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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.


Rotameric forms of the 4-OHE1-1-N7Gua estrogen-DNA adduct. (A) The α-isomer with purine ring system pointed away from the viewer; (B) The β-isomer with purine ring system pointed towards the viewer.
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metabolites-05-00475-f003: Rotameric forms of the 4-OHE1-1-N7Gua estrogen-DNA adduct. (A) The α-isomer with purine ring system pointed away from the viewer; (B) The β-isomer with purine ring system pointed towards the viewer.

Mentions: The known, final product of the proton assisted reaction of E1-3,4-Q with dG is the 4-OHE1-1-N7Gua estrogen-DNA adduct (Figure 2). NMR characterization of the 4-OHE1-1-N7Gua adduct revealed the presence of two diastereoisomers caused by rotational restriction of purine moiety about the C1(estrogen)-N7(guanine) bond [4]. These rotamers were labeled as α- and β-isomers consistent with estrogen nomenclature. The β-isomer has the purine moiety on the same side of the estrogen ring system has the 17-methyl group, the α-isomer has the purine moiety directed on the other side of the ring system (Figure 3). We have modeled two sets of tautomers 1 and 2 containing the A, B and C ring systems in both the α- and β-forms using high level density functional theory with all geometry optimization and SPE done in the presence of an aqueous system, M06-2X/QZVP//M06-2X/6-31 + G(d,p) level of theory.


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

Stack DE - Metabolites (2015)

Rotameric forms of the 4-OHE1-1-N7Gua estrogen-DNA adduct. (A) The α-isomer with purine ring system pointed away from the viewer; (B) The β-isomer with purine ring system pointed towards the viewer.
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Related In: Results  -  Collection

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

metabolites-05-00475-f003: Rotameric forms of the 4-OHE1-1-N7Gua estrogen-DNA adduct. (A) The α-isomer with purine ring system pointed away from the viewer; (B) The β-isomer with purine ring system pointed towards the viewer.
Mentions: The known, final product of the proton assisted reaction of E1-3,4-Q with dG is the 4-OHE1-1-N7Gua estrogen-DNA adduct (Figure 2). NMR characterization of the 4-OHE1-1-N7Gua adduct revealed the presence of two diastereoisomers caused by rotational restriction of purine moiety about the C1(estrogen)-N7(guanine) bond [4]. These rotamers were labeled as α- and β-isomers consistent with estrogen nomenclature. The β-isomer has the purine moiety on the same side of the estrogen ring system has the 17-methyl group, the α-isomer has the purine moiety directed on the other side of the ring system (Figure 3). We have modeled two sets of tautomers 1 and 2 containing the A, B and C ring systems in both the α- and β-forms using high level density functional theory with all geometry optimization and SPE done in the presence of an aqueous system, M06-2X/QZVP//M06-2X/6-31 + G(d,p) level of theory.

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.