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A series of natural and unnatural stereoisomers of reduced folate coenzymes have been studied for their capacity to facilitate binding of 5-fluoro-2'-dUMP (FdUMP) to bacterial thymidylate synthase (TS). The natural cosubstrate for the enzyme, (6R)-5,10-methylene-tetrahydrofolate (CH2-H4-folate), was 4-fold more potent than the unnatural 6S-form in promoting FdUMP binding to TS, but in a racemic mixture the effect of the 6R-form was not affected by the 6S-form. FdUMP binding to TS was also stimulated by tetrahydrofolate and dihydrofolate (85% and 30% as compared to (6RS)-CH2-H4-folate, respectively), but not by the stereoisomers of 5-methyl-tetrahydrofolate and 5-formyl-tetrahydrofolate (leucovorin). These results suggest that folates, which are not a natural cosubstrate for TS, have an additional role in facilitating FdUMP binding to TS.
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