Recognition and excision properties of 8-halogenated-7-deaza-2′-deoxyguanosine as 8-oxo-2′-deoxyguanosine analogues and fpg and hOGG1 inhibitors

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Abstract

Cellular DNA continuously suffers various types of damage, and unrepaired damage increases disease progression risk. 8-Oxo-2′-deoxyguanine (8-oxo-dG) is excised by repair enzymes, and their analogues are of interest as inhibitors and as bioprobes for study of these enzymes. We have developed 8-halogenated-7-deaza-2′-deoxyguanosine derivatives that resemble 8-oxo-dG in that they adopt the syn conformation. In this study, we investigated their effects on Fpg (formamidopyrimidine DNA glycosylase) and hOGG1 (human 8-oxoguanine DNA N-glycosylase 1). Relative to 8-oxo-dG, Cl- and Br-deaza-dG were good substrates for Fpg, whereas they were less efficient substrates for hOGG1. Kinetics and binding experiments indicated that, although hOGG1 effectively binds Cl- and Br-deaza-dG analogues with low Km values, their lower kcat values result in low glycosylase activities. The benefits of the high binding affinities and low reactivities of 8-oxo-dG analogues with hOGG1 have been successfully applied to the competitive inhibition of the excision of 8-oxoguanine from duplex DNA by hOGG1. The damage has been done: The binding affinities of 8-halogenated-7-deaza-dG derivatives for 8-oxo-dG repair enzymes and their effects on those enzymes' DNA repair properties were evaluated. In particular, Cl- and Br-deaza-dG were excised by Fpg, whereas they were less efficient substrates for hOGG1.

Original languageEnglish
Pages (from-to)1190-1198
Number of pages9
JournalChemBioChem
Volume16
Issue number8
DOIs
Publication statusPublished - May 26 2015

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DNA-Formamidopyrimidine Glycosylase
DNA
Enzymes
DNA Repair Enzymes
Repair
Substrates
Biosensing Techniques
Derivatives
Disease Progression
8-oxo-7-hydrodeoxyguanosine
7-deaza-2'-deoxyguanosine
8-hydroxyguanine
human oxoguanine glycosylase 1
Conformations
Kinetics
Experiments

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

Cite this

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title = "Recognition and excision properties of 8-halogenated-7-deaza-2′-deoxyguanosine as 8-oxo-2′-deoxyguanosine analogues and fpg and hOGG1 inhibitors",
abstract = "Cellular DNA continuously suffers various types of damage, and unrepaired damage increases disease progression risk. 8-Oxo-2′-deoxyguanine (8-oxo-dG) is excised by repair enzymes, and their analogues are of interest as inhibitors and as bioprobes for study of these enzymes. We have developed 8-halogenated-7-deaza-2′-deoxyguanosine derivatives that resemble 8-oxo-dG in that they adopt the syn conformation. In this study, we investigated their effects on Fpg (formamidopyrimidine DNA glycosylase) and hOGG1 (human 8-oxoguanine DNA N-glycosylase 1). Relative to 8-oxo-dG, Cl- and Br-deaza-dG were good substrates for Fpg, whereas they were less efficient substrates for hOGG1. Kinetics and binding experiments indicated that, although hOGG1 effectively binds Cl- and Br-deaza-dG analogues with low Km values, their lower kcat values result in low glycosylase activities. The benefits of the high binding affinities and low reactivities of 8-oxo-dG analogues with hOGG1 have been successfully applied to the competitive inhibition of the excision of 8-oxoguanine from duplex DNA by hOGG1. The damage has been done: The binding affinities of 8-halogenated-7-deaza-dG derivatives for 8-oxo-dG repair enzymes and their effects on those enzymes' DNA repair properties were evaluated. In particular, Cl- and Br-deaza-dG were excised by Fpg, whereas they were less efficient substrates for hOGG1.",
author = "Yizhen Yin and Shigeki Sasaki and Yosuke Taniguchi",
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T1 - Recognition and excision properties of 8-halogenated-7-deaza-2′-deoxyguanosine as 8-oxo-2′-deoxyguanosine analogues and fpg and hOGG1 inhibitors

AU - Yin, Yizhen

AU - Sasaki, Shigeki

AU - Taniguchi, Yosuke

PY - 2015/5/26

Y1 - 2015/5/26

N2 - Cellular DNA continuously suffers various types of damage, and unrepaired damage increases disease progression risk. 8-Oxo-2′-deoxyguanine (8-oxo-dG) is excised by repair enzymes, and their analogues are of interest as inhibitors and as bioprobes for study of these enzymes. We have developed 8-halogenated-7-deaza-2′-deoxyguanosine derivatives that resemble 8-oxo-dG in that they adopt the syn conformation. In this study, we investigated their effects on Fpg (formamidopyrimidine DNA glycosylase) and hOGG1 (human 8-oxoguanine DNA N-glycosylase 1). Relative to 8-oxo-dG, Cl- and Br-deaza-dG were good substrates for Fpg, whereas they were less efficient substrates for hOGG1. Kinetics and binding experiments indicated that, although hOGG1 effectively binds Cl- and Br-deaza-dG analogues with low Km values, their lower kcat values result in low glycosylase activities. The benefits of the high binding affinities and low reactivities of 8-oxo-dG analogues with hOGG1 have been successfully applied to the competitive inhibition of the excision of 8-oxoguanine from duplex DNA by hOGG1. The damage has been done: The binding affinities of 8-halogenated-7-deaza-dG derivatives for 8-oxo-dG repair enzymes and their effects on those enzymes' DNA repair properties were evaluated. In particular, Cl- and Br-deaza-dG were excised by Fpg, whereas they were less efficient substrates for hOGG1.

AB - Cellular DNA continuously suffers various types of damage, and unrepaired damage increases disease progression risk. 8-Oxo-2′-deoxyguanine (8-oxo-dG) is excised by repair enzymes, and their analogues are of interest as inhibitors and as bioprobes for study of these enzymes. We have developed 8-halogenated-7-deaza-2′-deoxyguanosine derivatives that resemble 8-oxo-dG in that they adopt the syn conformation. In this study, we investigated their effects on Fpg (formamidopyrimidine DNA glycosylase) and hOGG1 (human 8-oxoguanine DNA N-glycosylase 1). Relative to 8-oxo-dG, Cl- and Br-deaza-dG were good substrates for Fpg, whereas they were less efficient substrates for hOGG1. Kinetics and binding experiments indicated that, although hOGG1 effectively binds Cl- and Br-deaza-dG analogues with low Km values, their lower kcat values result in low glycosylase activities. The benefits of the high binding affinities and low reactivities of 8-oxo-dG analogues with hOGG1 have been successfully applied to the competitive inhibition of the excision of 8-oxoguanine from duplex DNA by hOGG1. The damage has been done: The binding affinities of 8-halogenated-7-deaza-dG derivatives for 8-oxo-dG repair enzymes and their effects on those enzymes' DNA repair properties were evaluated. In particular, Cl- and Br-deaza-dG were excised by Fpg, whereas they were less efficient substrates for hOGG1.

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