A computational foray into the mechanism and catalysis of the adduct formation reaction of guanine with crotonaldehyde
© 2018 Wiley Periodicals, Inc.
| Veröffentlicht in: | Journal of computational chemistry. - 1984. - 40(2019), 4 vom: 05. Feb., Seite 630-637 |
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| Format: | Online-Aufsatz |
| Sprache: | English |
| Veröffentlicht: |
2019
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| Zugriff auf das übergeordnete Werk: | Journal of computational chemistry |
| Schlagworte: | Journal Article Research Support, Non-U.S. Gov't DNA damage Michael addition water catalysis Aldehydes DNA Adducts Guanine 5Z93L87A1R 2-butenal |
| Zusammenfassung: | © 2018 Wiley Periodicals, Inc. Crotonaldehyde, a common environmental pollutant and product of endogenous lipid peroxidation, reacts with guanine to form DNA adducts with pronounced genotoxicity and mutagenicity. Here, we explore the molecular mechanism of this adduct formation using double-hybrid density functional theory methods. The reaction can be envisaged to occur in a two-step fashion via an aza-Michael addition leading to an intermediate ring-open adduct followed by a cyclization reaction giving the mutagenic ring-closed adduct. We find that (i) a 1,2-type addition is favored over a 1,4-type addition for the aza-Michael addition, and (ii) an initial tautomerization of the guanine moiety in the resulting ring-open adduct significantly reduces the barrier toward cyclization compared to the direct cyclization of the ring-open adduct in its keto-form. Overall, the aza-Michael addition is found to be rate-determining. We further find that participation of a catalytic water molecule significantly reduces the energy barriers of both the addition and cyclization reaction. © 2018 Wiley Periodicals, Inc |
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| Beschreibung: | Date Completed 26.05.2020 Date Revised 26.05.2020 published: Print-Electronic Citation Status MEDLINE |
| ISSN: | 1096-987X |
| DOI: | 10.1002/jcc.25595 |