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New analogs of dUMP, dTMP and 5-fluorodUMP, including the corresponding 5thiophosphates (dUMPS, dTMPS and FdUMPS), 5dithiophosphates (dUMPS2, dTMPS2 and FdUMPS2), 5Hphospho nates (dUMPH, dTMPH and FdUMPH) and 5S thiosulfates (dUSSO3, dTSSO3 and FdUSSO3), have been synthesized and their interactions studied with highly purified mammalian thymidylate synthase. dUMPS and dUMPS2 proved to be good substrates, and dTMPS and dTMPS2 classic competitive inhibitors, only slightly weaker than dTMP. Their 5-fluoro congeners behaved as potent, slowbinding inhibitors. By contrast, the corresponding 5Hphosphonates and 5Sthiosulfates displayed weak activities, only FdUMPH and FdUSSO3 exhibiting significant interactions with the enzyme, as weak competitive slowbinding inhibitors versus dUMP. The pHdependence of enzyme timeindependent inhibition by FdUMP and FdUMPS was found to correlate with the difference in pKa values of the phosphate and thiophosphate groups, the profile of FdUMPS being shifted (~1 pH unit) toward lower pH values, so that binding of dUMP and its analogs is limited by the phosphate secondary hydroxyl ionization. Hence, together with the effects of 5Hphosphonate and 5Sthiosulfate substituents, the much weaker interactions of the nucleotide analogs (35 orders of magnitude lower than for the parent 5phosphates) with the enzyme is further evidence that the enzymes active center prefers the dianionic phosphate group for optimum binding.

biological chemistry

Interaction of Thymidylate Synthase with the 5-Thiophosphates, 5-Dithiophosphates, 5-H-Phosphonates and 5-S-Thiosulfates of 2-Deoxyuridine, Thymidine and 5-Fluoro-2-Deoxyuridine