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Conjugated Eicosapentaenoic Acid Inhibits Human Topoisomerase IB With a Mechanism Different From Camptothecin

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Title Conjugated Eicosapentaenoic Acid Inhibits Human Topoisomerase IB With a Mechanism Different From Camptothecin
 
Creator Castelli, Silvia
Campagna, Alessia
Vassallo, Oscar
Tesauro, Cinzia
Fiorani, Paola
Tagliatesta, Pietro
Oteri, Francesco
Falconi, Mattio
Majumder, Hemanta K
Desideri, Alessandro
 
Subject Infectious Diseases and Immunology
 
Description 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.
 
Date 2009
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1004/1/33_ABB_2009.pdf
Castelli, Silvia and Campagna, Alessia and Vassallo, Oscar and Tesauro, Cinzia and Fiorani, Paola and Tagliatesta, Pietro and Oteri, Francesco and Falconi, Mattio and Majumder, Hemanta K and Desideri, Alessandro (2009) Conjugated Eicosapentaenoic Acid Inhibits Human Topoisomerase IB With a Mechanism Different From Camptothecin. Archives of Biochemistry and Biophysics, 486 (2). pp. 103-110.
 
Relation http://dx.doi.org/10.1016/j.abb.2009.04.007
http://www.eprints.iicb.res.in/1004/