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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan).
authors.forename: Yizhen
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan).
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan). taniguch@phar.kyushu-u.ac.jp.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Taniguchi
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D001483:Base Sequence; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045647:DNA Glycosylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D043382:DNA-Formamidopyrimidine Glycosylase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D054879:Halogenation; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D004791:Enzyme Inhibitors; C024829:8-hydroxyguanine; D006147:Guanine; C045550:7-deaza-2'-deoxyguanosine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D043382:DNA-Formamidopyrimidine Glycosylase; D003849:Deoxyguanosine
keywords: 8-oxo-dG; DNA damage; DNA repair enzymes; Fpg; hOGG1; inhibitors