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In contrast to their spontaneous deprotonation in aqueous solution, reactions of guanine and guanosine radical cations with water in the gas phase are exclusively initiated by hydration of the radical cations as reported in recent work (Y. Sun et al. , Phys. Chem. Chem. Phys. , 2018, 20 , 27510). As gas-phase hydration reactions closely mimic the actual scenario for guanine radical cations in double-stranded DNA, exploration of subsequent reactions within their water complexes can provide an insight into the resulting oxidative damage to nucleosides. Herein guided-ion beam mass spectrometry experiment and direct dynamics trajectory simulations were carried out to examine prototype complexes of the 9-methylguanine radical cation with one and two water ligands ( i.e. , 9MG˙ + ·(H 2 O) 1–2 ) in the gas phase, wherein the complexes were activated by collisional activation in the experiment and by thermal excitation at high temperatures in the simulations. Guided by mass spectroscopic measurements, trajectory results and reaction potential energy surface, three reaction pathways were identified. The first two reaction pathways start with H-atom abstraction from water by the O6 and N7 atoms in 9MG˙ + and are referred to as HA O6 and HA N7 , respectively. The primary products of HA O6 and HA N7 reactions, including [9MG + H O6 ] + /[9MG + H N7 ] + and ˙OH, react further to either form [8OH-9MG + H O6 ]˙ + and [8OH-9MG + H N7 ]˙ + via C8-hydroxylation or form radical cations of 6- enol -guanine (6- enol -G˙ + ) and 7H-guanine (7HG˙ + ) via S N 2-type methanol elimination. The third reaction pathway corresponds to the formation of 8OH-9MG + by H elimination from the complex, referred to as HE. Among these product channels, [8OH-9MG + H N7 ]˙ + has the most favorable formation probability, especially in the presence of additional water molecules. This product may serve as a preceding structure to the 8-oxo-7,8-dihydroguanine lesion in DNA and has implications for health effects of radiation exposure and radiation therapy.
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Crosslinking pathways, dynamics, and kinetics between guanosine and lysine following one- versus two-electron oxidation of guanosine
Abstract DNA–protein crosslinks (DPCs) remain as a poorly understood DNA lesion. Herein, crosslinking between guanosine and lysine was explored using a model system comprising 9-methylguanine (9MG) and CH3NH2. Crosslinking was induced by one-electron oxidized 9MG•+ radical cations and doubly oxidized [9MG – HN2]+ cations, and analyzed as a function of reaction energy using an electrospray ionization tandem mass spectrometer. Experiment was augmented by dynamics simulations and kinetics modeling. Alongside the formation of X-NH2CH3[9MG]•+ (X = C2, C8) via direct addition, 8-CH2NH2[9MG + HN7]+ was discovered as a new crosslink between 9MG•+ and CH3NH2. This crosslink results from methyl–hydrogen abstraction of CH3NH2 by the N7 of 9MG•+, followed by adding •CH2NH2 to [9MG + HN7]+. Notably, crosslinking is dramatically enhanced between [9MG – HN2]+ and CH3NH2, yielding major products X-+NH2CH3[9MG – HN2] (X = N2, N3, C5, and C8, along with their proton tautomers), which form from the direct CH3NH2 addition to [9MG – HN2]+, and minor products X-CH2NH2[9MG – HN2 + HO6]+ (X = N2, N3, C5, N7, and C8), which arise from the combination of methyl–hydrogen abstraction products. This work dissected and distinguished the roles of one- versus two-electron oxidized guanosine in DPC formation, offering novel insights into oxidative DNA damage.
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- Award ID(s):
- 2350109
- PAR ID:
- 10575262
- Publisher / Repository:
- Oxford University Press
- Date Published:
- Journal Name:
- Nucleic Acids Research
- Volume:
- 53
- Issue:
- 5
- ISSN:
- 0305-1048
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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