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

@inproceedings{Goos2001InteractionOT,
  title={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},
  author={Barbara Gołos and Jolanta Maria Dzik and Zygmunt Kazimierczuk and Joanna Cieśla and Zbigniew Zieliński and Jadwiga Jankowska and Adam Kraszewski and Jacek Stawinski and Wojciech Rode and David Shugar},
  booktitle={Biological chemistry},
  year={2001}
}
Abstract 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… Expand
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TLDR
Theoretical considerations, based on calculated aromaticities of the uracil and thiouracil rings, suggest that lack of substrate activity of 2,4-dithio-dUMP may result from increased pyrimidine ring aromaticity of the latter, leading to resistance of C(6) to nucleophilic attack by the enzyme active center cysteine. Expand
Studies on the interaction with thymidylate synthase of analogues of 2'-deoxyuridine-5'-phosphate and 5-fluoro-2'-deoxyuridine-5'-phosphate with modified phosphate groups.
TLDR
5-FdUMP and its analogues exhibited differing interactions with two binding sites on the enzyme molecule, consistent with cooperativity of binding, and a convenient procedure is described for the synthesis of 5-fluoro-2'-deoxyuridine-5'-methylphosphonate, applicable also to the preparation of other 5'-methyl phosphonate analogues. Expand
Molecular mechanism of thymidylate synthase-catalyzed reaction and interaction of the enzyme with 2- and/or 4-substituted analogues of dUMP and 5-fluoro-dUMP.
TLDR
Results of molecular modeling studies suggest interaction of the pyrimidine C(4) = O group, or its modification, with the N5,10-methylene, preserves high inhibitory potency of the drug but may alter its specificity for thymidylate synthases from various sources. Expand
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TLDR
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Trichinella spiralis thymidylate synthase: developmental pattern, isolation, molecular properties, and inhibition by substrate and cofactor analogues.
Thymidylate synthase specific activity was found to remain at a constant level in crude extracts from muscle larvae, isolated (1-15 months after infection) by pepsin-HCI digestion, as well as fromExpand
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