Effect of complex formation between Zn2+ ions and the anticancer drug mithramycin upon enzymatic activity of zinc(II)-dependent alcohol dehydrogenase

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Abstract
Mithramycin (MTR), a member of the aureolic group of anticancer antibiotics, is a drug that supposedly acts via the inhibition of transcription. It binds to bivalent cations such as Mg2+ and Zn2+. In this paper, we report the association of MTR with Zn2+, a biologically important bivalent cation whose coordination property leads to its important role as a cofactor in different enzymes and nucleosomal DNA-binding proteins. First, we have characterized the complex formation between MTR and Zn2+ using spectroscopic methods. In the second part, we have examined the effect of the association of Zn2+ with MTR on the enzymatic activity of a typical zinc(II)-dependent alcohol dehydrogenase (ADH) from yeast. Our data show that MTR forms a single complex with Zn2+ in a mole ratio of 2:1 in terms of MTR:Zn2+. We also observe a negative effect for the preincubation of ADH with MTR upon the enzymatic activity. These results indicate that MTR induced structural changes in the enzyme as a sequel to its complex formation with Zn2+ present in the enzyme, thereby leading to a loss of enzymatic activity.

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