Mechanism of two-electron oxidation of deoxyguanosine 5'-monophosphate by a platinum(IV) complex.
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.
Choi
Sunhee
S
Department of Chemistry and Biochemistry, Middlebury College, Middlebury, Vermont 05753, USA. choi@middlebury.edu
Cooley
Richard B
RB
Hakemian
Amanda S
AS
Larrabee
Yuna C
YC
Bunt
Richard C
RC
Maupas
Stéphane D
SD
Muller
James G
JG
Burrows
Cynthia J
CJ
D003848:Deoxyguanine Nucleotides / Q000737:chemistry* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology; D010084:Oxidation-Reduction; D021241:Spectrometry, Mass, Electrospray Ionization
D003848:Deoxyguanine Nucleotides; D009944:Organoplatinum Compounds; C484372:trans-d,l-1,2-diaminocyclohexanetetrachloroplatinum; C007257:2'-deoxyguanosine 5'-phosphate