title: A plant phytotoxin, solanapyrone A, is an inhibitor of DNA polymerase beta and lambda.
abstract: Solanapyrone A, a phytotoxin and enzyme inhibitor isolated from a fungus (SUT 01B1-2) selectively inhibits the activities of mammalian DNA polymerase beta and lambda (pol beta and lambda) in vitro. The IC50 values of the compound were 30 microm for pol beta and 37 microm for pol lambda. Because pol beta and lambda are in a family and their three-dimensional structures are thought to be highly similar to each other, we used pol beta to analyze the biochemical relationship with solanapyrone A. On pol beta, solanapyrone A antagonistically competed with both the DNA template and the nucleotide substrate. BIAcore analysis demonstrated that solanapyrone A bound selectively to the N-terminal 8-kDa domain of pol beta. This domain is known to bind single-stranded DNA, provide 5'-phosphate recognition of gapped DNA, and cleave the sugar-phosphate bond 3' to an intact apurinic/apyrimidinic (AP) site (i.e. AP lyase activity) including 5'-deoxyribose phosphate lyase activity. Solanapyrone A inhibited the single-stranded DNA-binding activity but did not influence the activities of the 5'-phosphate recognition in gapped DNA structures and the AP lyase. Based on these results, the inhibitory mechanism of solanapyrone A is discussed.
authors.affiliation: Laboratory of Food & Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan. mizushin@nutr.kobegakuin.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mizushina
authors.forename: Shinji
authors.initials: S
authors.lastname: Kamisuki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kasai
authors.forename: Noriko
authors.initials: N
authors.lastname: Shimazaki
authors.forename: Masaharu
authors.initials: M
authors.lastname: Takemura
authors.forename: Hitomi
authors.initials: H
authors.lastname: Asahara
authors.forename: Stuart
authors.initials: S
authors.lastname: Linn
authors.forename: Shonen
authors.initials: S
authors.lastname: Yoshida
authors.forename: Akio
authors.initials: A
authors.lastname: Matsukage
authors.forename: Osamu
authors.initials: O
authors.lastname: Koiwai
authors.forename: Fumio
authors.initials: F
authors.lastname: Sugawara
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Kengo
authors.initials: K
authors.lastname: Sakaguchi
mesh_terms: D004247:DNA / Q000378:metabolism; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009281:Naphthalenes / Q000378:metabolism / Q000494:pharmacology*; D019384:Nucleic Acid Synthesis Inhibitors; D011753:Pyrones / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D009281:Naphthalenes; D019384:Nucleic Acid Synthesis Inhibitors; D011753:Pyrones; C113266:solanapyrone A; D004247:DNA; D019951:DNA Polymerase beta