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 language | English |
|---|---|
| Pages (from-to) | 1190-1198 |
| Number of pages | 9 |
| Journal | ChemBioChem |
| Volume | 16 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - May 26 2015 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Organic Chemistry
Cite this
Recognition and excision properties of 8-halogenated-7-deaza-2′-deoxyguanosine as 8-oxo-2′-deoxyguanosine analogues and fpg and hOGG1 inhibitors. / Yin, Yizhen; Sasaki, Shigeki; Taniguchi, Yosuke.
In: ChemBioChem, Vol. 16, No. 8, 26.05.2015, p. 1190-1198.Research output: Contribution to journal › Article
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TY - JOUR
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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U2 - 10.1002/cbic.201402690
DO - 10.1002/cbic.201402690
M3 - Article
VL - 16
SP - 1190
EP - 1198
JO - ChemBioChem
JF - ChemBioChem
SN - 1439-4227
IS - 8
ER -