Differential induction of Leishmania donovani bi-subunit topoisomerase I–DNA cleavage complex by selected flavones and camptothecin: activity of flavones against camptothecin-resistant topoisomerase I
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
Differential induction of Leishmania donovani bi-subunit topoisomerase I–DNA cleavage complex by selected flavones and camptothecin: activity of flavones against camptothecin-resistant topoisomerase I
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| Creator |
Das, Benu Brata
Sen, Nilkantha Roy, Amit Bose Dasgupta, Somdeb Ganguly, Agneyo Mohanta, Bikash Chandra Dinda, Biswanath Majumder, Hemanta K |
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| Subject |
Infectious Diseases and Immunology
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| Description |
Emergence of the bi-subunit topoisomerase I in the
kinetoplastid family (Trypanosoma and Leishmania)
has brought a new twist in topoisomerase research
related to evolution, functional conservation and
preferential sensitivities to the specific inhibitors of
type IB topoisomerase family. In the present study,we
describe that naturally occurring flavones baicalein,
luteolin and quercetin are potent inhibitors of the
recombinant Leishmania donovani topoisomerase I.
These compounds bind to the free enzyme and also
intercalate into the DNA at a very high concentration
(300 mM) without binding to the minor grove. Here,
we show that inhibition of topoisomerase I by these
flavones is due to stabilization of topoisomerase I–
DNA cleavage complexes, which subsequently
inhibit the religation step. Their ability to stabilize
the covalent topoisomerase I–DNA complex in vitro
and in living cells is similar to that of the known
topoisomerase I inhibitor camptothecin (CPT). However,
in contrast toCPT, baicaleinand luteolinfailed to
inhibit the religation step when the drugs were added
to pre-formed enzyme substrate binary complex. This
differential mechanism to induce the stabilization of
cleavable complex with topoisomerase I and DNA by
these selected flavones and CPT led us to investigate
the effect of baicalein and luteolin on CPT-resistant
mutant enzyme LdTOP1D39LS lacking 1–39 amino
acids of the large subunit [B. B. Das, N. Sen,
S. B. Dasgupta, A. Ganguly and H. K. Majumder (2005 J. Biol. Chem. 280, 16335–16344]. Baicalein and luteolin
stabilize duplex oligonucleotide cleavage with
LdTOP1D39LS. This observation was further supported
by the stabilization of in vivo cleavable complex
by baicalein and luteolin with highly CPT-resistant
L.donovani strain. Taken together, our data suggest
that the interacting amino acid residues of topoisomerase
I may be partially overlapping or different for
flavones and CPT. This study illuminates new properties
of the flavones and provide additional insights into
the ligand binding properties of L.donovani topoisomerase
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| Date |
2006
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/449/1/NUCLEIC_ACIDS_RESEARCH%2C__34(_4)%2C_1121%2D1132_[149].pdf
Das, Benu Brata and Sen, Nilkantha and Roy, Amit and Bose Dasgupta, Somdeb and Ganguly, Agneyo and Mohanta, Bikash Chandra and Dinda, Biswanath and Majumder, Hemanta K (2006) Differential induction of Leishmania donovani bi-subunit topoisomerase I–DNA cleavage complex by selected flavones and camptothecin: activity of flavones against camptothecin-resistant topoisomerase I. Nucleic Acids Research, 34 (4). pp. 1121-1132. |
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| Relation |
http://dx.doi.org/10.1093/nar/gkj502
http://www.eprints.iicb.res.in/449/ |
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