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 alpha (pol alpha) and beta (pol beta), 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 alpha, pol beta, and topo II, while the olide-type triterpenes with a ketone group suppressed the activities of pol beta and topo II, but not pol alpha. The other triterpenes from the callus hardly influenced these enzyme activities. As also described previously [J. Biochem. 130 (2001) 657], pol beta 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.
Mizushina
Yoshiyuki
Y
Laboratory of Food & Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan. mizushin@nutr.kobegakuin.ac.jp
Ikuta
Akira
A
Endoh
Kenji
K
Oshige
Masahiko
M
Kasai
Nobuyuki
N
Kamiya
Kohei
K
Satake
Toshiko
T
Takazawa
Hiroshi
H
Morita
Hiromasa
H
Tomiyasu
Hiroaki
H
Yoshida
Hiromi
H
Sugawara
Fumio
F
Sakaguchi
Kengo
K
D004256:DNA Polymerase I / Q000378:metabolism; D019951:DNA Polymerase beta / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D010946:Plants, Medicinal / Q000737:chemistry* / Q000254:growth & development; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D014315:Triterpenes; D004256:DNA Polymerase I; D019951:DNA Polymerase beta; D004259:DNA-Directed DNA Polymerase; D004250:DNA Topoisomerases, Type II