Inhibition of Zn(II) binding type IA topoisomerases by organomercury compounds and Hg(II)

PloS One
Bokun ChengYuk-Ching Tse-Dinh

Abstract

Type IA topoisomerase activities are essential for resolving DNA topological barriers via an enzyme-mediated transient single strand DNA break. Accumulation of topoisomerase DNA cleavage product can lead to cell death or genomic rearrangement. Many antibacterial and anticancer drugs act as topoisomerase poison inhibitors that form stabilized ternary complexes with the topoisomerase covalent intermediate, so it is desirable to identify such inhibitors for type IA topoisomerases. Here we report that organomercury compounds were identified during a fluorescence based screening of the NIH diversity set of small molecules for topoisomerase inhibitors that can increase the DNA cleavage product of Yersinia pestis topoisomerase I. Inhibition of relaxation activity and accumulation of DNA cleavage product were confirmed for these organomercury compounds in gel based assays of Escherichia coli topoisomerase I. Hg(II), but not As(III), could also target the cysteines that form the multiple Zn(II) binding tetra-cysteine motifs found in the C-terminal domains of these bacterial topoisomerase I for relaxation activity inhibition. Mycobacterium tuberculosis topoisomerase I activity is not sensitive to Hg(II) or the organomercury compounds due...Continue Reading

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Citations

Jan 11, 2017·Journal of Medicinal Chemistry·Giovanni CapranicoGiovanni Chillemi
Oct 1, 2016·Medicinal Research Reviews·Sandhya BansalVibha Tandon
May 13, 2018·International Journal of Molecular Sciences·Qingxuan ZhouYuk-Ching Tse-Dinh
Jan 7, 2021·Microorganisms·Ahmed SeddekYuk-Ching Tse-Dinh

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Methods Mentioned

BETA
electrophoresis
Assay
cleavage assay

Software Mentioned

mfold

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