Glycinamide ribotide formylation

Methotrexate is a potent inhibitor of dihydrofolate reductase, with an affinity 1,000-fold greater than that of dUiydrofolate. Chemotherapy consists of alternating periods of administration of methotrexate and folate (normally as 5-formyl-tetrahydrofolate, leucovorin) to replete the normal tissues and avoid induction of folate deficiency- so-called leucovorin rescue. As well as depleting tissue pools of tetrahydrofolate, methotrexate leads to the accumulation of relatively large amounts of 10-formyl-dihydrofolate, which is apotentinhibitor of both thymidylate synthetase and glycinamide ribotide transformylase, an intermediate step in purine nucleotide synthesis. It is likely that this, rather than simple depletion of tetrahydrofolate, is the basis of the cytotoxic action of methotrexate (Barametal., 1988). 

The coenzymes are formed from dihydrofolic acid by the enzyme dihydrofolate hydrogenase which gives tetrahydrofolic acid (Osborn, Freeman and Huennekens, 1958), and this is then modified by various one-carbon substituents. The coenzyme for the insertion of C-2 into purines, i.e. for the formylation of the ribotide 9 14) to give (9.1 s)y is -formyl-5563738-tetrahydrofolic acid. For the earlier stage of the insertion of C-8, i.e. for the formylation of glycinamide ribotide to form (eventually) (9./ ), the coenzyme is -methenyl-tetrahydrofolic acid (9-/6). The... 

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