6,6’-Dihydroxythiobinupharidine as a poison of human type II topoisomerases |
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| Institution: | 1. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA;2. Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel;3. Department of Oncology, Soroka University Medical Center, Beer Sheva 84105, Israel;4. The Jacob Blaustein Institutes for Desert Research, French Associates Institute for Agriculture and Biotechnology of Drylands, Ben-Gurion University of the Negev, Sede Boqer Campus, Beer Sheva 84990, Israel;5. Department of Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, TN 37232-6307, USA;6. VA Tennessee Valley Healthcare System, Nashville, TN 37212, USA;1. Institute of Software Technology, Graz University of Technology, Austria;2. Department of Computer Science, Tufts University, Medford, MA, USA;3. Institut für Informatik, Freie Universität Berlin, Germany;4. University of Sydney, Sydney, Australia;5. Department of Mathematics and Computer Science, TU Eindhoven, the Netherlands;1. Faculty of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China;2. Affiliated Hospital of Hubei University of Chinese Medicine, Hubei Provincial Hospital of Traditional Chinese Medicine, China;1. Centre for Natural Products & Traditional Knowledge, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India;2. Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India;3. Analytical & Structural Chemistry Department, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India;4. Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India;1. Universidad Nacional de Colombia, Departamento de Farmácia, Facultad de Ciencias, Cra. 30 No. 45-03, Postal Code 111321, Bogotá, D. C., Colombia;2. Universidade Federal de Santa Catarina, Departamento de Bioquímica – Centro de Ciências Biológicas, Campus Universitário, BairroTrindade, Cx. Postal 5069, CEP: 88040-970, Florianópolis, SC, Brazil;3. Pontificia Universidad Javeriana, Departamento de Química, Facultad de Ciencias, Carrera 7 No. 43-82, Edificio Carlos Ortiz (52), Oficina 617, Postal Code 110231, Bogotá, D. C., Colombia |
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| 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 Nuphar 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. |
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| Keywords: | 6 6’-Dihydroxythiobinupharidine Covalent poison DNA cleavage Topoisomerase IIα Topoisomerase IIβ |
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