-acid transaminase 2.6.1.42 NCLIV_023450
3-hydroxyisobutyryl-CoA hydrolase 3.1.2.4 NCLIV_000930
3-hydroxyisobutyryl-CoA hydrolase 3.1.2.4 NCLIV_048430
Hydroxymethylglutaryl-CoA lyase 4.1.3.4 NCLIV_020790
Enoyl-CoA hydratase 4.2.1.17 NCLIV_012140
Enoyl-CoA hydratase 4.2.1.17 NCLIV_017550
Enoyl-CoA hydratase 4.2.1.17 NCLIV_022740
Enoyl-CoA hydratase 4.2.1.17 NCLIV_054880
Methylglutaconyl-CoA hydratase 4.2.1.18 Missing in annotation
Leucine-tRNA ligase 6.1.1.4 NCLIV_012860
Leucine-tRNA ligase 6.1.1.4 NCLIV_039310
Isoleucine-tRNA ligase 6.1.1.5 NCLIV_002610
Valine-tRNA ligase 6.1.1.9 NCLIV_007730
Valine-tRNA ligase 6.1.1.9 NCLIV_059740
Acetoacetate-CoA ligase 6.2.1.16 NCLIV_061250
Methylcrotonoyl-CoA carboxylase 6.4.1.4 NCLIV_036840

 

List of genes annotated as tRNA-Leu in N. caninum genome

 

NC_LIV_tRNA_020002 NC_LIV_tRNA_030001 NC_LIV_tRNA_030002 NC_LIV_tRNA_030003
NC_LIV_tRNA_080001 NC_LIV_tRNA_100012 NC_LIV_tRNA_110009 NC_LIV_tRNA_110010
NC_LIV_tRNA_120007 NC_LIV_tRNA_130007 NC_LIV_tRNA_140010  

 

List of genes annotated as tRNA-Ile in N. caninum genome

 

NC_LIV_tRNA_080005 NC_LIV_tRNA_090001 NC_LIV_tRNA_100006 NC_LIV_tRNA_120009
NC_LIV_tRNA_140025      

 

List of genes annotated as tRNA-Val in N. caninum genome

 

NC_LIV_tRNA_020002 NC_LIV_tRNA_100021 NC_LIV_tRNA_110006 NC_LIV_tRNA_130001
NC_LIV_tRNA_130002 NC_LIV_tRNA_130010 NC_LIV_tRNA_140006 NC_LIV_tRNA_140013
NC_LIV_tRNA_140021      

 

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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