Inhibition of DNA polymerases and DNA topoisomerase II by triterpenes produced by plant callus

We found that some triterpene compounds could not only selectively inhibit the activities of mammalian DNA polymerase α (pol α) and β (pol β), but could also potently inhibit DNA topoisomerase II (topo II) [Biochem. J. 350 (2000) 757]. Here, we report that natural triterpenes produced by callus from...

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Veröffentlicht in:Biochemical and biophysical research communications 2003-05, Vol.305 (2), p.365-373
Hauptverfasser: Mizushina, Yoshiyuki, Ikuta, Akira, Endoh, Kenji, Oshige, Masahiko, Kasai, Nobuyuki, Kamiya, Kohei, Satake, Toshiko, Takazawa, Hiroshi, Morita, Hiromasa, Tomiyasu, Hiroaki, Yoshida, Hiromi, Sugawara, Fumio, Sakaguchi, Kengo
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Sprache:eng
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Zusammenfassung:We found that some triterpene compounds could not only selectively inhibit the activities of mammalian DNA polymerase α (pol α) and β (pol β), but could also potently inhibit DNA topoisomerase II (topo II) [Biochem. J. 350 (2000) 757]. Here, we report that natural triterpenes produced by callus from an ancient Chinese medicinal plant were also inhibitors of the enzymes, and some were more selective than others. The natural triterpenes with a carboxyl group equally inhibited the activities of pol α, pol β, and topo II, while the olide-type triterpenes with a ketone group suppressed the activities of pol β and topo II, but not pol α. The other triterpenes from the callus hardly influenced these enzyme activities. As also described previously [J. Biochem. 130 (2001) 657], pol β and topo II have a three-dimensionally similar triterpene-binding region, which is a pocket in which specific compounds can insert. The newly found triterpene inhibitors might structure-dependently insert into the pocket, and the pocket structure of each enzyme might, three-dimensionally but slightly, differ among them. The triterpene frames could be used for screening new inhibitors of the enzymes, and computer-simulated drug design using the frame and pocket structure may in theory be a possible approach to develop new inhibitors.
ISSN:0006-291X
1090-2104
DOI:10.1016/S0006-291X(03)00765-4