Conjugated eicosapentaenoic acid (cEPA) has been found to have antitumor effects which has been ascribed to their ability to inhibit DNA topoisomerases and DNA polymerases. We here show that cEPA inhibits the catalytic activity of human topoisomerase I, but unlike camptothecin it does not stabilize the cleavable complex, indicating a different mechanism of action. cEPA inhibits topoisomerase by impeding the catalytic cleavage of the DNA substrate as demonstrated using specific oligonucleotide substrates, and prevents the stabilization of the cleavable complex by camptothecin. Preincubation of the inhibitor with the enzyme is required to obtain complete inhibition. Molecular docking simulations indicate that the preferred cEPA binding site is proximal to the active site with the carboxylic group strongly interacting with the positively charged K443 and K587. Taken together the results indicate that cEPA inhibitor does not prevent DNA binding but inhibits DNA cleavage, binding in a region close to the topoisomerase active site.

Castelli, S., Campagna, A., Vassallo, O., Tesauro, C., Fiorani, P., Tagliatesta, P., et al. (2009). Conjugated eicosapentaenoic acid inhibits human topoisomerase IB with a mechanism different from camptothecin. ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 486(2), 103-110 [10.1016/j.abb.2009.04.007].

Conjugated eicosapentaenoic acid inhibits human topoisomerase IB with a mechanism different from camptothecin.

CASTELLI, SILVIA;TAGLIATESTA, PIETRO;FALCONI, MATTIA;DESIDERI, ALESSANDRO
2009-01-01

Abstract

Conjugated eicosapentaenoic acid (cEPA) has been found to have antitumor effects which has been ascribed to their ability to inhibit DNA topoisomerases and DNA polymerases. We here show that cEPA inhibits the catalytic activity of human topoisomerase I, but unlike camptothecin it does not stabilize the cleavable complex, indicating a different mechanism of action. cEPA inhibits topoisomerase by impeding the catalytic cleavage of the DNA substrate as demonstrated using specific oligonucleotide substrates, and prevents the stabilization of the cleavable complex by camptothecin. Preincubation of the inhibitor with the enzyme is required to obtain complete inhibition. Molecular docking simulations indicate that the preferred cEPA binding site is proximal to the active site with the carboxylic group strongly interacting with the positively charged K443 and K587. Taken together the results indicate that cEPA inhibitor does not prevent DNA binding but inhibits DNA cleavage, binding in a region close to the topoisomerase active site.
2009
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/11 - BIOLOGIA MOLECOLARE
English
Con Impact Factor ISI
Human DNA topoisomerase IB (hTop IB) Conjugated eicosapentaenoic acid (cEPA) Camptothecin (CPT) Inhibition Anticancer drug Molecular docking Autodock Clustering
Castelli, S., Campagna, A., Vassallo, O., Tesauro, C., Fiorani, P., Tagliatesta, P., et al. (2009). Conjugated eicosapentaenoic acid inhibits human topoisomerase IB with a mechanism different from camptothecin. ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 486(2), 103-110 [10.1016/j.abb.2009.04.007].
Castelli, S; Campagna, A; Vassallo, O; Tesauro, C; Fiorani, P; Tagliatesta, P; Oteri, F; Falconi, M; Majumder, H; Desideri, A
Articolo su rivista
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/28528
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