Studies on the Mechanism of Action of Azinomycin B:  Definition of Regioselectivity and Sequence Selectivity of DNA Cross-Link Formation and Clarification of the Role of the Naphthoate

Coleman, Robert S.; Perez, Ronelito J.; Burk, Christopher H.; Navarro, Arturo Anadón

doi:10.1021/ja025563k

Cited by 74 publications

(60 citation statements)

References 30 publications

(41 reference statements)

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“…1B) (12,13). Computational modeling of the AZB ICL structure is consistent with the entire AZB molecule residing in the major groove of the DNA without nucleobase intercalation by the naphthalate moiety (14,15).…”

supporting

confidence: 56%

Structure of a DNA glycosylase that unhooks interstrand cross-links

Mullins

Warren

Bradley

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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DNA glycosylases are important editing enzymes that protect genomic stability by excising chemically modified nucleobases that alter normal DNA metabolism. These enzymes have been known only to initiate base excision repair of small adducts by extrusion from the DNA helix. However, recent reports have described both vertebrate and microbial DNA glycosylases capable of unhooking highly toxic interstrand cross-links (ICLs) and bulky minor groove adducts normally recognized by Fanconi anemia and nucleotide excision repair machinery, although the mechanisms of these activities are unknown. Here we report the crystal structure of Streptomyces sahachiroi AlkZ (previously Orf1), a bacterial DNA glycosylase that protects its host by excising ICLs derived from azinomycin B (AZB), a potent antimicrobial and antitumor genotoxin. AlkZ adopts a unique fold in which three tandem winged helix-turn-helix motifs scaffold a positively charged concave surface perfectly shaped for duplex DNA. Through mutational analysis, we identified two glutamine residues and a β-hairpin within this putative DNA-binding cleft that are essential for catalytic activity. Additionally, we present a molecular docking model for how this active site can unhook either or both sides of an AZB ICL, providing a basis for understanding the mechanisms of base excision repair of ICLs. Given the prevalence of this protein fold in pathogenic bacteria, this work also lays the foundation for an emerging role of DNA repair in bacteria-host pathogenesis.

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supporting

confidence: 56%

Structure of a DNA glycosylase that unhooks interstrand cross-links

Mullins

Warren

Bradley

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…These important properties make HSA, a preferred target protein molecule for exploring the fate of bound molecule. Besides HSA, deoxyribonucleic acid (DNA) is also a primary intracellular target molecule upon which most of the anticancer drugs exert their cytotoxic effects [14,15]. Drug or small molecules react with DNA mostly through non-covalent interactions on several sites in the DNA molecule.…”

Section: Introductionmentioning

confidence: 99%

Biophysical Interactions of Novel Oleic Acid Conjugate and its Anticancer Potential in HeLa Cells

et al. 2015

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Novel conjugate 2,6-Diisopropylphenol-Oleic acid (2,6P-OLA) has shown potent anticancer activity on various cancer cell lines (Khan et al. Lipids 47:973-986, 2012). In the present study, the protein-or/ and DNA-binding property of 2,6P-OLA was evaluated that could predict its potential toxic effect, in vitro. Preferential structural stability and interaction mechanism of 2,6P-OLA to human serum albumin (HSA) and calf thymus DNA (CT-DNA) was used as model molecules, employing fluorescence spectroscopy (FS) and circular dichroism (CD) methods. The binding and apoptotic activities of conjugate were determined on bacterial recombinant DNA, pBR322 and human cancer cell line, HeLa, respectively. FS studies showed a strong conjugate binding affinity to HSA with overall binding constant of K = 7.66 (±0.03) × 10(2) M(-1). Higher concentration induced detectable changes in the CD spectrum of HSA. The conjugate complexation altered HSA secondary conformation by an increase in α-helices and decrease in β-sheets. Flourescence quenching studies with CT-DNA exhibited K = 1.215 × 10(2) L mol(-1) where 2,6P-OLA efficiently displaced the ethidium bromide (EtBr) bound DNA indicating its strong competition with EtBr for intercalation. Similarly, 2,6P-OLA was able to partially bind pBR322, resulting in decrease the intensity of EtBr gradually. The conjugate significantly reduced survival of HeLa cells. Morphological studies revealed altered cell morphology, suggesting apoptotic death of HeLa cells. Overall, our data shows that 2,6P-OLA bind well with both HSA and DNA and possessed anticancer activities.

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“…The natural products azinomycin A and B are mechanistically related to fasicularin in the sense that they bear an aziridine-based warhead, but they also have a reactive epoxide in their structure. 75,76 The combination of two electrophiles confers the azinomycins with the ability to cross-link DNA. They have a specificity for N7G-N7G cross-links with some N7G-N7A observed as well.…”

Section: Figmentioning

confidence: 99%

Properties and reactivity of nucleic acids relevant to epigenomics, transcriptomics, and therapeutics

2016

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Developments in epigenomics, toxicology, and therapeutic nucleic acids all rely on a precise understanding of nucleic acid properties and chemical reactivity. In this review we discuss the properties and chemical reactivity of each nucleobase and attempt to provide some general principles for nucleic acid targeting or engineering. For adenine-thymine and guaninecytosine base pairs, we review recent quantum chemical estimates of their Watson-Crick interaction energy, - stacking energies, as well as the nuclear quantum effects on tautomerism. Reactions that target nucleobases have been crucial in the development of new sequencing technologies and we believe further developments in nucleic acid chemistry will be required to deconstruct the enormously complex transcriptome.

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Studies on the Mechanism of Action of Azinomycin B: Definition of Regioselectivity and Sequence Selectivity of DNA Cross-Link Formation and Clarification of the Role of the Naphthoate

Cited by 74 publications

References 30 publications

Structure of a DNA glycosylase that unhooks interstrand cross-links

Structure of a DNA glycosylase that unhooks interstrand cross-links

Biophysical Interactions of Novel Oleic Acid Conjugate and its Anticancer Potential in HeLa Cells

Properties and reactivity of nucleic acids relevant to epigenomics, transcriptomics, and therapeutics

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