Exploration of mechanisms for the transformation of 8-hydroxy guanine radical to FAPyG by density functional theory.
The potential energy surface for the transformation of 8-hydroxy guanine radical to formamidopyrimidine adducts via four pathways has been mapped out using B3LYP density functional theory and the IEF-polarizable continuum model (PCM) solvation model. Results of the calculations are consistent with experimental studies indicating that numerous compounds may be formed during the oxidation and subsequent reduction of guanine, some of which can react over time to form the observed 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FAPyG) adduct. All four pathways begin with the 8-hydroxyguanine radical (8-OHGrad) species. Pathway 1 proceeds with reduction of the 8-OHGrad to a hemiaminal species, which undergoes ring opening to either FAPyG or 2,5-diamino-4-hydroxy-6-formamidopyrimidine (2,5FAPyG). Pathway 2 begins with a water-assisted proton transfer from the hydroxyl group of 8-OHGrad to form an 8-oxyguanine radical. This radical species can undergo ring opening and subsequent reduction to form either FAPyG or 2,5FAPyG. Pathways 3 and 4 lead to formation of only the FAPyG ring-opened adduct. Both begin with ring opening of 8-OHGrad to yield a formimidic acid radical, which can either be reduced to the formimidic acid and then undergo tautomerization to FAPyG (pathway 3) or initially tautomerize to form one of two FAPyG radicals before being reduced to FAPyG (pathway 4). Of the four possible reaction pathways explored, pathway 2 appears to be slightly lower in energy than pathway 4, which in turn is lower in energy than pathways 1 and 3. The calculations indicate that reactions proceeding via pathway 2 may yield a 2,5FAPyG adduct, which is thermodynamically less stable than the FAPyG adduct but may be formed at least initially. Interconversion of the two isomers is possible via a hemiaminal adduct. In the presence of water, it is energetically possible to form the FAPyG adduct from the formimidic acid, the hemiaminal, and the 2,5FAPyG adducts. Calculations at the B3LYP/6-31+G(d) level of theory suggest that it will be possible to differentiate between the different intermediate adducts using IR and NMR spectroscopy.
Munk
Barbara H
BH
Department of Chemistry, Wayne State University, Detroit, Michigan 48202, USA.
Burrows
Cynthia J
CJ
Schlegel
H Bernhard
HB
D002241:Carbohydrates / Q000737:chemistry; D004734:Energy Metabolism; D005609:Free Radicals / Q000737:chemistry; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry; D006859:Hydrogen / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011743:Pyrimidines / Q000737:chemistry*; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism; D013816:Thermodynamics
D002241:Carbohydrates; D005609:Free Radicals; D011743:Pyrimidines; C071023:2,6-diamino-4-hydroxy-5-formamidopyrimidine; C024829:8-hydroxyguanine; D006147:Guanine; D006859:Hydrogen