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

Adam Jarmuła, Romana Anulewicz, Andrzej Leś, Michał K. Cyrański, Ludwik Adamowicz, Maria Bretner, Krzysztof Felczak, Tadeusz Kulikowski, Tadeusz M. Krygowski, Wojciech Rode

Research output: Contribution to journalArticle

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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 attack by the enzyme active center cysteine and (iii) altered planarity of the pyrimidine ring and deflections, with respect to the ring plane, of substituents at C(2), C(4) and C(5). 5-Fluoro substitution apparently activates the pyrimidine ring towards the interaction with thymidylate synthase by producing local strain, which results in an increased reactivity as predicted by the Walsh-Bent rule.

Original languageEnglish (US)
Pages (from-to)277-286
Number of pages10
JournalBiochimica et Biophysica Acta (BBA)/Protein Structure and Molecular
Volume1382
Issue number2
DOIs
StatePublished - Feb 17 1998

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Thymidylate Synthase
Crystal structure
Substitution reactions
Protons
Fluorodeoxyuridylate
Enzymes
Thiouracil
Uracil
Bond length
Acidity
X-Ray Diffraction
Fluorouracil
Cysteine
Hydrogen
Hydrogen bonds
2'-deoxyuridylic acid
pyrimidine
X ray diffraction
Crystals

Keywords

  • Aromaticity
  • DUMP analogue
  • Thymidylate synthase
  • Walsh-Bent rule
  • X-ray diffraction

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Structural Biology
  • Biophysics

Cite this

Crystal structures of 5-fluoro-dUrd and its 2 and/or 4-thio analogues : Models of substituted dUMP pyrimidine ring interacting with thymidylate synthase. / Jarmuła, Adam; Anulewicz, Romana; Leś, Andrzej; Cyrański, Michał K.; Adamowicz, Ludwik; Bretner, Maria; Felczak, Krzysztof; Kulikowski, Tadeusz; Krygowski, Tadeusz M.; Rode, Wojciech.

In: Biochimica et Biophysica Acta (BBA)/Protein Structure and Molecular, Vol. 1382, No. 2, 17.02.1998, p. 277-286.

Research output: Contribution to journalArticle

Jarmuła, Adam ; Anulewicz, Romana ; Leś, Andrzej ; Cyrański, Michał K. ; Adamowicz, Ludwik ; Bretner, Maria ; Felczak, Krzysztof ; Kulikowski, Tadeusz ; Krygowski, Tadeusz M. ; Rode, Wojciech. / Crystal structures of 5-fluoro-dUrd and its 2 and/or 4-thio analogues : Models of substituted dUMP pyrimidine ring interacting with thymidylate synthase. In: Biochimica et Biophysica Acta (BBA)/Protein Structure and Molecular. 1998 ; Vol. 1382, No. 2. pp. 277-286.
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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 attack by the enzyme active center cysteine and (iii) altered planarity of the pyrimidine ring and deflections, with respect to the ring plane, of substituents at C(2), C(4) and C(5). 5-Fluoro substitution apparently activates the pyrimidine ring towards the interaction with thymidylate synthase by producing local strain, which results in an increased reactivity as predicted by the Walsh-Bent rule.",
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AU - Jarmuła, Adam

AU - Anulewicz, Romana

AU - Leś, Andrzej

AU - Cyrański, Michał K.

AU - Adamowicz, Ludwik

AU - Bretner, Maria

AU - Felczak, Krzysztof

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