Binding to DNA of selected lexitropsins and effects on prokaryotic topoisomerase activity.
The binding behaviour toward DNA of some minor groove binders related to distamycin was studied by means of circular dichroism. In addition their influence on the activity of topoisomerases isolated from Streptomyces noursei has been investigated. The monocationic imidazole containing ligands (lexitropsins) show a decreased affinity to AT pairs but an increased affinity to GC pairs which contrasts the AT-preferred binding of Dst-2 and Dst-3. For the monocationic triimidazole containing lexitropsin the affinity for GC over AT pairs was most pronounced. It was also found that the imidazole containing lexitropsins are inhibitors of topoisomerases. These minor groove binders interfere more strongly with the DNA gyrase activity than with the prokaryotic topoisomerase I. Our results indicate that Dst-3 most effectively inhibits gyrase and topoisomerase I activity. However, the inhibitory effect is neither related to the base pair specificity nor to the binding strength of different ligands. The mechanism of interference of minor groove binders with topoisomerase activity is more complex. It is considered that different factors, such as the nature of the ligand together with their DNA binding parameters and the target sequences of the enzymes play a role in the inhibitory effects of minor groove binders.
Department of Molecular Biology, University of Jena, Germany.
G
G
Burckhardt
G
G
Luck
K
K
Störl
C
C
Zimmer
J W
JW
Lown
D000818:Animals; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000187:drug effects / Q000378:metabolism*; D004214:Distamycins / Q000494:pharmacology; D009429:Netropsin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013696:Temperature; D059005:Topoisomerase II Inhibitors
D004214:Distamycins; D059005:Topoisomerase II Inhibitors; C053654:lexitropsin; D009429:Netropsin; D004247:DNA; D004264:DNA Topoisomerases, Type I