title: Mechanism of two-electron oxidation of deoxyguanosine 5'-monophosphate by a platinum(IV) complex.
abstract: Many transition metal complexes mediate DNA oxidation in the presence of oxidizing radiation, photosensitizers, or oxidants. The final DNA oxidation products vary depending on the nature of metal complexes and the structure of DNA. Here we propose a mechanism of oxidation of a nucleotide, deoxyguanosine 5'-monophosphate (dGMP) by trans-d,l-1,2-diaminocyclohexanetetrachloroplatinum (trans-Pt(d,l)(1,2-(NH(2))(2)C(6)H(10))Cl(4), [Pt(IV)Cl(4)(dach)]; dach = diaminocyclohexane) to produce 7,8-dihydro-8-oxo-2'-deoxyguanosine 5'-monophosphate (8-oxo-dGMP) stoichiometrically. The reaction was studied by high-performance liquid chromatography (HPLC), (1)H and (31)P nuclear magnetic resonance (NMR), and electrospray ionization mass spectrometry (ESI-MS). The proposed mechanism involves Pt(IV) binding to N7 of dGMP followed by cyclization via nucleophilic attack of a phosphate oxygen at C8 of dGMP. The next step is an inner-sphere, two-electron transfer to produce a cyclic phosphodiester intermediate, 8-hydroxyguanosine cyclic 5',8-(hydrogen phosphate). This intermediate slowly converts to 8-oxo-dGMP by reacting with solvent H(2)O.
authors.affiliation: Department of Chemistry and Biochemistry, Middlebury College, Middlebury, Vermont 05753, USA. choi@middlebury.edu
authors.forename: Sunhee
authors.initials: S
authors.lastname: Choi
authors.forename: Richard B
authors.initials: RB
authors.lastname: Cooley
authors.forename: Amanda S
authors.initials: AS
authors.lastname: Hakemian
authors.forename: Yuna C
authors.initials: YC
authors.lastname: Larrabee
authors.forename: Richard C
authors.initials: RC
authors.lastname: Bunt
authors.forename: Stéphane D
authors.initials: SD
authors.lastname: Maupas
authors.forename: James G
authors.initials: JG
authors.lastname: Muller
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Burrows
mesh_terms: D003848:Deoxyguanine Nucleotides / Q000737:chemistry* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology; D010084:Oxidation-Reduction; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D003848:Deoxyguanine Nucleotides; D009944:Organoplatinum Compounds; C484372:trans-d,l-1,2-diaminocyclohexanetetrachloroplatinum; C007257:2'-deoxyguanosine 5'-phosphate