Effect of folate diastereoisomers on the binding of 5-fluoro-2'-deoxyuridine-5'-monophosphate to thymidylate synthase.
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.
van der Wilt
C L
CL
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Pinedo
H M
HM
de Jong
M
M
Peters
G J
GJ
D005468:Fluorodeoxyuridylate / Q000378:metabolism*; D005492:Folic Acid / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013379:Substrate Specificity; D013940:Thymidylate Synthase / Q000378:metabolism*
D005468:Fluorodeoxyuridylate; D005492:Folic Acid; D013940:Thymidylate Synthase