Profiling base excision repair glycosylases with synthesized transition state analogs

Aurea M. Chu, James C. Fettinger, Sheila S. David

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Two base excision repair glycosylase (BER) transition state (TS) mimics, (3R,4R)-1-benzyl (hydroxymethyl) pyrrolidin-3-ol (1NBn) and (3R,4R)- (hydroxymethyl) pyrrolidin-3-ol (1N), were synthesized using an improved method. Several BER glycosylases that repair oxidized DNA bases, bacterial formamidopyrimdine glycosylase (Fpg), human OG glycosylase (hOGG1) and human Nei-like glycosylase 1 (hNEIL1) exhibit exceptionally high affinity (K d∼pM) with DNA duplexes containing the 1NBn and 1N nucleotide. Notably, comparison of the K d values of both TS mimics relative to an abasic analog (THF) in duplex contexts paired opposite C or A suggest that these DNA repair enzymes use distinctly different mechanisms for damaged base recognition and catalysis despite having overlapping substrate specificities.

Original languageEnglish (US)
Pages (from-to)4969-4972
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number17
DOIs
StatePublished - Sep 1 2011

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DNA Repair
Repair
DNA Repair Enzymes
Bacterial DNA
DNA
Substrate Specificity
Catalysis
Nucleotides
Substrates

Keywords

  • 8-Oxo-7,8-dihydro-2-deoxyguanosine
  • Base excision repair
  • DNA glycosylase
  • Fpg
  • hNEIL1
  • hOGG1
  • Nei
  • Pyrrolidine analogs
  • Transition state analogs

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Profiling base excision repair glycosylases with synthesized transition state analogs. / Chu, Aurea M.; Fettinger, James C.; David, Sheila S.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 21, No. 17, 01.09.2011, p. 4969-4972.

Research output: Contribution to journalArticle

Chu, Aurea M. ; Fettinger, James C. ; David, Sheila S. / Profiling base excision repair glycosylases with synthesized transition state analogs. In: Bioorganic and Medicinal Chemistry Letters. 2011 ; Vol. 21, No. 17. pp. 4969-4972.
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