Recycling of folate (Thymidylate synthase cycle)

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. The de novo folate biosynthesis pathway is present in both Plasmodium falciparum and Toxoplasma gondii and the drugs targeting folate biosynthesis pathway has long been prescribed as anti-malarial agents. The enzymes for the biosynthesis of folate are absent in the genomes of Cryptosporidia. Thymidylate cycle, a part of folate pathway is present in Cryptosporidia. This 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 P. falciparum and T. gondii. The orthologs of these bifunctional enzymes are also present in Cryptosporidium species. This suggests that in contrast to the ability of P. falciparum and T. gondii to de novo synthesise and salvage folate, Cryptosporidia only have the ability to salvage folate from host.

 

Enzyme EC Number Gene id
Bifunctional dihydrofolate reductase/thymidylate synthase 1.5.1.3; 2.1.1.45 CMU_010300
Serine hydroxymethyltransferase 2.1.2.1 CMU_026590
Serine hydroxymethyltransferase 2.1.2.1 CMU_026630
Folate/biopterin (BT1 family) transporter none CMU_007860

 

Open in a new window

 

 

Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Dihydrofolate Host    
Serine Host Glycine Glycine and serine metabolism