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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.


Possible mechanistic routes in the reaction of E1-3,4-Q (both deuterium labeled and unlabeled) with dG to form the estrogen-DNA adduct 4-OHE1-1-N7Gua.
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metabolites-05-00475-f002: Possible mechanistic routes in the reaction of E1-3,4-Q (both deuterium labeled and unlabeled) with dG to form the estrogen-DNA adduct 4-OHE1-1-N7Gua.

Mentions: We have use the in vitro reaction of E-3,4-Q with deoxyguanosine (dG) as a platform to investigate the mechanism and intermediates form during the production of estrogen-DNA adducts. Earlier worked demonstrated that reaction proceed through an intermediate that decomposes in a unimolecular fashion to the final 4-OHE-1-N7Gua depurinated adduct (Figure 2) [16]. It was shown that a proton assisted Michael addition leads to an intermediate that still contains the ribose moiety. This intermediate then converts to the final product by glycosidic bond cleavage.


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

Stack DE - Metabolites (2015)

Possible mechanistic routes in the reaction of E1-3,4-Q (both deuterium labeled and unlabeled) with dG to form the estrogen-DNA adduct 4-OHE1-1-N7Gua.
© Copyright Policy
Related In: Results  -  Collection

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

metabolites-05-00475-f002: Possible mechanistic routes in the reaction of E1-3,4-Q (both deuterium labeled and unlabeled) with dG to form the estrogen-DNA adduct 4-OHE1-1-N7Gua.
Mentions: We have use the in vitro reaction of E-3,4-Q with deoxyguanosine (dG) as a platform to investigate the mechanism and intermediates form during the production of estrogen-DNA adducts. Earlier worked demonstrated that reaction proceed through an intermediate that decomposes in a unimolecular fashion to the final 4-OHE-1-N7Gua depurinated adduct (Figure 2) [16]. It was shown that a proton assisted Michael addition leads to an intermediate that still contains the ribose moiety. This intermediate then converts to the final product by glycosidic bond cleavage.

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.