An exploration of mechanisms for the transformation of 8-oxoguanine to guanidinohydantoin and spiroiminodihydantoin by density functional theory.
The potential energy surface for formation of 2-amino-5-hydroxy-7,9-dihydropurine-6,8-dione (5-OH-OG), guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp) from 8-oxoguanine (8-oxoG) has been mapped out using B3LYP density functional theory, the aug-cc-pVTZ and 6-31+G(d,p) basis sets and the IEF-polarizable continuum model (PCM) solvation model. Three pathways for formation of 5-OH-OG from 8-oxoG were evaluated: (A) stepwise loss of two electrons and two protons to form the quinonoid intermediate 2-amino-7,9-dihydro-purine-6,8-dione (8-oxoG(ox)) followed by hydration; (B) stepwise loss of two electrons and one proton and net addition of hydroxide, in which the key step is nucleophilic addition to the 8-oxoG radical cation; and (C) stepwise loss of one electron and one proton and addition of hydroxyl radical to the 8-oxoG radical cation. The data suggest that all three pathways are energetically feasible mechanisms for the formation of 5-OH-OG, however, Pathway A may be kinetically favored over Pathway B. Although lower in energy, Pathway C may be of limited biological significance since it depends on the local concentration of hydroxyl radical. Pathways for hydrolysis and decarboxylation of 5-OH-OG to form Gh via either a carboxylic acid or substituted carbamic acid intermediate have been evaluated with the result that cleavage of the N1-C6 bond is clearly favored over that of the C5-C6 bond. Formation of Sp from 5-OH-OG via stepwise proton transfer and acyl migration or ring opening followed by proton transfer and ring closure have also been explored and suggest that deprotonation of the hydroxyl group facilitates a 1,2 acyl shift. Results of the calculations are consistent with experimental studies showing dependence of the Gh/Sp product ratio on pH. Under neutral and basic conditions, the data predict that formation of Sp is kinetically favored over the pathways for formation of Gh. Under acidic conditions, Gh is predicted to be the kinetically favored product.
Munk
Barbara H
BH
Department of Chemistry, Wayne State University, Detroit, Michigan 48202, USA.
Burrows
Cynthia J
CJ
Schlegel
H Bernhard
HB
D006146:Guanidines / Q000737:chemistry*; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D006827:Hydantoins / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D044367:Phase Transition; D012996:Solutions; D013141:Spiro Compounds / Q000737:chemistry*; D014867:Water / Q000737:chemistry
D006146:Guanidines; D006827:Hydantoins; D012996:Solutions; D013141:Spiro Compounds; C467338:guanidinohydantoin; C408822:spiroiminodihydantoin; D014867:Water; D006151:Guanosine; C024829:8-hydroxyguanine; D006147:Guanine