NMR Study of the Effects of Some Bleomycin C-termini on the Structure of a DNA Hairpin with the 5'-GC-3' Binding Site

Overview

Journal J Biol Inorg Chem

Publisher Springer

Specialty Biochemistry

Date 2016 Nov 19

PMID 27858165

Citations 2

Authors

Teresa E Lehmann

Sally A Murray

Azure D Ingersoll

Teresa M Reilly

Shelby E Follett

Kevin E Macartney

Mark H Harpster

Affiliations

Soon will be listed here.

Abstract

The antibiotics known as bleomycins constitute a family of natural products clinically employed for the treatment of a wide spectrum of cancers. The drug acts as an antitumor agent by virtue of the ability of a metal complex of the antibiotic to cleave DNA. Bleomycins are differentiated by their C-terminal regions. Previous structural studies involving metal-bleomycin-DNA triads have allowed the identification of the bithiazole-(C-terminus substituent) segment in this molecule as the one that most closely interacts with DNA. Three different modes of binding of metallo-bleomycins to DNA (partial or total intercalation of the bithiazole unit between DNA bases, or binding to the minor groove) have been proposed in the literature. The therapeutic use of bleomycin is frequently associated with the development of pulmonary fibrosis. The severity of this side effect has been attributed to the C-terminus of the antibiotic by some researchers. The degree of pulmonary toxicity of bleomycin-A and -A, were found to be higher than those of bleomycin-B and peplomycin. Since the introduction of Blenoxane to clinical medicine in 1972, attempts have been made at modifying the basic bleomycin structure at the C-terminus to improve its therapeutic index. However, the pharmacological and toxicological importance of particular C-termini on bleomycin remains unclear. The present study was designed to determine the effect of Zn(II)bleomycin-A, -A, -B, and Zn(II)peplomycin on the structure of a DNA hairpin containing the 5'-GC-3' binding site. We provide evidence that different Zn(II)bleomycins affect the structure of the tested DNA segment in different fashions.

Citing Articles

Structural changes of Zn(II)bleomycin complexes when bound to DNA hairpins containing the 5'-GT-3' and 5'-GC-3' binding sites studied through NMR spectroscopy.

Follett S, Murray S, Ingersoll A, Reilly T, Lehmann T Magnetochemistry. 2018; 4(1).

PMID: 30464999 PMC: 6241535. DOI: 10.3390/magnetochemistry4010004.

Interaction of Zn(II)bleomycin-A and Zn(II)peplomycin with a DNA hairpin containing the 5'-GT-3' binding site in comparison with the 5'-GC-3' binding site studied by NMR spectroscopy.

Follett S, Ingersoll A, Murray S, Reilly T, Lehmann T J Biol Inorg Chem. 2017; 22(7):1039-1054.

PMID: 28748309 PMC: 5985968. DOI: 10.1007/s00775-017-1482-z.

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