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Properties of the binding of copper by bleomycin
Authors:Daniel Solaiman  Eswara A Rao  William Antholine  David H Petering
Institution:University of Wisconsin-Milwaukee Milwaukee U.S.A.
Abstract:The glycopeptide, bleomycin, binds metal ions including Cu2+. It is the copper complex of this material that is isolated from Streptomyces verticillus. Both free ligand and copper complex are excellent antitumor agents in animals. The biochemical and pharmacological relationship between these compounds has not been established. The present study begins an analysis of the chemistry and biochemistry of copper-bleomycin with structural and equilibrium properties of the complex. Potentiometric and fluorometric titrations of bleomycin confirm three acidic groups with pKa values of 7.50, 4.93, and 2.72. The conjugate nitrogen bases of these groups, comprise three of the binding sites for Cu2+ according to similar titrations of copper-bleomycin. The fourth is a conjugate base of an acid with a very large pKa that cannot be measured by these techniques. The participation of a fourth such group is inferred from both proton release studies of the binding of metal and ligand above pH 8 and from several studies of the thermodynamic stability of copper bleomycin. At low pH binding of copper to bleomycin occurs in two steps, as observed by several independent techniques which monitor either the metal or the ligand. Log stability constants for the reactions Cu2+ + HkBlm ? CuHk-nBlm + nH+ and CuHk-nBlm ? CuHk-n-rBlm + rH+ are 1.32 and ?4.31, respectively, with n of 2.21 in the first equation and r of 2.07 in the second equation. The derived logarithm of the pH independent stability constant for copper bleomycin multiplied by the protonation constant for the unknown fourth ligand in the binding site is 12.16. This agrees closely with values obtained from measurements of conditional formation constants. One of the groups which binds in the second reaction is the substituted pyrimidine.
Keywords:Address reprint requests to: David H  Petering  Department of Chemistry and the Laboratory for Molecular Biomedical Research (Contribution 110)  University of Wisconsin-Milwaukee  Milwaukee  WI 53201
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