Pyrimido[1,2-alpha]purin-10(3H)-one: a reactive electrophile in the genome.

Schnetz-Boutaud N, Daniels JS, Hashim MF, Scholl P, Burrus T, Marnett LJ
Chem Res Toxicol. 2000 13 (10): 967-70

PMID: 11080044 · DOI:10.1021/tx000135i

Malondialdehyde and base propenal react with deoxyguanosine residues in DNA to form an exocyclic adduct, pyrimido[1, 2-alpha]purin-10(3H)-one (1), that has been detected at high levels in genomic DNA of healthy humans. Previous studies have shown that tris(hydroxymethyl)aminomethane adds to 1 at elevated pH, forming an enaminoimine (2), but it is uncertain whether 1 reacts directly or hydrolyzes under basic conditions to N(2)-(3-oxo-1-propenyl)deoxyguanosine (3) prior to amine addition. We report that 1 reacts at neutral pH with hydroxylamines to form oximes. The rate of reaction of 1 with hydroxylamines at pH 7 is at least 150 times faster than the rate of hydrolysis of 1 to 3. Thus, 1 is directly reactive to nucleophiles. These observations indicate that 1 is an electrophile in the human genome that may react with cellular nucleophiles to form novel cross-linked adducts.

MeSH Terms (12)

DNA Adducts Genome Humans Hydrogen-Ion Concentration Hydroxylamines Isotope Labeling Malondialdehyde Oligonucleotides Phosphorus Radioisotopes Purines Pyrimidines Spectrophotometry, Ultraviolet

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