EPR spectroscopic investigation of the lability of oxygen in activated bleomycin: implications for the mechanism of bleomycin-mediated DNA degradation.
EPR spectroscopic investigation of the lability of oxygen in activated bleomycin: implications for the mechanism of bleomycin-mediated DNA degradation.
复制标题
活化博莱霉素中氧不稳定性的 EPR 光谱研究：对博莱霉素介导的 DNA 降解机制的影响。
DOI：
10.1021/bi00057a012
复制
发表时间：
1993
期刊：
影响因子：
2.9
通讯作者：
Peisach,J
中科院分区：
文献类型：
--
作者：
Sam,JW;Peisach,J
Revised Manuscript Received November 30, 1992 abstract: Bleomycin (BLM), an antitumor antibiotic, is capable of degrading DN A through the formation of activated BLM, an activated irom-oxygen complex of the drug with a unique EPR spectrum. A recent study [Rabow, L. E., McGall, G. H., Stubbe, J., & Kozarich, J. W.(1990) J. Am. Chem. Soc. 112, 3203-3208] has cast doubt onto the “hydroxyl-radical-rebound” mechanism, commonly accepted for cytochrome P-450 [McMurray, T. J., & Groves, J. T.(1985) in Cytochrome P-450: Structure, Mechanism, and Biochemistry (Ortiz de Montellano, P., Ed.) pp 1-28, Plenum, New York] and proposed for the anaerobic nucleic base release reaction of BLM, by demonstrating that the source of oxygen in the products of this reaction is solvent molecules and not molecular oxygen. A centra] issue in this debate is whethef the oxygen of activated BLM is available for exchange with that of solvent. The lability of oxygen in activated BLM has been investigated through the use of EPR spectroscopy to measure the exchange of 170 (7= 5/2) between activated BLM and solvent. Evidence for the lack ofoxygen exchange between activated BLM and solvent is presented, and the implications of this result for the mechanism of BLM-mediated DNA degradation are discussed.The bleomycins (BLM) constitute a family of glycopeptide antibiotics originally isolated in 1966 from Streptomyces verticillus (Umezawa et al., 1966). Currently, BLM is an important member of our chemotherapeutic armamentarium. The drug is known to bind varioustransitionmetal ions, and when complexed with Fe, Cu, or Co, it is capable of activating oxygen and cleaving DNA [for recent reviews, see Stubbe and Kozarich (1987) and Petering et al., 1990)]. At present, the best understood metal-BLM'complex is that with iron. Studies of Fe-BLM and the mechanism through which oxygen is activated and DNA is degraded has receivedmuch attention due to the usefulness of BLM not only as an antineoplastic agent but also as a model for non-heme iron-mediated oxygen activation.
