Bleomycin-induced strand-scission of DNA. Mechanism of deoxyribose cleavage.

作者：L. Giloni, Masaru Takeshita, Francis Johnson, Charles R. Iden, Arthur P. Grollman · 发表于：Journal of Biological Chemistry · 年份：1981 · DOI：10.1016/s0021-9258(19)68888-5 · 被引用次数：413 · 研究领域：DNA and Nucleic Acid Chemistry、Metal complexes synthesis and properties、DNA Repair Mechanisms

The bleomycins, a family of glycopeptides with antineoplastic activity, bind to DNA and cause strand-scission in a reaction requiring Fe(I1) and oxygen.Strandscission is accompanied by the simultaneous release of free bases and four low molecular weight compounds that react with 2-thiobarbituric acid to form chromophores absorbing maximally at 532 nm.The structure of these four products was elucidated as follows: formic acid hydrolysis released thymine, cytosine, adenine, and guanine, respectively; treatment of each compound with phenylhydrazine yielded 1-phenylpyrazole.The adenine-containing compound was reduced with sodium borohydride and the trimethylsilyl derivative was prepared.High resolution mass spectrometry of this derivative revealed silylated 3-(adenin-B'-y1)-2-propen-1-01, consistent with formulation of the original compound as 3-(adenin-9'-~1)-2-propenal.The reaction product containing thymine was similarly shown to be 3-(thymin-l'-yl)-2-propenal.The 3-substituted propenal structures proposed were confirmed by chemical synthesis.Oligonucleotides, produced by bleomycin-induced strand-scission, were found to contain glycolic acid residues esterified through the hydroxyl group to the 3'-phosphate termini.We conclude that the primary reaction products resulting from bleomycin-induced strand-scission of DNA have a common structure: Base-CH=CH-CHO.These observations are consistent with a reaction mechanism initiated by free radical abstraction of the C-4' proton of deo...