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

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 Mg(2+) and Zn(2+). In this paper, we report the association of MTR with Zn(2+), 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 Zn(2+) using spectroscopic methods. In the second part, we have examined the effect of the association of Zn(2+) 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 Zn(2+) in a mole ratio of 2:1 in terms of MTR:Zn(2+). 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 Zn(2+) present in the enzyme, thereby leading to a loss of enzymatic activity.