Interaction of 2-thio-5-fluoro-dump and 4-thio-5-fluoro-dump with mammalian normal and tumor and helminthic thymidylate synthases: Influence of c(4)-substituents on specificity for enzyme inactivation

Jolanta M. Dzik, Zbigniew Zieliński, Joanna Cieśla, Maria Bretner, Tadeusz Kulikowski, David Shugar, Joseph Bertino, Wojciech Rode

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

To determine how 5-fluoro-dUMP modifications may affect its specificity, 2-thio-5-fluoro-dUMP and 4-thio-5-fluoro-dUMP were compared as inhibitors of thymidylate synthases isolated from parental and FdUrd-resistant mouse leukemia L1210 cells, human and rat colon adenocarcinomas, regenerating rat liver and the tapeworm, Hymenolepis diminuta, differing in sensitivity to time- and N5,10-methylenetetrahydrofolate-dependent inactivation by 5-fluoro-dUMP (Ki values ranging from 10-9 to 10-7 M). Inactivation by 2-thio-5-fluoro-dUMP, relative to 5-fluoro-dUMP, was 5-20-fold weaker, with specificity for inactivation of different thymidylate synthases paralleling that of 5-fluoro-dUMP. By contrast, 4-thio-5-fluoro-dUMP showed very different specificity, being as potent an inactivator for some enzymes as 5-fluoro-dUMP, but 45-85-fold weaker for others. The results suggest that an interplay between substituents at C(4) and C(5) of the pyrimidine ring may affect the specificity of thymidylate synthase inactivation.

Original languageEnglish (US)
Pages (from-to)1301-1308
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume195
Issue number3
DOIs
StatePublished - Sep 30 1993

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Biophysics
  • Biochemistry
  • Cell Biology

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