| Project/Area Number |
61490017
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
広領域
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| Research Institution | Kyoto University |
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Principal Investigator |
SUGIURA Yukio Institute for Chemical Pesearch Kyoto University Professor, 化学研究所, 教授 (40025698)
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| Project Period (FY) |
1986 – 1987
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| Project Status |
Completed (Fiscal Year 1987)
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| Budget Amount *help |
¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 1987: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1986: ¥3,600,000 (Direct Cost: ¥3,600,000)
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| Keywords | Bleomycin / DNA cleavage / Non-heme iron / Metal complex / 活性酸素 / ブレオマイシン金属錯体 / 塩基配列特異性 / DNA塩基認識 / 生物無機化学 |
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| Research Abstract |
The antitumor antibiotic bleomycin cleaves DNA in a reaction that is dependent on the presence of certain metal ions such as iron, manganese and vanadium. Bleomycin is a bifunctional compound consisting of the binding and attackng sites toward DNA. The <beta>-aminoalanine-pyrimidine-<beta>-hydroxyhistidine portion of bleomycin is essential for the metal chelation and dioxygen activation, and the bithiazole moiety contributes to the selective interaction with guanine base of DNA. The bleomycin-iron complexes with CO, NO and RCN were characterized by various spectroscopic methods. Of special interest is the fact that bleomycin-iron complex and porphyrin-iron complex are remarkably similar properties. The DNA cleavage by metallobleomycin occurs preferentiall at guanine-pyrimidine(5'->3') sequences, in particular GC site. In the modification of DNA by anthramycin which reacts covalently with the 2-amino group of guanine in the minor groove, the present result showed a drastic change of the sequence-specific cleavage mode by metallobleomycin. By contrast, the modification of guanine N-7 with aflatoxin B1 or dimethyl sulfate revealed no obvious alterations. These results support that metallobleomycin prefers the binding in the minor groove of B-DNA helix. In addition, the DNase I footprinting results showed that (1) the DNA binding site of metallobleomycin occupies approximately three base pairs involving 5'-XGC sequence and (2) the bleomycin-cobalt complex highly blocks the G base adjacent to 5'-side of the cleaved base. On the basis of these observations, we clarified stereochemical fit of metallobleomycin in d(ATGCCA)_2 by inspection of computerconstructed molecular model.
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