On the role of the bithiazole moiety in sequence-selective DNA cleavage by Fe.bleomycin

A recent study of Fe(II).bleomycin-mediated DNA strand scission suggested that the metal binding domain of the drug is also the primary determinant of the observed sequence selectivity of strand scission (Carter, B. J., Murty, V. S., Reddy, K. S., Wang, S.-N., and Hecht, S. M. (1990) J. Biol. Chem....

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Bibliographic Details
Published in:The Journal of biological chemistry 1994-04, Vol.269 (14), p.10899-10904
Main Authors: KANE, S. A, NATRAJAN, A, HECHT, S. M
Format: Article
Language:English
Subjects:
Antibiotics. Antiinfectious agents. Antiparasitic agents
Binding Sites
Biological and medical sciences
Bleomycin - chemistry
Bleomycin - pharmacology
Carbohydrate Sequence
DNA - drug effects
Edetic Acid
Hydrolysis
Medical sciences
Miscellaneous. Antibiotics with multiple activities
Molecular Sequence Data
Pharmacology. Drug treatments
Thiazoles - analysis
Thiazoles - pharmacology
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Summary:A recent study of Fe(II).bleomycin-mediated DNA strand scission suggested that the metal binding domain of the drug is also the primary determinant of the observed sequence selectivity of strand scission (Carter, B. J., Murty, V. S., Reddy, K. S., Wang, S.-N., and Hecht, S. M. (1990) J. Biol. Chem. 265, 4193-4196). Although it is well established that the bithiazole moiety+C-terminal substituent of bleomycin are required for DNA binding, the role of the bithiazole in sequence-selective DNA recognition remains unclear. To determine whether the bithiazole moiety exhibits an intrinsic DNA binding selectivity, three synthetic EDTA-conjugated bithiazole derivatives were used to mediate DNA cleavage in the presence of Fe2+ and dithiothreitol. Incubation of these Fe(II).EDTA-bithiazoles in the presence of a 5'-32P end-labeled DNA duplex resulted in strand scission at every position to essentially the same extent. The relative cleavage efficiencies among the bithiazoles were a strong function of their ionic state. These findings imply that the bithiazoles can bind to many sites on the DNA; they support a model of bleomycin-DNA interaction in which the bithiazole moiety+C-terminal substituent are required only for DNA binding, whereas the metal binding domain is responsible for metal ion coordination and oxygen activation as well as being the primary determinant of sequence-selective DNA cleavage.
ISSN:0021-9258
1083-351X
DOI:10.1016/s0021-9258(17)34143-1