10formyltetrahydrofolate

10-formyltetrahydrofolate (10-formyl-THF) is a one-carbon carrier in the folate metabolic network. It is a formylated derivative of tetrahydrofolate (THF) in which a formyl group is attached at the N10 position. As a donor of formyl groups, it participates in several anabolic reactions that depend on one-carbon units.

Biosynthesis and pools: 10-formyl-THF is generated from formate and THF by formyl-THF synthetase in bacteria. In mammals, cytosolic and mitochondrial one-carbon metabolism uses multifunctional enzymes such as MTHFD1 and, in mitochondria, MTHFD1L to produce 10-formyl-THF from formate within the folate cycle. This metabolite feeds both cytosolic and mitochondrial folate pools and supports downstream formylation reactions.

Role in purine biosynthesis: 10-formyl-THF provides formyl groups in two essential steps of de novo purine synthesis. GAR transformylase transfers a formyl group from 10-formyl-THF to GAR to form FGAR, while AICAR transformylase uses 10-formyl-THF to convert AICAR into FAICAR. These formyl transfer reactions are required for the construction of the purine ring and ultimately for synthesis of inosine monophosphate (IMP).

Role in tRNA formylation: In bacteria and many organelles, 10-formyl-THF donates a formyl group to the initiator methionyl-tRNA (tRNAfMet) to formyl-Met-tRNAi, a modification that facilitates initiation of protein synthesis. In eukaryotic cytosol, tRNA formylation is generally absent, but mitochondrial translation can involve formylated initiator tRNA.

Clinical relevance: Folate status and one-carbon metabolism influence DNA synthesis and repair. Deficiencies or disruptions in 10-formyl-THF–dependent pathways can impair purine synthesis and cell proliferation; antifolate drugs exploit these pathways in disease treatment.