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 |
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? |
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