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

  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},
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
Selective activation of deoxycytidine kinase by thymidine-5'-thiosulphate and release by deoxycytidine in human lymphocytes.
It is suggested that the enhancement of dCK activity is a compensatory mechanism in cells that might be induced by different "inhibitors" of DNA synthesis leading to damage of DNA. Expand
Thymidylate synthase inhibitors.
This chapter reviews recent developments in the understanding and clinical applications of FP and folate-based TS inhibitors, which has maintained this group of drugs in the forefront of anticancer drug pharmacology and therapeutics. Expand
Role of ionization of the phosphate cosubstrate on phosphorolysis by purine nucleoside phosphorylase (PNP) of bacterial (E. coli) and mammalian (human) origin
Comparison of the pH-dependence of the substrate properties of Pi versus SPi points to both monoanionic and dianionic forms of Pi as substrates, with a marked preference for the dianion species in the pH range 5–8, reflected by enzyme efficiency three orders of magnitude higher at pH 8 than that at pH 5. Expand
The effect of Arg209 to Lys mutation in mouse thymidylate synthase.
It is documented that mouse thymidylate synthase R209, similar to the corresponding L. casei R218, is essential for both dUMP binding and enzyme reaction. Expand
Synthesis of 6,6′-(S)-cyclo-2′-deoxyuridine featuring a unique Barbier-style cyclization
Here we present the synthesis of the novel nucleoside 6,6′-(S)-cyclo-2′-deoxyuridine (1). This efficient synthesis is carried out starting from 2′-deoxyuridine and reaches the deprotected product inExpand
Synthesis of nucleoside and oligonucleoside dithiophosphates
Nucleoside and oligonucleoside dithiophosphates are normal nucleotide and oligonucleotide mimics in which two nonbridging oxygen atoms at a phosphomonoester of a nucleotide or internucleotideExpand
Tidal chain reaction and the origin of replicating biopolymers
  • R. Lathe
  • Physics
  • International Journal of Astrobiology
  • 2005
Template-directed polymer assembly is a likely feature of prebiotic chemistry, but the product blocks further synthesis, preventing amplification and Darwinian selection. Nucleic acids are unusualExpand


Synthesis and interactions with thymidylate synthase of 2,4-dithio analogues of dUMP and 5-fluoro-dUMP.
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.
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.
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
Interaction of 5-fluoro-4-thio-2'-deoxyuridine 5'-phosphate with mammalian tumour thymidylate synthase: role of the pyrimidine N(3)-H dissociation.
The role of the pyrimidine N(3)-H in binding of dUMP derivatives to thymidylate synthase was evaluated with the aid of a new dUMP analogue, 5-fluoro-4-thio-dUMP, synthesized by an improved thiationExpand
Synthesis and interaction with thymidylate synthase of 5'-dithiophosphate and 5'-fluorothiophosphate of thymidine.
While dTMPS2 proved to be an inhibitor, competitive vs dUMP, with K(i)app = 94 microM, the 5'-fluorothiophosphate congener displayed no activity, indicating that the enzyme requires for binding the presence of a dianionic 5'-phosphate group in a nucleotide. Expand
A calorimetric study of the binding of 2'-deoxyuridine-5'-phosphate and its analogs to thymidylate synthetase.
Preliminary date are presented which suggest that two-site binding of FdUMP occurs on prolonged incubation during equilibrium dialysis, and a model in which binding occurs through an electrostatic interaction between dianionic nucleotide and protonated enzyme residues is suggested. Expand
Mechanism of inhibition of mammalian tumor and other thymidylate synthases by N4-hydroxy-dCMP, N4-hydroxy-5-fluoro-dCMP, and related analogues.
Kinetic studies with purified enzyme from five sources demonstrated that addition of a 5-fluoro substituent to N4-OH-dCMP increased its affinity from 2- to 20-fold for the enzyme from different sources. Expand
2-Thio derivatives of dUrd and 5-fluoro-dUrd and their 5'-monophosphates: synthesis, interaction with tumor thymidylate synthase, and in vitro antitumor activity.
The beta-anomer 1 exhibited antitumor activity in a mouse leukemic cell line L5178Y (IC50 approximately 10(-6) M), hence 40-100-fold weaker than 5-fluoro-dUrd, but exhibited at least 10-fold higher selectivity with respect to the tumor cells than the beta-Anomer 1. Expand
5-Substituted N(4)-hydroxy-2'-deoxycytidines and their 5'-monophosphates: synthesis, conformation, interaction with tumor thymidylate synthase, and in vitro antitumor activity.
Thymidylate synthase inhibition was studied with two forms of the enzyme differing in sensitivities toward 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP), isolated from parental and FdUrd-resistant L1210 cell lines. Expand
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