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, preincubation 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 drugbinding 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.
Tesauro, C., Fiorani, P., D'Annessa, I., Chillemi, G., Turchi, G., Desideri, A. (2010). Erybraedin C, a natural compound from the plant Bituminaria bituminosa, inhibits both the cleavage and religation activities of human topoisomerase I. BIOCHEMICAL JOURNAL, 425(3), 531-539 [10.1042/BJ20091127.].
Erybraedin C, a natural compound from the plant Bituminaria bituminosa, inhibits both the cleavage and religation activities of human topoisomerase I.
DESIDERI, ALESSANDRO
2010-01-01
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, preincubation 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 drugbinding 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.File | Dimensione | Formato | |
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