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Interaction of Zn(II)bleomycin-A2 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

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Abstract

Bleomycins are a group of glycopeptide antibiotics synthesized by Streptomyces verticillus that are widely used for the treatment of various neoplastic diseases. These antibiotics have the ability to chelate a metal center, mainly Fe(II), and cause site-specific DNA cleavage. Bleomycins are differentiated by their C-terminal regions. Although this antibiotic family is a successful course of treatment for some types of cancers, it is known to cause pulmonary fibrosis. Previous studies have identified that bleomycin-related pulmonary toxicity is linked to the C-terminal region of these drugs. This region has been shown to closely interact with DNA. We examined the binding of Zn(II)peplomycin and Zn(II)bleomycin-A2 to a DNA hairpin of sequence 5′-CCAGTATTTTTACTGG-3′, containing the binding site 5′-GT-3′, and compared the results with those obtained from our studies of the same MBLMs bound to a DNA hairpin containing the binding site 5′-GC-3′. We provide evidence that the DNA base sequence has a strong impact in the final structure of the drug–target complex.

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Abbreviations

A:

Adenine

Ala:

β-Aminoalanine

Bit:

Bithiazole

BLMs:

Bleomycins

C:

Cytosine

1D:

One dimensional

2D:

Two dimensional

Δδs:

Differences in chemical shifts

Δω :

Difference in peak width

FID:

Free induction decay

G:

Guanine

Gul:

α-l-Gulose

Hist:

β-Hydoxyhistidine

Mann:

α-d-Mannose

MBLMs:

Metallo-bleomycins

NMR:

Nuclear magnetic resonance

NOE:

Nuclear Overhauser effect cross signals

NOESY:

Nuclear Overhauser effect spectroscopy

OL:

Oligonucleotide

OL1 :

5′-AGCCTTTTGGCCT-3′

OL2 :

5′-CCAGTATTTTTACTGG-3′

PEP:

Peplomycin

ppm:

Parts per million

Pyr:

Pyrimidinyl propionamide

SDS:

Sodium dodecyl sulfate

T:

Thymine

Tails:

C-terminus substituents

Thr:

Threonine

TOCSY:

Totally correlated spectroscopy

Val:

Methylvalerate

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Acknowledgements

This work was supported in whole by the National Institute of Health [Grant R15GM106258]. Our gratitude also goes to Nippon Kayaku Co., Ltd. (Tokyo, Japan) for the generous gift of peplomycin. We also acknowledge Dr. Alexander Goroncy for help collecting the NMR data presented in this work.

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Authors and Affiliations

  1. Department of Chemistry, University of Wyoming, 1000 E. University Avenue, Laramie, WY, 82071, USA

    Shelby E. Follett, Azure D. Ingersoll, Sally A. Murray, Teresa M. Reilly & Teresa E. Lehmann

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  1. Shelby E. Follett
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  2. Azure D. Ingersoll
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  3. Sally A. Murray
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  4. Teresa M. Reilly
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  5. Teresa E. Lehmann
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Correspondence to Teresa E. Lehmann.

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Follett, S.E., Ingersoll, A.D., Murray, S.A. et al. Interaction of Zn(II)bleomycin-A2 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. J Biol Inorg Chem 22, 1039–1054 (2017). https://doi.org/10.1007/s00775-017-1482-z

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