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5',8-cyklo-2'-deoksyadenozyna. Podwójne uszkodzenie w obrębie pojedynczego nukleozydu/nukleotydu

Karwowski B.T.

Wiadomości Chemiczne

2010

[Z] 64, 11-12

1013-1052

Free radicals can react with different biomolecules present in the cells such as lipids, sugars or nucleic acid peptides. These free radicals initiate reactions with DNA or RNA molecules and then can lead to changes in the genome sequence. These mutations are most probably responsible for a number of different diseases (involving a change in the genome sequence) or, at least, can accompany them. Reactive oxygen species and more specifically - hydroxyl radical can react with DNA molecules and lead to changes in their structures. Formation of radicals at C5' and C8 atoms of 2'-deoxyadenosine leads, through intramolecular cyclisation, to 5',8-cyclo-2'-deoxyadenosine (cdA) derivatives. Frequency of DNA damage occurrence surges with an increase of an ionizing radiation dose. Different repair systems are however present in cellular machinery: BER, which exploits glycosylase and NER - a more complex process involving the removal of damaged oligonucleotides. The later is the basic mechanism for removal the 5',6-cyclo-2'-deoxynucleosides and 5',8-cyclo-2'-deoxynucleosides like cdA. Their defective activity may be responsible for many types of diseases, such as Parkinson, Alzheimer, chronic hepatitis, HCV, atopic dermatitis and different types of cancer. The mechanistic, structural and biochemical studies presented in this work produce quite clear answer as to the approximate range level of the (5'R)-cdA and (5'S)-cdA accumulation in the genome after the lesion period. Using quantum chemistry methods (DFT) paths of the cyclisation reaction have been determined. From the structural analysis point of view, it has been demonstrated that the covalent bond between C(5') and C(8) in nucleoside induces an unusual West conformation of the furanose ring. Based on the NMR data analysis it can be postulated that the rigid and fixed structure of cdA can strongly influence the global geometry of oligonucleosides. Moreover, using the quantum mechanic study of double strand DNA it has been demonstrated that the presence of (5'S)-cdA provokes a "domino effect" extending towards the 5'-end of the strand with this lesion. No domino effect is observed for the 3'-end. The obtained biological results indicate that the presence of (5'S)-cdA in the complementary strand to the strand under repair on the 5'-end side is the critical factor for the inhibition of the BER process of DNA.