Human topoisomerase I poisoning by protoberberines

Potential roles for both drug-DNA and drug-enzyme interactions

Tsai K. Li, Eleanor Bathory, Edmond J. LaVoie, A. R. Srinivasan, Wilma K. Olson, Ronald R. Sauers, Leroy-Fong Liu, Daniel S. Pilch

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Protoberberines represent a structural class of organic cations that induce topoisomerase I-mediated DNA cleavage, a behavior termed topoisomerase I poisoning. We have employed a broad range of biophysical, biochemical, and computer modeling techniques to characterize and cross-correlate the DNA- binding and topoisomerase poisoning properties of four protoberberine analogues that differ with respect to the substituents on their A- and/or D- rings. Our data reveal the following significant features: (i) The binding of the four protoberberines unwinds duplex DNA by approximately 11°, an observation consistent with an intercalative mode of interaction. (ii) Enthalpically favorable interactions, such as stacking interactions between the intercalated ligand and the neighboring base pairs, provide 2,3-dimethoxy >> 3,4-dimethoxy. These differences in topoisomerase I poisoning activity may reflect the differing abilities of the analogues to interact with specific functionalities on the enzyme, thereby stabilizing the enzyme in its cleavable state. In the aggregate, our results are consistent with a mechanistic model in which both ligand-DNA and ligand-enzyme interactions are important for the poisoning of topoisomerase I by protoberberines, with the DNA-directed interactions involving ring D and the enzyme-directed interactions involving ring A. It is reasonable to suggest that the poisoning of topoisomerase I by a broad range of other naturally occurring and synthetic ligands may entail a similar mechanism.

Original languageEnglish
Pages (from-to)7107-7116
Number of pages10
JournalBiochemistry
Volume39
Issue number24
DOIs
Publication statusPublished - Jun 20 2000
Externally publishedYes

Fingerprint

Type I DNA Topoisomerase
Drug Interactions
Poisoning
DNA
Ligands
Enzymes
Pharmaceutical Preparations
4 alpha-glucanotransferase
DNA Cleavage
Aptitude
Cations
Base Pairing
Observation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Li, T. K., Bathory, E., LaVoie, E. J., Srinivasan, A. R., Olson, W. K., Sauers, R. R., ... Pilch, D. S. (2000). Human topoisomerase I poisoning by protoberberines: Potential roles for both drug-DNA and drug-enzyme interactions. Biochemistry, 39(24), 7107-7116. https://doi.org/10.1021/bi000171g

Human topoisomerase I poisoning by protoberberines : Potential roles for both drug-DNA and drug-enzyme interactions. / Li, Tsai K.; Bathory, Eleanor; LaVoie, Edmond J.; Srinivasan, A. R.; Olson, Wilma K.; Sauers, Ronald R.; Liu, Leroy-Fong; Pilch, Daniel S.

In: Biochemistry, Vol. 39, No. 24, 20.06.2000, p. 7107-7116.

Research output: Contribution to journalArticle

Li, TK, Bathory, E, LaVoie, EJ, Srinivasan, AR, Olson, WK, Sauers, RR, Liu, L-F & Pilch, DS 2000, 'Human topoisomerase I poisoning by protoberberines: Potential roles for both drug-DNA and drug-enzyme interactions', Biochemistry, vol. 39, no. 24, pp. 7107-7116. https://doi.org/10.1021/bi000171g
Li, Tsai K. ; Bathory, Eleanor ; LaVoie, Edmond J. ; Srinivasan, A. R. ; Olson, Wilma K. ; Sauers, Ronald R. ; Liu, Leroy-Fong ; Pilch, Daniel S. / Human topoisomerase I poisoning by protoberberines : Potential roles for both drug-DNA and drug-enzyme interactions. In: Biochemistry. 2000 ; Vol. 39, No. 24. pp. 7107-7116.
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