Absolute configurations and stability of cyclic guanosine mono‐adducts with glyoxal and methylglyoxal

Abstract

Glyoxal and methylglyoxal are two endogenous and mutagenic 1,2-dicarbonyl compounds, which can readily form adducts with guanosine. The molecular structures of cyclic guanosine-glyoxal (G-g) and guanosine-methylglyoxal (G-mg) mono-adducts have been extensively studied before. However, diastereoisomers of these adducts have not yet been studied in detail. In this work, one pair of G-g and two pairs of G-mg diastereoisomers were baseline separated by reverse phase HPLC, whose structures were identified as the previously reported cyclic forms, and their absolute configurations were determined by circular dichroism, the octant rule, and molecular modeling. According to the HPLC elution order, configurations of two G-g (as well as trans G-mg) were (6R,7R) and (6S,7S), respectively. Meanwhile, the stability of each isomer in neutral solution was also investigated, which revealed the stability order G-g > cis G-mg > trans G-mg and also indicated distinct transformation processes for different G-mg configurations. Trans G-mg only racemized between each other, while cis G-mg transformed to both cis and trans forms. Different intermediates in the racemization processes were proposed to explain the observations. These results may shed light on further understanding the roles of these two small molecules in mutagenesis.

The Butter Flavorant, Diacetyl, Forms a Covalent Adduct with 2-Deoxyguanosine, Uncoils DNA, and Leads to Cell Death

“…Structures of the reaction products of reactive dicarbonyls, such as glyoxal and methylglyoxal, have been unequivocally elucidated. 14 Our recent investigations have established that dehydroascorbic acid (DHA), another naturally occurring dicarbonyl, reacts with guanosine to form a cyclic adduct. 18 The presence of the 1,2-dicarbonyl motif in DA (Figure 1) makes it reasonable to speculate that its mutagenicity may arise from an interaction with a guanine nucleobase.…”

“…There is great interest in the ability of 1,2-dicarbonyl compounds to react with nucleobases, especially guanosine. Structures of the reaction products of reactive dicarbonyls, such as glyoxal and methylglyoxal, have been unequivocally elucidated . Our recent investigations have established that dehydroascorbic acid (DHA), another naturally occurring dicarbonyl, reacts with guanosine to form a cyclic adduct .…”

“…Information about the chronic toxic effects of DA is surprisingly sparse. The interaction of structurally analogous dicarbonyls such as methylglyoxal and glyoxal (Figure ) with guanosine has been studied in detail and the resulting adducts well-characterized. − Methylglyoxal is a documented mutagen at physiologically occurring concentrations, causing abnormal gene expression . Covalent modification of guanosine with cyclic adduct formation is a common characteristic of compounds carrying the 1,2-dicarbonyl motif, many of those compounds being nutritionally relevant.…”