title: Erybraedin C, a natural compound from the plant Bituminaria bituminosa, inhibits both the cleavage and religation activities of human topoisomerase I.
abstract: The interaction of human topoisomerase I and erybraedin C, a pterocarpan purified from the plant Bituminaria bituminosa, that was shown to have an antitumour activity, was investigated through enzymatic activity assays and molecular docking procedures. Erybraedin C is able to inhibit both the cleavage and the religation steps of the enzyme reaction. In both cases, pre-incubation of the drug with the enzyme is required to produce a complete inhibition. Molecular docking simulations indicate that, when interacting with the enzyme alone, the preferential drug-binding site is localized in proximity to the active Tyr723 residue, with one of the two prenilic groups close to the active-site residues Arg488 and His632, essential for the catalytic reaction. When interacting with the cleavable complex, erybraedin C interacts with both the enzyme and DNA in a way similar to that found for topotecan. This is the first example of a natural compound able to act on both the cleavage and religation reaction of human topoisomerase I.
authors.affiliation: CNR National Research Council, INFM National Institute for Physics of Matter, CNISM and Department of Biology, University of Rome Tor Vergata, Via Della Ricerca Scientifica, Rome 00133, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Tesauro
authors.forename: Paola
authors.initials: P
authors.lastname: Fiorani
authors.forename: Ilda
authors.initials: I
authors.lastname: D'Annessa
authors.forename: Giovanni
authors.initials: G
authors.lastname: Chillemi
authors.forename: Gino
authors.initials: G
authors.lastname: Turchi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Desideri
mesh_terms: D001120:Arginine / Q000737:chemistry; D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D004264:DNA Topoisomerases, Type I / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007887:Fabaceae / Q000378:metabolism*; D006639:Histidine / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D010936:Plant Extracts / Q000494:pharmacology*; D011485:Protein Binding; D036343:Pterocarpans / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D010936:Plant Extracts; D036343:Pterocarpans; D059004:Topoisomerase I Inhibitors; C488769:erybraedin C; D014443:Tyrosine; D006639:Histidine; D019772:Topotecan; D001120:Arginine; D004264:DNA Topoisomerases, Type I