Phenylalanine and tyrosine metabolism

Phenylalanine is an essential amino acid for all apicomplexans, which needs to be salvaged from host. Like humans, Toxoplasma gondii has the ability to convert phenylalanine to tyrosine [1] as it possesses two nearly identical isoforms of aromatic amino acid hydroxylase. These enzymes can catalyse hydroxylation of both phenylalanine and tyrosine with higher substrate specificity for tyrosine. This suggests their role in the synthesis of both tyrosine and L-DOPA. The hydroxylation of tyrosine to L-DOPA is the rate-limiting step in dopamine biosynthesis and this might have been the cause of behavioural changes in T. gondii infected humans and animals [2]. A recent study also demonstrated the increase in dopamine levels by several folds in T. gondii infected dopaminergic cells and the positive correlation between number of infected cells and dopamine levels [3]. It is also suggested that this may play a role in cyst wall formation and increased reactive oxygen species in host [2]. The orthologs for the two aromatic amino acid hydroxylases in T. gondii are also present in Neospora caninum genome. Plasmodium, Theileria and Cryptosporidium species do not have this enzyme and are auxotrophic for tyrosine [1]. All other enzymes present in Plasmodium falciparum phenylalanine and tyrosine metabolism pathway are also present in T. gondii and N. caninum. The main enzymes are aspartate transaminase and aromatic amino acid transaminase which convert phenylalanine and tyrosine into phenylpyruvate and hydroxy-phenylpyruvate respectively. These reactions also produce glutamate. The enzymes which catalyse degradation of phenylpyruvates are missing in N. caninum, T. gondii and P. falciparum genomes.

 

Enzyme EC Number Gene id
Aromatic amino acid hydroxylase (Phenylalanine 4-hydroxylase/Tyrosine 3-hydroxylase) 1.14.16.1; 1.14.16.2 NCLIV_069650
Aromatic amino acid hydroxylase (Phenylalanine 4-hydroxylase/Tyrosine 3-hydroxylase) 1.14.16.1; 1.14.16.2 NCLIV_069680
Leucyl, phenylalanine-tRNA-protein transferase 2.3.2.6 NCLIV_022350
Aspartate transaminase 2.6.1.1 NCLIV_064760
Aromatic-amino-acid transaminase 2.6.1.57 NCLIV_049590
4a-hydroxytetrahydrobiopterin dehydratase 4.2.1.96 NCLIV_046820
Phenylpyruvate tautomerase 5.3.2.1 NCLIV_042400
Tyrosine-tRNA ligase 6.1.1.1 NCLIV_034220
Tyrosine-tRNA ligase 6.1.1.1 NCLIV_066920
Phenylalanine-tRNA ligase 6.1.1.20 NCLIV_012080
Phenylalanine-tRNA ligase 6.1.1.20 NCLIV_042270
Phenylalanine-tRNA ligase 6.1.1.20 NCLIV_053190

 

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

 

NC_LIV_tRNA_020008 NC_LIV_tRNA_070005 NC_LIV_tRNA_130003 NC_LIV_tRNA_140011

 

 

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

 

NC_LIV_tRNA_110004 NC_LIV_tRNA_110005 NC_LIV_tRNA_140024

 

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Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Phenylalanine Host L-DOPA Host
Tetrahydrobiopterin Folate biosynthesis Dihydrobiopterin Folate biosynthesis
2-oxoglutarate Pyruvate metabolism, Tricarboxylic acid (TCA) cycle L-Glutamate Glutamate metabolism
    Phenylpyruvate Host?
    2-Hydroxy-3-(4-hydroxyphenyl)propenoate Host?