N5N10FormylTHF

N5,N10-formyl-THF is a derivative of tetrahydrofolate in which formyl groups are associated with the nitrogen atoms at the N5 and N10 positions of the folate molecule. It is commonly described in the form of 10-formyl-THF or formyl-THF, and it functions as a one-carbon donor in cellular one-carbon metabolism.

In de novo purine biosynthesis, N5,N10-formyl-THF provides formyl groups in two enzymatic steps. GAR transformylase transfers a formyl group from 10-formyl-THF to GAR, forming FGAR, and AICAR transformylase uses 10-formyl-THF to convert AICAR to FAICAR. These reactions are essential for the production of inosine monophosphate (IMP), the purine nucleotide precursor.

Biosynthesis and turnover: 10-formyl-THF is generated from tetrahydrofolate by formyltransferases that utilize formate as a donor. In humans, the cytosolic MTHFD1 enzyme provides dehydrogenase, cyclohydrolase, and formyltransferase activities to interconvert folate derivatives, including the production of 10-formyl-THF from other one-carbon carriers. In bacteria, analogous reactions are performed by separate enzymes. The folate cycle links these forms to other one-carbon transfer reactions within the cell.

Clinical and biological significance: Adequate pools of 10-formyl-THF are necessary for efficient purine synthesis and cell proliferation. Disruption of folate metabolism, whether by nutritional deficiency or antifolate drugs such as methotrexate, impairs nucleotide synthesis. Folate supplementation strategies or rescue agents like leucovorin can modulate these effects by replenishing tetrahydrofolate derivatives.