1. 6,6’-Dihydroxythiobinupharidine as a poison of human type II topoisomerases
- Author
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Esha D. Dalvie, Jacob Gopas, Avi Golan-Goldhirsh, and Neil Osheroff
- Subjects
Topoisomerase iiα ,Clinical Biochemistry ,Pharmaceutical Science ,Human type ,01 natural sciences ,Biochemistry ,Poisons ,Article ,chemistry.chemical_compound ,Alkaloids ,Dna cleavage ,Drug Discovery ,Humans ,Nuphar lutea ,Molecular Biology ,chemistry.chemical_classification ,biology ,Plant Extracts ,010405 organic chemistry ,Topoisomerase ,Organic Chemistry ,Active site ,biology.organism_classification ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,DNA Topoisomerases, Type II ,Enzyme ,chemistry ,biology.protein ,Molecular Medicine ,DNA - Abstract
A number of natural products with medicinal properties increase DNA cleavage mediated by type II topoisomerases. In an effort to identify additional natural compounds that affect the activity of human type II topoisomerases, a blind screen of a library of 341 Mediterranean plant extracts was conducted. Extracts from Nuphcir lutea, the yellow water lily, were identified in this screen. N. lutea has been used in traditional medicine by a variety of indigenous populations. The active compound in N. lutea, 6,6’-dihydroxythiobinupharidine, was found to enhance DNA cleavage mediated by human topoisomerase IIα and IIβ ~8-fold and ~3-fold, respectively. Mechanistic studies with topoisomerase IIα indicate that 6,6’-dihydroxythiobinupharidine is a “covalent poison” that acts by adducting the enzyme outside of the DNA cleavage-ligation active site and requires the N-terminal domain of the protein for its activity. Results suggest that some of the medicinal properties of N. lutea may result from the interactions between 6,6’-dihydroxythiobinupharidine and the human type II enzymes.
- Published
- 2019
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