This chapter examines the reactions of enzymes that employ tetrahydrobiopterin or derivatives of tetrahydropteroyl poly-γ-glutamates for promoting transformations involving hydroxylation and 1-carbon unit transfer. The transfer of 1-carbon units at this oxidation level originally was thought to involve two derivatives of H4-folate, 10-formyl-H4-folate and 5,10-methenyl-H4-folate, which acted as cofactors for the two transformylases in de novo purine biosynthesis. However, recent work has shown that the glycinamide ribonucleotide transformylase (GAR TFase) from E. coli and from avian liver utilize 10-formyl-H4-folate as the actual cofactor. The preference for 10-formyl-H,-folate was masked by the presence of the opposite, unreactive diastereomer (R at C-6 in H4-folate), which is an excellent competitive inhibitor of the enzyme. The apparent reactivity of the 5,10-methenyl-H4-folate in the same assay arose because of a contaminating cyclohydrolase activity capable of selectively hydrolyzing it to the correct diastereomer of 10-formyl-H4-folate. The further examination of both GAR TFase and AICAR TFase with 5- and/or 8-deazafolate analogs formylated at N-10 has eliminated mechanisms requiring cyclization to the 5,10-methenyl species prior to 1-carbon unit transfer.
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