Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1979 Nov;76(11):5616–5620. doi: 10.1073/pnas.76.11.5616

Structural studies of of "active complex" of bleomycin: assignment of ligands to the ferrous ion in a ferrous-bleomycin-carbon monoxide complex.

N J Oppenheimer, L O Rodriguez, S M Hecht
PMCID: PMC411700  PMID: 93279

Abstract

Proton NMR studies at 360 MHz establish the binary Fe(II)-bleomycin complex to be paramagnetic with a spectrum covering 70 ppm. Addition of carbon monoxide generates a stable, diamagnetic Fe(II)-bleomycin-CO complex that is a putative structural analog of the "active" Fe(II)-bleomycin-O2 complex. The following six groups have been determined to be coordinated to the Fe(II) ion from analysis of the highly resolved 1H NMR spectra of this complex: CO, the primary and secondary amine nitrogens of the beta-aminoalanine moiety, the carbamoyl moiety on the 3-position of mannose, the pyrimidine N-1, and the imidazole N-1. The Fe(II)-bleomycin-CO complex binds to DNA, as shown by fluorescence quenching experiments, but Fe(II)-bleomycin-CO does not mediate thymine release. These results necessitate a major revision in the current model for metal coordination to bleomycin.

Full text

PDF
5616

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Cass A. E., Galdes A., Hill A. O., McClelland C. E. The binding of zinc(II) to bleomycin: an investigation using 1H NMR spectroscopy. FEBS Lett. 1978 May 15;89(2):187–190. doi: 10.1016/0014-5793(78)80214-2. [DOI] [PubMed] [Google Scholar]
  2. D'Andrea A. D., Haseltine W. A. Sequence specific cleavage of DNA by the antitumor antibiotics neocarzinostatin and bleomycin. Proc Natl Acad Sci U S A. 1978 Aug;75(8):3608–3612. doi: 10.1073/pnas.75.8.3608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Dabrowiak J. C., Greenaway F. T., Grulich R. Transition-metal binding site of bleomycin A2. A carbon-13 nuclear magnetic resonance study of the zinc(II) and copper(II) derivatives. Biochemistry. 1978 Sep 19;17(19):4090–4096. doi: 10.1021/bi00612a034. [DOI] [PubMed] [Google Scholar]
  4. Dabrowiak J. C., Greenaway F. T., Longo W. E., Van Husen M., Crooke S. T. A spectroscopic investigation of the metal binding site of bleomycin A2. The Cu(II) and Zn(II) derivatives. Biochim Biophys Acta. 1978 Feb 16;517(2):517–526. doi: 10.1016/0005-2787(78)90218-6. [DOI] [PubMed] [Google Scholar]
  5. Espejo R. T., Canelo E. S. Properties of bacteriophage PM2: a lipid-containing bacterial virus. Virology. 1968 Apr;34(4):738–747. doi: 10.1016/0042-6822(68)90094-9. [DOI] [PubMed] [Google Scholar]
  6. Gupta R. K., Redfield A. G. Double nuclear magnetic resonance observation of electron exchange between ferri- and ferrocytochrome c. Science. 1970 Sep 18;169(3951):1204–1206. doi: 10.1126/science.169.3951.1204. [DOI] [PubMed] [Google Scholar]
  7. Iitaka Y., Nakamura H., Nakatani T., Muraoka Y., Fujii A., Takita T., Umezawa H. Chemistry of bleomycin. XX. The X-ray structure determination of P-3A Cu(II)-complex a biosynthetic intermediate of bleomycin. J Antibiot (Tokyo) 1978 Oct;31(10):1070–1072. doi: 10.7164/antibiotics.31.1070. [DOI] [PubMed] [Google Scholar]
  8. Lown J. W., Sim S. K. The mechanism of the bleomycin-induced cleavage of DNA. Biochem Biophys Res Commun. 1977 Aug 22;77(4):1150–1157. doi: 10.1016/s0006-291x(77)80099-5. [DOI] [PubMed] [Google Scholar]
  9. Müller W. E., Yamazaki Z., Breter H. J., Zahn R. K. Action of bleomycin on DNA and RNA. Eur J Biochem. 1972 Dec 18;31(3):518–525. doi: 10.1111/j.1432-1033.1972.tb02560.x. [DOI] [PubMed] [Google Scholar]
  10. Nakayama Y., Kunishima M., Omoto S., Takita T., Umezawa H. Letter: Chemistry of bleomycin. XII. Iso-bleomycin A2, product of carbamoyl group migration. J Antibiot (Tokyo) 1973 Jul;26(7):400–402. [PubMed] [Google Scholar]
  11. Oppenheimer N. J., Rodriguez L. O., Hecht S. M. Proton nuclear magnetic resonance study of the structure of bleomycin and the zinc-bleomycin complex. Biochemistry. 1979 Aug 7;18(16):3439–3445. doi: 10.1021/bi00583a001. [DOI] [PubMed] [Google Scholar]
  12. Sausville E. A., Peisach J., Horwitz S. B. A role for ferrous ion and oxygen in the degradation of DNA by bleomycin. Biochem Biophys Res Commun. 1976 Dec 6;73(3):814–822. doi: 10.1016/0006-291x(76)90882-2. [DOI] [PubMed] [Google Scholar]
  13. Sausville E. A., Peisach J., Horwitz S. B. Effect of chelating agents and metal ions on the degradation of DNA by bleomycin. Biochemistry. 1978 Jul 11;17(14):2740–2746. doi: 10.1021/bi00607a007. [DOI] [PubMed] [Google Scholar]
  14. Sugiura Y., Kikuchi T. Formation of superoxide and hydroxy radicals in iron(II)-bleomycin-oxygen system: electron spin resonance detection by spin trapping. J Antibiot (Tokyo) 1978 Dec;31(12):1310–1312. doi: 10.7164/antibiotics.31.1310. [DOI] [PubMed] [Google Scholar]
  15. Sugiura Y. Metal coordination core of bleomycin : comparison of metal complexes between bleomycin and its biosynthetic intermediate. Biochem Biophys Res Commun. 1979 Mar 30;87(2):643–648. doi: 10.1016/0006-291x(79)91842-4. [DOI] [PubMed] [Google Scholar]
  16. Takita T., Muraoka Y., Nakatani T., Fujii A., Iitaka Y., Umezawa H. Chemistry of bleomycin. XXI. Metal-complex of bleomycin and its implication for the mechanism of bleomycin action. J Antibiot (Tokyo) 1978 Oct;31(10):1073–1077. doi: 10.7164/antibiotics.31.1073. [DOI] [PubMed] [Google Scholar]
  17. Umezawa H., Maeda K., Takeuchi T., Okami Y. New antibiotics, bleomycin A and B. J Antibiot (Tokyo) 1966 Sep;19(5):200–209. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES