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Computational Study of the Oxidation of Guanine To Form 5‑Carboxyamido-5-formamido-2-iminohydantoin (2Ih)

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journal contribution
posted on 15.10.2019, 18:47 by Sebastien P. Hebert, H. Bernhard Schlegel
Oxidative damage to DNA leads to a number of two-electron oxidation products of guanine such as 8-oxo-7,8-dihydroguanine (8oxoG). 5-Carboxyamido-5-formamido-2-iminohydantoin (2Ih) is another two-electron oxidation product that forms in competition with 8oxoG. The pathways for the formation of 2Ih have been studied by density functional theory using the ωB97XD functional with the 6-31+G­(d,p) basis set and SMD implicit water solvation plus a small number of explicit water molecules positioned to help stabilize charged species and facilitate reaction steps. For oxidative conditions that produce hydroxyl radical, such as Fenton chemistry, hydroxy radical can add at C4, C5, or C8. Addition at C4 or C5 followed by loss of H2O produces guanine radical. Guanine radical can also be produced directly by oxidation of guanine by reactive oxygen species (ROS). A C5-OH intermediate can be formed by addition of superoxide to C5 of guanine radical followed by reduction. Alternatively, the C5-OH intermediate can be formed by hydroxy radical addition at C5 and oxidation by 3O2. The competition between oxidative and reductive pathways depends on the reaction conditions. Acyl migration of the C5-OH intermediate yields reduced spiroiminodihydantoin (Spred). Subsequent water addition at C8 of Spred and N7–C8 ring opening produces 2Ih. Hydroxy radical addition at C8 can lead to a number of products. Oxidation and tautomerization produces 8oxoG. Alternatively, addition of superoxide at C5 and reduction results in a C5, C8 dihydroxy intermediate. For this species, the low energy pathway to 2Ih is N7–C8 ring opening followed by acyl migration. Ring opening occurs more easily at C8–N9 but leads to a higher energy analogue of 2Ih. Thus, the dominant pathway for the production of 2Ih depends on the nature of the reactive oxygen species and on the presence or absence of reducing agents.

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