Phenylalanine and tyrosine metabolism

Phenylalanine is an essential amino acid for all apicomplexans, which needs to be salvaged from the 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. One of these enzymes is constitutively expressed and the other is stage-specific and expressed during bradyzoite formation. In contrast to other aromatic amino acid hydroxylases, these enzymes have an N-terminal signal peptide and localises to the parasite plasma membrane and parasitophorous vacuole. 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 be 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]. Plasmodium, Theileria and Cryptosporidium species do not have this enzyme and are auxotrophic for tyrosine [1]. Other enzymes present in T. gondii are also present in the Plasmodium falciparum phenylalanine and tyrosine metabolism pathway. 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 both T. gondii and P. falciparum genomes.

 

Enzyme EC Number Gene id Protein localisation Localisation data source
Aromatic amino acid hydroxylase (Phenylalanine 4-hydroxylase/Tyrosine 3-hydroxylase) 1.14.16.1; 1.14.16.2 TGME49_212740    
Aromatic amino acid hydroxylase (Phenylalanine 4-hydroxylase/Tyrosine 3-hydroxylase) 1.14.16.1; 1.14.16.2 TGME49_287510    
Leucyl, phenylalanine-tRNA-protein transferase 2.3.2.6 TGME49_202590    
Aspartate transaminase 2.6.1.1 TGME49_248600 Cytosol Previous publication
Aromatic-amino-acid transaminase 2.6.1.57 TGME49_234440    
4a-hydroxytetrahydrobiopterin dehydratase 4.2.1.96 TGME49_226010    
Phenylpyruvate tautomerase 5.3.2.1 TGME49_290040 Extracellular? Previous publication
Tyrosine-tRNA ligase 6.1.1.1 TGME49_251880 Mitochondrion Previous publication
Tyrosine-tRNA ligase 6.1.1.1 TGME49_273410    
Phenylalanine-tRNA ligase 6.1.1.20 TGME49_210750    
Phenylalanine-tRNA ligase 6.1.1.20 TGME49_234505 Cytosol Previous publication
Phenylalanine-tRNA ligase 6.1.1.20 TGME49_306960 Cytosol Previous publication

 

List of genes annotated as tRNA-Phe in T. gondii genome

 

TGME49_009230 TGME49_049830 TGME49_102011 TGME49_109360
TGME49_118615      

 

List of genes annotated as tRNA-Tyr in T. gondii genome

 

TGME49_013510 TGME49_034680 TGME49_034690 TGME49_100635
TGME49_120655      

 

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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?