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 influence of cdG on 8-oxodG excision by OGG1 and FPG glycosylases

“…Unfortunately, no precise data concerning, for example, electron transfer chain is available (Popov et al, 2020). However, there are evidences showing only β-elimination products of FPG activity and both β,δ-elimination products of OGG1 action (Yin et al, 2015;Tesfahun et al, 2021), which were also observed in this study. The explanation may be that due to the liability of the AP-site, the mechanism of its degradation differs depending on the reaction conditions.…”

The mechanism of the glycosylase reaction with hOGG1 base-excision repair enzyme: concerted effect of Lys249 and Asp268 during excision of 8-oxoguanine

“…The supply of up to 19 kcal/mol accelerates the bond cleavage 10 14 -fold (4). All of the BER enzymes are typically lesion-specific which is particularly true for the hOGG1, which operates against oxoG with astonishing specificity (15–28). Misbehavior of hOGG1 most likely cannot occur, as a catalytic checkpoint prevents even scission of G forcibly inserted into the catalytic site (29).…”

Inhibitory Effect of 8‐Halogenated 7‐Deaza‐2′‐deoxyguanosine Triphosphates on Human 8‐Oxo‐2′‐deoxyguanosine Triphosphatase, hMTH1, Activities

“…We have reported 8‐halogenated‐7‐deazadG derivatives, with similar shapes, electrostatic potentials as 8‐oxo‐dG and the same syn ‐conformation . We found that these derivatives were good substrates for Fpg (also termed MutM and Fapy‐DNA glycosylase in Escherichia coli ) and exhibited high affinity and inhibitory activity against hOGG1 (human 8‐oxo‐guanine DNA N ‐glycosylase) with DNA duplexes . Thus, we were specifically interested in whether the 8‐halogenated‐7‐deaza‐2′‐deoxyguanosine triphosphate (8‐halogenated‐7‐deazadGTP) derivatives are recognized by hMTH1.…”