Evidence that 5-Formyltetrahydropteroylglutamate has a Metabolic Role in One-Carbon Metabolism

Abstract

The metabolic function of 5-formyltetrahydrofolate and its polyglutamate forms (H₄PteGlu_n) have not been elucidated. There are no known biosynthetic reactions in which it serves as the one-carbon donor, and until recently only a single enzyme was known to use this folate derivative as a substrate. Methenyltetrahydrofolate synthetase catalyzes the conversion of 5-CHO-H₄PteGlu_n to 5,10-CH^+-H₄PteGlu_n as shown in Equation 1.^1,2 This irreversible reaction was considered a salvage pathway for the reincorporation of one-carbon

$$ \matrix{ 5 - CHO - {{H}_{4}}PteGl{{u}_{n}} + ATP \to 5,10 - C{{H}^{ + }} - {{H}_{4}}PteGl{{u}_{n}} + ADP{\text{ }} + {\text{ }}Pi{\text{ }} } $$

(1)

units into those folate derivatives active in biosynthetic reactions. In 1984, when methenyltetrahydrofolate synthetase was first purified to homogeneity from eucaryotic and procaryotic sources, it was not established that 5-CHO-H₄PteGlu_n was a normal metabolite of the cell. Some believed that 5-CHO-H₄PteGlu_n was an artifact of isolation, but this did not explain the existence of an enzyme that utilized it as a substrate. Since that time the presence of 5-CHO-H₄PteGlu_n in cells has been firmly established, and methenyltetrahydrofolate activity has been shown to be present in a wide variety of cells.^3,4