Metabolism of 10-formyldihydrofolate in humans

The metabolism of 10-formyldihydrofolate is reviewed in this article. It had been the dogma that only tetrahydrofolates participate in enzyme-catalyzed one-carbon transfer reactions, until we showed in 1986 that 10-formyldihydrofolate serves as a substrate for aminoimidazolecarboxamide ribotide (AICAR) transformylase. Our data from studies in humans, cultured cells and bacteria as well as in vitro experiments indicate that the oxidation of 10-formyltetrahydrofolate to 10-formyldihydrofolate takes place, and 10-formyldihydrofolate is subsequently converted to dihydrofolate by AICAR transformylase. Dihydrofolate is then reduced to tetrahydrofolate and further metabolized by the well-established enzyme reactions. We believe that a new folate metabolic map is needed which incorporates the oxidation of 10-formyltetrahydrofolate and the utilization of 10-formyldihydrofolate by AICAR transformylase.