Thymidylate synthetase: Mechanism of inhibition by 5-fluoro-2′-deoxyuridylate

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Abstract

Inhibition of thymidylate synthetase by 5-fluoro-2′-deoxyuridylate requires methylenetetrahydrofolate. Both 5-fluoro-2′-deoxyuridylate and methylenetetrahydrofolate are covalently bound to the enzyme, as shown by the stability of the complex to denaturation by sodium dodecyl sulfate and urea, and to trichloroacetic acid precipitation. By contrast, 5-trifluoromethyl-2′-deoxyuridylate is not covalently bound. We postulate that in the enzyme-inhibitor-cofactor complex, the 6-carbon of 5-fluoro-2′-deoxyuridylate is bound covalently to the enzyme, with the methylene group covalently linking to the 5-carbon of the nucleotide to either the N-5 or N-10 position of tetrahydrofolate.

References (19)

  • K-U. Hartmann et al.

    J. Biol. Chem

    (1961)
  • A. Fridland et al.

    J. Biol. Chem

    (1971)
  • M.Y. Lorenson et al.

    J. Biol. Chem

    (1967)
  • E.J. Pastore et al.

    J. Biol. Chem

    (1962)
  • R.L. Blakley

    J. Biol. Chem

    (1963)
  • M.I.S. Lomax et al.

    J. Biol. Chem

    (1967)
  • R.L. Blakley
  • S.S. Cohen et al.
  • C. Heidelberger et al.

    Cancer Res

    (1960)
There are more references available in the full text version of this article.

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This work was supported in parts by grants CA 07175 and CRTY-5002 from the National Cancer Institute, National Institutes of Health.

2

American Cancer Society Professor of Oncology.

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