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

Authors
Journal
Biochemical and Biophysical Research Communications
0006-291X
Publisher
Elsevier
Publication Date
Volume
48
Issue
6
Identifiers
DOI: 10.1016/0006-291x(72)90892-3
Disciplines
  • Biology

Abstract

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.

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