title: Pyrimido[1,2-alpha]purin-10(3H)-one: a reactive electrophile in the genome.
abstract: 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.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: N
authors.initials: N
authors.lastname: Schnetz-Boutaud
authors.forename: J S
authors.initials: JS
authors.lastname: Daniels
authors.forename: M F
authors.initials: MF
authors.lastname: Hashim
authors.forename: P
authors.initials: P
authors.lastname: Scholl
authors.forename: T
authors.initials: T
authors.lastname: Burrus
authors.forename: L J
authors.initials: LJ
authors.lastname: Marnett
mesh_terms: D018736:DNA Adducts / Q000138:chemical synthesis* / Q000494:pharmacology; D016678:Genome; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006898:Hydroxylamines / Q000737:chemistry; D007553:Isotope Labeling; D008315:Malondialdehyde / Q000737:chemistry; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry; D010761:Phosphorus Radioisotopes; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet
chemical_list: D018736:DNA Adducts; D006898:Hydroxylamines; D009841:Oligonucleotides; D010761:Phosphorus Radioisotopes; D011687:Purines; D011743:Pyrimidines; C107643:pyrimido(1,2-a)purin-10(3H)-one; D008315:Malondialdehyde