PMID: 9540799Apr 16, 1998Paper

Crystal structures of 5-fluoro-dUrd and its 2 and/or 4-thio analogues: models of substituted dUMP pyrimidine ring interacting with thymidylate synthase

Biochimica Et Biophysica Acta
Adam JarmułaW Rode

Abstract

In order to understand the influence on thymidylate synthase interactions with dUMP analogues of the pyrimidine ring 2- and/or 4-thio, and 5-fluoro substitutions, X-ray diffractions by crystals of 5-fluoro-dUrd and its 2- and 4-thio, and 2,4-dithio analogues were measured, the four structures solved and refined. The following conclusions were suggested by results of comparative analyses of structural parameters (bond lengths, valence angles), followed by theoretical considerations based on calculated resonance structure distributions and aromaticity indices of the uracil, thiouracil, fluorouracil and fluorothiouracil rings. The effect of 4-thio substitution of FdUMP, altering specificity of inactivation of thymidylate synthases from various sources, is probably due to weaker proton acceptor power of the 4-thio substituent and increasing acidity (enhanced proton-donor power) of the N(3)-H moiety, resulting in an impaired fitness into the network of hydrogen bonds in the enzyme active center cleft. 2,4-Dithio substitution results in (i) impaired pyrimidine ring recognition by the enzyme active center, due to the 4-thio substituent (ii) increased pyrimidine ring aromaticity in dUMP, leading to resistance of C(6) to nucleophilic at...Continue Reading

References

Oct 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·L W Hardy, E Nalivaika
Oct 1, 1987·Medicinal Research Reviews·K T Douglas
Jan 31, 1968·Journal of the American Chemical Society·R J CushleyJ J Fox
Jan 1, 1995·Annual Review of Biochemistry·C W Carreras, D V Santi
Sep 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·L Liu, D V Santi
Jul 15, 1995·Physical Review. D·J R Morris

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Citations

Dec 16, 2004·Nucleosides, Nucleotides & Nucleic Acids·Sunil Dutta Soni, Thamarapu Srikrishnan
Sep 28, 2005·Organic & Biomolecular Chemistry·Wen-Jwu WangGabriele Bocelli

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