title: 3-O-methylfunicone, a selective inhibitor of mammalian Y-family DNA polymerases from an Australian sea salt fungal strain.
abstract: We isolated a pol inhibitor from the cultured mycelia extract of a fungal strain isolated from natural salt from a sea salt pan in Australia, which was identified as 3-O-methylfunicone by spectroscopic analyses. This compound selectively inhibited the activities of mammalian Y-family DNA polymerases (pols) (i.e., pols eta, iota and kappa). Among these pols, human pol kappa activity was most strongly inhibited, with an IC(50) value of 12.5 microM. On the other hand, the compound barely influenced the activities of the other families of mammalian pols, such as A-family (i.e., pol gamma), B-family (i.e., pols alpha, delta and epsilon) or X-family (i.e., pols beta, lambda and terminal deoxynucleotidyl transferase), and showed no effect on the activities of fish pol delta, plant pols, prokaryotic pols and other DNA metabolic enzymes, such as calf primase of pol alpha, human immunodeficiency virus type-1 (HIV-1) reverse transcriptase, human telomerase, T7 RNA polymerase, mouse IMP dehydrogenase (type II), human topoisomerases I and II, T4 polynucleotide kinase or bovine deoxyribonuclease I. This compound also suppressed the growth of two cultured human cancer cell lines, HCT116 (colon carcinoma cells) and HeLa (cervix carcinoma cells), and UV-treated HeLa cells exhibited lower clonogenic survival in the presence of inhibitor.
authors.affiliation: Laboratory of Food & Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo, Japan. mizushin@nutr.kobegakuin.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mizushina
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Motoshima
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Ken
authors.initials: K
authors.lastname: Hirano
authors.forename: Fumio
authors.initials: F
authors.lastname: Sugawara
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D001315:Australia; D002417:Cattle; D045744:Cell Line, Tumor; D004253:DNA Nucleotidylexotransferase / Q000737:chemistry; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D005658:Fungi / Q000737:chemistry*; D006801:Humans; D007168:IMP Dehydrogenase / Q000737:chemistry; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors; D009713:Nucleotidyltransferases / Q000737:chemistry; D011753:Pyrones / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D012492:Salts; D012623:Seawater / Q000382:microbiology*; D013329:Structure-Activity Relationship
chemical_list: C450900:3-O-methylfunicone; D000970:Antineoplastic Agents; D019384:Nucleic Acid Synthesis Inhibitors; D011753:Pyrones; D012492:Salts; D007168:IMP Dehydrogenase; D009713:Nucleotidyltransferases; D004253:DNA Nucleotidylexotransferase; D004259:DNA-Directed DNA Polymerase