The merits of bipartite transition-state mimics for inhibition of uracil DNA glycosylase

Yu Lin Jiang, Chunyang Cao, James T. Stivers, Fenhong Song, Yoshi Ichikawa

Research output: Contribution to journalArticlepeer-review

Abstract

The glycosidic bond hydrolysis reaction of the enzyme uracil DNA glycosylase (UDG) occurs by a two-step mechanism involving complete bond breakage to the uracil anion leaving group in the first step, formation of a discrete glycosyl cation-uracil anion intermediate, followed by water attack in a second transition-state leading to the enzyme-bound products of uracil and abasic DNA. We have synthesized and determined the binding affinities of unimolecular mimics of the substrate and first transition-state (TS1) in which the uracil base is covalently attached to the sugar, and in addition, bimolecular mimics of the second addition transition state (TS2) in which the base and sugar are detached. We find that the bipartite mimics of TS2 are superior to the TS1 mimics. These results indicate that bipartite TS2 inhibitors could be useful for inhibition of glycosylases that proceed by stepwise reaction mechanisms.

Original languageEnglish (US)
Pages (from-to)244-262
Number of pages19
JournalBioorganic Chemistry
Volume32
Issue number4
DOIs
StatePublished - Aug 1 2004

Keywords

  • 1-Azadeoxyribose
  • Enzyme inhibition
  • Transition-state mimics
  • Uracil DNA glycosylase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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