Folate biosynthesis
Folic acid, also known as Vitamin B9 is important to several biological functions. The folate derivative, 5,10-methylene-tetrahydrofolate is essential for the synthesis of dTMP from dUMP and it is therefore crucial for DNA replication and cell division. Tetrahydrofolate is an essential substrate in the biosynthesis of amino acid, glycine. Drugs targeting folate biosynthesis pathway has long been prescribed as anti-malarial agents. The two essential precursors of folate biosynthesis are 4-aminobenzoate (a product of shikimate biosynthesis pathway) and GTP. Thymidylate cycle, a part of folate biosynthesis pathway (below) plays important role in the generation of amino acid glycine and dTMP. Dihydrofolate reductase enzyme replenishes tetrahydrofolate from dihydrofolate for the above mentioned biosynthetic processes. The dihydrofolate reductase and thymidylate synthase activities are catalysed by a bifunctional enzyme in both Plasmodium falciparum and Coccidians Toxoplasma gondii and Neospora caninum. In addition to the de novo folate biosynthesis pathway, T. gondii and N. caninum can salvage folate from host. Massimine et al demonstrated the uptake of radio-labelled exogenous folic acid and revealed the presence of common folate transporter which has high affinity for folic acid. This transporter is suggested to be bidirectional and concentration-dependent. They also added that T. gondii and other apicomplexans encode folate transporters as there are putative transporters homologous to BT1 family proteins present in these apicomplexan genomes [1].
T. gondii and N. caninum also possess the enzymes for the synthesis of tetrahydrobiopterin and dihydrobiopterin. Tetrahydrobiopterin is an important cofactor in the hydroxylation of phenylalanine to tyrosine (catalysed by the enzyme phenylalanine hydroxylase), a reaction which is present in the Coccidians (phenylalanine metabolism) and absent in Plasmodium species. The enzymes 1.1.1.153 (catalyses conversion of 6-pyruvoyl-5,6,7,8-tetrahydropterin into tetrahydrobiopterin) and 1.5.1.34 (converts dihydrobiopterin to tetrahydrobiopterin) are absent in P. falciparum. The two aromatic amino acid hydroxylase enzymes present in these Coccidia genomes utilise tetrahydrobiopterin as cofactor. Homology-based search has also led to the identification of five enzymes catalysing biosynthesis of molybdopterin from GTP in T. gondii. The orthologs of four of the five molybdopterin synthesis enzymes in T. gondii were identified in N. caninum genome, whereas the other one is missing in the gene models. Sulfite oxidase, an enzyme utilising molybdopterin as cofactor is present in T. gondii. This sulfite oxidase enzyme is also missing in N. caninum gene models. It is not exactly known whether the sulfite oxidase function is absent in N. caninum.
Enzyme | EC Number | Gene id |
---|---|---|
Sepiapterin reductase | 1.1.1.153 | NCLIV_031930 |
6,7-dihydropteridine reductase | 1.5.1.34 | NCLIV_014630 |
Bifunctional dihydrofolate reductase/thymidylate synthase | 1.5.1.3; 2.1.1.45 | NCLIV_065390 |
Bifunctional methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase | 1.5.1.5; 3.5.4.9 | NCLIV_029470 |
Molybdopterin cofactor synthesis protein 2 (MOCS2/MoaE) | 2.-.-.- | NCLIV_034285 |
Serine hydroxymethyltransferase | 2.1.2.1 | NCLIV_049400 |
Methionyl-tRNA formyltransferase | 2.1.2.9 | NCLIV_050010 |
Bifunctional dihydropteroate synthase/dihydro-hydroxymethylpterin pyrophosphokinase | 2.5.1.15; 2.7.6.3 | NCLIV_027230 |
Aminodeoxychorismate synthase | 2.6.1.85 | NCLIV_022000 |
Alkaline phosphatase | 3.1.3.1 | NCLIV_007470 |
Alkaline phosphatase | 3.1.3.1 | NCLIV_039680 |
Gamma-glutamyl hydrolase | 3.4.19.9 | NCLIV_018100 |
GTP cyclohydrolase | 3.5.4.16 | NCLIV_008130 |
Dihydroneopterin aldolase | 4.1.2.25 | Missing in annotation |
Aminodeoxy-chorismate lyase | 4.1.3.38 | Missing in annotation |
6-pyruvoyltetrahydro-pterin synthase | 4.2.3.12 | Missing in annotation |
Bifunctional tetrahydrofolylpolyglutamate synthase/dihydrofolate synthase | 6.3.2.12; 6.3.2.17 | NCLIV_035540 |
Molybdopterin cofactor synthesis protein 1 (MOCS1/MoaA) | none | NCLIV_000440 |
Molybdopterin cofactor synthesis protein 1 (MOCS1) | none | NCLIV_013520 |
Molybdopterin cofactor synthesis protein 1 (MOCS1/MoaC) | none | NCLIV_017070 |
Folate/biopterin (BT1 family) transporter | none | NCLIV_020200 |
Pterin (BT1 family) transporter | none | NCLIV_023040 |
Folate/Methotrexate transporter | none | NCLIV_026780 |
Pterin (BT1 family) transporter | none | NCLIV_031680 |
Folate/biopterin (BT1 family) transporter | none | NCLIV_039560 |
Folate/Methotrexate transporter | none | NCLIV_047540 |
Molybdopterin cofactor synthesis protein 3 (MOCS3/MoaB) | none | NCLIV_049260 |
Pterin (BT1 family) transporter | none | NCLIV_050350 |
Molybdopterin dependent enzymes in N. caninum genome
Enzyme | EC Number | Gene id |
---|---|---|
Sulfite oxidase | 1.8.3.1 | NCLIV_002115 |
Sources and fates of metabolites
Substrate | Source pathways | Product | Fate pathways |
---|---|---|---|
GTP | Purine metabolism | Glycoaldehyde | ? |
Chorismate | Shikimate biosynthesis | Pyruvate | Glycolysis, Pyruvate metabolism, Alanine metabolism |
Glutamine | Glutamate metabolism | Glutamate | Glutamate metabolism |
Folate | Host | ||
Serine | Glycine, serine and cysteine metabolism | Glycine | Glycine, serine and cysteine metabolism |
Methionyl-tRNA | Methionine metabolism | ||
Dihydrobiopterin | Phenylalanine and tyrosine metabolism | Tetrahydrobiopterin | Phenylalanine and tyrosine metabolism |
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