Identification of adducts formed by reaction of guanine nucleosides with malondialdehyde and structurally related aldehydes

Abstract

Malondialdehyde and a series of acrolein derivatives substituted in the beta-position with good leaving groups react with guanine and guanine nucleosides to form two different types of adducts. The reaction with guanosine is typical. One adduct exhibits ultraviolet absorbance maxima at 253, 319, and 348 nm and is fluorescent. Its NMR spectrum exhibits three new aromatic proton resonances derived from malondialdehyde. The mass spectrum exhibits an M + 1 at 320. The spectroscopic properties are consistent with the structure, 3-beta-D-erythro-pentofuranosyl-pyrimido[1,2-alpha]purin-10(3H)-one (PyP-ribose). The second guanosine adduct is an equal mixture of diastereomers that exhibit ultraviolet maxima at 217 and 244 nm and mirror image circular dichroism spectra. The NMR spectrum and mass spectrum (M + 1 = 392) indicate the addition of two molecules of MDA to one molecule of guanosine. Two-dimensional NMR (COSY) analysis reveals the presence of propano and enal functionalities. The spectroscopic and chemical properties suggest an oxadiazabicyclo[3.3.1]nonene structure that is confirmed by X-ray crystallography. Comparison of the deoxyguanosine adducts of malondialdehyde to those of the structurally related carbonyl compounds, methyl glyoxal and acrolein, provides a structural basis to explain the unique ability of malondialdehyde to induce frameshift mutations in bacterial mutagenesis systems.

Transitional Cell Hyperplasia and Carcinomas in Urinary Bladders of Transgenic Mice with Keratin 5 Promoter-Driven Cyclooxygenase-2 Overexpression

“…Malondialdehyde is generated from the peroxidation of membrane phospholipids (35) and is also produced as a by-product of prostaglandin synthesis (36). Malondialdehyde has been shown to react with DNA to form adducts (37) and to be mutagenic (38). Another DNA lesion that occurs as a result of oxidative stress is 8-hydroxydeoxyguanosine.…”

Neurotoxicity and Metabolism of the Catecholamine-Derived 3,4-Dihydroxyphenylacetaldehyde and 3,4-Dihydroxyphenylglycolaldehyde: The Role of Aldehyde Dehydrogenase

“…Aldehydes readily form adducts with glutathione (GSH) (Esterbauer et al, 1975), nucleic acids (Basu et al, 1988), and protein amino acids (Nadkarni and Sayre, 1995). Furthermore, the ability of aldehydes TOXICITY AND METABOLISM OF DOPAL AND DOPEGAL: ROLE OF ALDH to cross-link proteins and DNA and to even form DNAprotein cross-links (through various adduction mechanisms) has been reported (Nair et al, 1986;Brooks and Theruvathu, 2005).…”

Metabolism and Elimination of the Endogenous DNA Adduct, 3-(2-Deoxy-β-D-erythropentofuranosyl)-pyrimido[1,2-α]purine-10(3H)-one, in the Rat

“…3-(2-Deoxy-␤-D-erythropentofuranosyl)-pyrimido[1,2-␣]purine-10(3H)-one (M 1 dG) 3 is an endogenous pyrimidopurinone adduct formed by reacting deoxyguanosine with malondialdehyde, a product of enzymatic and nonenzymatic lipid peroxidation reactions, or base propenal, a DNA peroxidation product (5)(6)(7)(8)(9)(10)(11). This adduct is mutagenic in bacteria and mammalian cells (12)(13)(14)(15) and is a substrate for nucleotide excision repair (13,16).…”