A Computational Foray into the Mechanism and Catalysis of the Adduct Formation Reaction of Guanine with Crotonaldehyde

Asja A. Kroeger, Amir Karton

Research output: Contribution to journalArticle

Abstract

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. (C) 2018 Wiley Periodicals, Inc.

Original languageEnglish
Pages (from-to)630-637
Number of pages8
JournalJournal of Computational Chemistry
Volume40
Issue number4
DOIs
Publication statusPublished - 5 Feb 2019

Cite this

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title = "A Computational Foray into the Mechanism and Catalysis of the Adduct Formation Reaction of Guanine with Crotonaldehyde",
abstract = "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. (C) 2018 Wiley Periodicals, Inc.",
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A Computational Foray into the Mechanism and Catalysis of the Adduct Formation Reaction of Guanine with Crotonaldehyde. / Kroeger, Asja A.; Karton, Amir.

In: Journal of Computational Chemistry, Vol. 40, No. 4, 05.02.2019, p. 630-637.

Research output: Contribution to journalArticle

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T1 - A Computational Foray into the Mechanism and Catalysis of the Adduct Formation Reaction of Guanine with Crotonaldehyde

AU - Kroeger, Asja A.

AU - Karton, Amir

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N2 - 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. (C) 2018 Wiley Periodicals, Inc.

AB - 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. (C) 2018 Wiley Periodicals, Inc.

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KW - LIPID-PEROXIDATION

KW - MICHAEL-ADDITION

KW - GENOTOXICITY

KW - ACROLEIN

KW - TAUTOMERIZATION

KW - THERMOCHEMISTRY

KW - MUTAGENICITY

KW - ACETALDEHYDE

KW - FUNCTIONALS

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