formylTHF

FormylTHF, or formyl-tetrahydrofolate, refers to tetrahydrofolate derivatives bearing a formyl group. There are two major isomeric forms of formylTHF that are biologically important: N5-formyl-THF (5-formyl-THF) and N10-formyl-THF. Each serves distinct roles in one-carbon metabolism and folate biology.

N10-formyl-THF functions as a critical one-carbon donor in de novo purine biosynthesis. It donates formyl groups in two enzymatic steps: GAR transformylase converts glycinamide ribonucleotide to formylglycinamide ribonucleotide, and AICAR transformylase converts AICAR to formyl-AICAR. This formyl group transfer is essential for the construction of the purine ring, linking folate metabolism to nucleotide synthesis.

N5-formyl-THF, also known as 5-formyl-THF, is commonly viewed as a reservoir form of folate. It can be interconverted with other folate cofactors and contributes to one-carbon metabolism, providing a source of formyl groups when needed. In clinical contexts, 5-formyl-THF is the active component of folinic acid, a form of rescue therapy used to mitigate toxicity from antifolate chemotherapy (such as methotrexate) by replenishing folate cofactors downstream of the enzyme blocked by the drug.

Biologically, formylTHF derivatives are interconverted within the folate cycle, fueling processes such as purine biosynthesis, thymidylate synthesis, and overall one-carbon metabolism. Disruptions in formylTHF availability or handling can impact DNA synthesis and cellular proliferation, linking folate chemistry to growth and disease.