title: Taxol derivatives are selective inhibitors of DNA polymerase alpha.
abstract: During screening for mammalian DNA polymerase inhibitors, we found and succeeded in isolating a potent inhibitor from a higher plant, Taxus cuspidate. The compound was unexpectedly determined to be taxinine, an intermediate of paclitaxel (taxol) metabolism. Taxinine was found to selectively inhibit DNA polymerase alpha (pol.alpha) and beta (pol.beta). We therefore, tested taxol and other derivatives and found that taxol itself had no such inhibitory effect, and only taxinine could inhibit both pol.alpha and beta. The other compounds used, one derivative, cephalomannine, and five intermediates synthesized chemically inhibited only the pol.alpha activity in vitro. None of the compounds, including taxinine, influenced the activities of the other DNA polymerases, which are reportedly targeted by many pol.beta inhibitors. With both pol.alpha and beta, all of the compounds tested noncompetitively inhibited with respect to both the DNA template-primer and the dNTP substrate.
authors.affiliation: Frontier Research Center for Genome & Drug Discovery, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Oshige
authors.forename: Mika
authors.initials: M
authors.lastname: Takenouchi
authors.forename: Yasutaro
authors.initials: Y
authors.lastname: Kato
authors.forename: Sinji
authors.initials: S
authors.lastname: Kamisuki
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Kouji
authors.initials: K
authors.lastname: Kuramochi
authors.forename: Isamu
authors.initials: I
authors.lastname: Shiina
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Suenaga
authors.forename: Yo-ichi
authors.initials: Y
authors.lastname: Kawakita
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Kuroda
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Fumio
authors.initials: F
authors.lastname: Sugawara
authors.forename: Kengo
authors.initials: K
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors*; D026942:DNA Topoisomerases / Q000187:drug effects; D004330:Drosophila / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors / Q000302:isolation & purification / Q000494:pharmacology; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology; D043823:Taxoids / Q000302:isolation & purification / Q000494:pharmacology*; D020946:Taxus / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D043823:Taxoids; C473166:taxinine; D004256:DNA Polymerase I; D026942:DNA Topoisomerases; D017239:Paclitaxel