Nucleobase oxidation

M.R. Gore, V.A. Szalai, P.A. Ropp, I.V. Yang, J.S. Silverman and H.H. Thorp, Detection of attomole quantities of DNA targets on gold microelectrodes by electrocatalytic nucleobase oxidation, Anal. Chem., 75... 

The direct electron transfer process between a excited molecule and nucleobase which occur either upon collision or excitation of a ground-state complex. Studies of this processes have helped define the energetic and geometric requirements for nucleobase oxidation and reduction. 

Nucleobase oxidations have been also detected through a piperidine heating treatment allowing the hydrolysis of oxidized bases and the production of DNA fragments with 3 - and 5 -phosphate ends (resulting of the loose of the oxidized nucleoside) (55). 

In order to detect nucleobase oxidation if any, a heating step in piperidine 1 M was also performed, but no clear evolution of the cleavage patterns was observed in accordance to systems realizing probably preferentially deoxyribose oxidation. 

Some of these activated species like HO Cu -hydroperoxo, or Cu -hydroxo have been also proposed in the case of the oxidations of the DNA nucleobases (55). Various mechanisms like HO addition on a double-bound, hydrogen abstraction on the methyl groups or electron transfer induce nucleobases oxidations and copper complexes are oxidant enough to perform them, but, in the presence of excess of reductants, such as in the conditions often used during DNA oxidation by copper complexes, oxidized nucleobases (base radicals and radical cations) may be reduced back to undamaged species. Thus the ability of copper complexes to oxidize nucleobases could be underestimated. 

Hydroxyl radical addition to bases such as guanine, proceeds very rapidly and leads to the formation of 8-hydroxydesoxyguanosine, which is used as a fingerprint of nucleobase oxidative damage. 

Oxidative nucleobase modifications leading to strand scission 98CRV1109. 

Schimanski, A., Ereisinger, E., Erxleben, A. and Lippert, B. (1998) Interactions between [AuX4] (X = Cl, CN) and cytosine and guanine model nucleobases salt formation with (hemi-) protonated bases, coordination, and oxidative degradation of guanine. Inorganica Chimica Acta, 283, 223. 

Radical attack yields nucleobase radical adducts that must undergo either oxidation or rednction to yield a stable final prodnct. The cellular oxidant in these reactions may be molecnlar oxygen or high-valent transition metal ions (e.g., Fe ), while the reduc-tant may be either thiols, snperoxide radical, or low-valent transition metal ions (e.g., Fe ). In many cases, the base remains largely intact and the seqnence of chemical events can be readily inferred. In some other cases, more extensive base decomposition occurs. Here, we will consider a set of representative examples that provide a framework for understanding virtnally all radical-mediated base damage reactions. 

There are examples in which base radicals undergo reaction with adjacent base residues. The 5-(2 -deoxyuridinyl)methyl radical (63, Scheme 8.30) can forge an intrastrand cross-link with adjacent purine residues. Cross-link formation is favored with a guanine residue on the 5 -side of the pyrimidine radical and occurs under low-oxygen conditions. A mechanism was not proposed for this process, but presumably the reaction involves addition of the nucleobase alkyl radical to the C8-position of the adjacent purine residue. Molecular oxygen likely inhibits crosslink formation by trapping the radical 63, as shown in Scheme 8.24. The radical intermediate 89 must undergo oxidation to yield the final cross-linked product 90,... 

Under low oxygen conditions, C5 -sugar radicals can react with the base residue on the same nucleotide. In purine nucleotides, the carbon-centered radical 91 can add to the C8-position of the nucleobase (Scheme 8.31). Oxidation of the intermediate nucleobase radical 92 yields the 8,5 -cyclo-2 -deoxypurine lesion 93197,224,225,230-233 Similarly, in pyrimidine nucleotides, the C5 -radical can add to the C6-position of nucleobase. Reduction of the resulting radical intermediate yields the 5, 6-cyclo-5,6-dihydro-2 -deoxypyrimidine lesion 94,234-236... 

However, the biochemical significance of the latter studies is challenged by the fact that the transformation of transient purine and pyrimidine radicals into diamagnetic decomposition products is oxygen-independent in the solid state. Therefore, it is necessary to study the chemistry of one-electron nucleobase intermediates in aerated aqueous solutions in order to investigate the role of oxygen in the course of reactions that give rise to oxidation products within DNA and model compounds. In this respect, type I photo-... 

Scheme 1 Structures of the Sa and Sd hairpin linkers, electron donor nucleobases and their oxidation potentials, and the hairpins 3G and 3GAGG shown in Fig. 1...

Planar Py and Ptz are expected to stack well among nucleobases, and so were used as the probe molecules to measure the hole transfer rate. The oxidation potentials of Py and Ptz were lower than those of the four nucleobases. We examined the sequence and distance dependences of the hole transfer rate by monitoring the decay and formation of the transient absorption of Py,+ and Ptz + during pulse radiolysis of ODN conjugated with Py and Ptz (PtzPy-(n) (n=l 5)). 

In general, reduction potentials of nucleobases have been studied much less than their oxidation potentials, and in particular water-based data are rather lacking [2, 35]. We therefore listed the available polarographic potentials measured in dimethylformamide and data obtained from pulse radiolysis studies or fluorescence quenching measurements. From the data in Table 1, it is evident that the pyrimidine bases are most easily reduced. The reduction potential of the T=T CPD lesion is close to the estimated value of the undamaged thymine base [34, 36]. 

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