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Identifying the Tautomeric Form of a Deoxyguanosine-Estrogen Quinone Intermediate.

Stack DE - Metabolites (2015)

Bottom Line: This tautomeric form was further verified by use of deuterium labelling of the catechol precursor use to form the estrogen o-quinone.HPLC-MS analysis indicates a reactive intermediate with a m/z of 552.22 consistent with a tautomeric form containing no deuterium.This intermediate is consistent with a reaction mechanism that involves: (1) proton assisted Michael addition; (2) re-aromatization of the estrogen A ring; and (3) glycosidic bond cleavage to form the known estrogen-DNA adduct, 4-OHE₁-1-N7Gua.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Nebraska at Omaha, 6001 Dodge Street, Omaha, NE 68182, USA. dstack@unomaha.edu.

ABSTRACT
Mechanistic insights into the reaction of an estrogen o-quinone with deoxyguanosine has been further investigated using high level density functional calculations in addition to the use of 4-hyroxycatecholestrone (4-OHE₁) regioselectivity labeled with deuterium at the C1-position. Calculations using the M06-2X functional with large basis sets indicate the tautomeric form of an estrogen-DNA adduct present when glycosidic bonds cleavage occurs is comprised of an aromatic A ring structure. This tautomeric form was further verified by use of deuterium labelling of the catechol precursor use to form the estrogen o-quinone. Regioselective deuterium labelling at the C1-position of the estrogen A ring allows discrimination between two tautomeric forms of a reaction intermediate either of which could be present during glycosidic bond cleavage. HPLC-MS analysis indicates a reactive intermediate with a m/z of 552.22 consistent with a tautomeric form containing no deuterium. This intermediate is consistent with a reaction mechanism that involves: (1) proton assisted Michael addition; (2) re-aromatization of the estrogen A ring; and (3) glycosidic bond cleavage to form the known estrogen-DNA adduct, 4-OHE₁-1-N7Gua.

No MeSH data available.


Relaxed potential energy scan of increasing N7-C1' bond length for the T-2m and T-1m tautomers, HF/MIDI! theory (PCM = water).
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metabolites-05-00475-f006: Relaxed potential energy scan of increasing N7-C1' bond length for the T-2m and T-1m tautomers, HF/MIDI! theory (PCM = water).

Mentions: Using the structures of T-2mα and T-1mα as a starting geometries, a scan of the potential energy surface with respect to the N7-C1' bond was undertaken to see if the calculated value for this bond dissociation energy matched the experimental ΔG‡ of 26.8 kcal/mol for either tautomer. Figure 6 shows the results of scanning the N7-C1' bond length 3.0 angstroms in 0.3 angstrom increments. These relaxed scans were done at the HF/MIDI! level of theory modelled in an aqueous environment. The results show an increase of energy to just above 25 kcal/mol and 27 kcal/mol for the T-2mα and T-1mα tautomers, respectively. Both values are close to the experimental ΔG‡ value.


Identifying the Tautomeric Form of a Deoxyguanosine-Estrogen Quinone Intermediate.

Stack DE - Metabolites (2015)

Relaxed potential energy scan of increasing N7-C1' bond length for the T-2m and T-1m tautomers, HF/MIDI! theory (PCM = water).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588807&req=5

metabolites-05-00475-f006: Relaxed potential energy scan of increasing N7-C1' bond length for the T-2m and T-1m tautomers, HF/MIDI! theory (PCM = water).
Mentions: Using the structures of T-2mα and T-1mα as a starting geometries, a scan of the potential energy surface with respect to the N7-C1' bond was undertaken to see if the calculated value for this bond dissociation energy matched the experimental ΔG‡ of 26.8 kcal/mol for either tautomer. Figure 6 shows the results of scanning the N7-C1' bond length 3.0 angstroms in 0.3 angstrom increments. These relaxed scans were done at the HF/MIDI! level of theory modelled in an aqueous environment. The results show an increase of energy to just above 25 kcal/mol and 27 kcal/mol for the T-2mα and T-1mα tautomers, respectively. Both values are close to the experimental ΔG‡ value.

Bottom Line: This tautomeric form was further verified by use of deuterium labelling of the catechol precursor use to form the estrogen o-quinone.HPLC-MS analysis indicates a reactive intermediate with a m/z of 552.22 consistent with a tautomeric form containing no deuterium.This intermediate is consistent with a reaction mechanism that involves: (1) proton assisted Michael addition; (2) re-aromatization of the estrogen A ring; and (3) glycosidic bond cleavage to form the known estrogen-DNA adduct, 4-OHE₁-1-N7Gua.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Nebraska at Omaha, 6001 Dodge Street, Omaha, NE 68182, USA. dstack@unomaha.edu.

ABSTRACT
Mechanistic insights into the reaction of an estrogen o-quinone with deoxyguanosine has been further investigated using high level density functional calculations in addition to the use of 4-hyroxycatecholestrone (4-OHE₁) regioselectivity labeled with deuterium at the C1-position. Calculations using the M06-2X functional with large basis sets indicate the tautomeric form of an estrogen-DNA adduct present when glycosidic bonds cleavage occurs is comprised of an aromatic A ring structure. This tautomeric form was further verified by use of deuterium labelling of the catechol precursor use to form the estrogen o-quinone. Regioselective deuterium labelling at the C1-position of the estrogen A ring allows discrimination between two tautomeric forms of a reaction intermediate either of which could be present during glycosidic bond cleavage. HPLC-MS analysis indicates a reactive intermediate with a m/z of 552.22 consistent with a tautomeric form containing no deuterium. This intermediate is consistent with a reaction mechanism that involves: (1) proton assisted Michael addition; (2) re-aromatization of the estrogen A ring; and (3) glycosidic bond cleavage to form the known estrogen-DNA adduct, 4-OHE₁-1-N7Gua.

No MeSH data available.