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Characterization of the ATPase activity of topoisomerase II from Leishmania donovani and identification of residues conferring resistance to etoposide

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Title Characterization of the ATPase activity of topoisomerase II from Leishmania
donovani and identification of residues conferring resistance to etoposide
 
Creator Sengupta, Tanushri
Mukherjee, Mandira
Das, Aditi
Mandal, Chhabinath
Das, Rakhee
Mukherjee, Tanmoy
Majumder, Hemanta K
 
Subject Drug Development/Diagnostics & Biotechnology
Infectious Diseases and Immunology
 
Description We have cloned and expressed the 43 kDa N-terminal domain
of Leishmania donovani topoisomerase II. This protein has an
intrinsic ATPase activity and obeys Michaelis–Menten kinetics.
Cross-linking studies indicate that the N-terminal domain exists
as a dimer both in the presence and absence of nucleotides. Etoposide,
an effective antitumour drug, traps eukaryotic DNA topoisomerase
II in a covalent complex with DNA. In the present
study, we report for the first time that etoposide inhibits the
ATPase activity of the recombinant N-terminal domain of L.
donovani topoisomerase II. We have modelled the structure of this 43 kDa protein and performed molecular docking analysis
with the drug. Mutagenesis of critical amino acids in the vicinity
of the ligand-binding pocket reveals less efficient inhibition of the
ATPase activity of the enzyme by etoposide. Taken together, these
results provide an insight for the development of newer therapeutic
agents with specific selectivity.
 
Publisher Portland Press
 
Date 2005
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/303/1/390BIOCHEMICAL_JOURNAL_390_419%2D426;2005[30].pdf
Sengupta, Tanushri and Mukherjee, Mandira and Das, Aditi and Mandal, Chhabinath and Das, Rakhee and Mukherjee, Tanmoy and Majumder, Hemanta K (2005) Characterization of the ATPase activity of topoisomerase II from Leishmania donovani and identification of residues conferring resistance to etoposide. Biochemical Journal, 390. pp. 419-426. ISSN 0264-6021
 
Relation http://dx.doi.org/10.1042/BJ20042128
http://www.eprints.iicb.res.in/303/