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. © 2018 Wiley Periodicals, Inc.

Self‐catalyzed keto‐enol tautomerization of malonic acid

“…A further mechanism for keto‐enol tautomerizations is available, involving concerted movement of two protons between the substrate and an acid catalyst molecule, such as formic acid. Further studies have shown that acid catalyzed double hydrogen atom transfer reactions occur in a wide variety of situations, including other tautomerizations, decomposition and bimolecular reactions, and in keto‐enol tautomerizations of dimer complexes . Furthermore, this mechanism may also play a role in the isomerization of free radicals, in the hydration of SO 3 , and in the hydrolysis of carbonyl compounds in the atmosphere, as well as in the unimolecular rearrangement of oxygenated volatile organic compounds …”