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 language | English |
|---|---|
| Pages (from-to) | 630-637 |
| Number of pages | 8 |
| Journal | Journal of Computational Chemistry |
| Volume | 40 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 5 Feb 2019 |
Cite this
}
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 journal › Article
TY - JOUR
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
PY - 2019/2/5
Y1 - 2019/2/5
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.
KW - DNA damage
KW - water catalysis
KW - Michael addition
KW - INDUCED DNA-DAMAGE
KW - LIPID-PEROXIDATION
KW - MICHAEL-ADDITION
KW - GENOTOXICITY
KW - ACROLEIN
KW - TAUTOMERIZATION
KW - THERMOCHEMISTRY
KW - MUTAGENICITY
KW - ACETALDEHYDE
KW - FUNCTIONALS
U2 - 10.1002/jcc.25595
DO - 10.1002/jcc.25595
M3 - Article
VL - 40
SP - 630
EP - 637
JO - Journal of Computational Chemistry
JF - Journal of Computational Chemistry
SN - 0192-8651
IS - 4
ER -