title: Inhibitory action of conjugated C18-fatty acids on DNA polymerases and DNA topoisomerases.
abstract: We reported previously that unsaturated linear-chain FA of the cis-configuration with a C18-hydrocarbon chain such as linoleic acid (18:2delta9c,12c) could potently inhibit the activities of mammalian DNA polymerases and DNA topoisomerases, but their saturated forms could not. There are chemically two classes of unsaturated FA, normal and conjugated, but only the conjugated forms show potent antitumor activity. In this report, we study the inhibitory effects of chemically synthesized conjugated C18-FA on mammalian DNA polymerases and DNA topoisomerases as compared with normal unsaturated FA. The conjugated alpha-eleostearic acid (18:3delta9c,11t, 13t) was the strongest of all the FA tested. For the inhibition, the conjugated form is crucially important. The energy-minimized 3-D structures of the FA were calculated, and both a length of less than 20 A and a width of 8.13-9.24 A in the C18-FA structure were found to be important for enzyme inhibition. The 3-D structure of the active site of both DNA polymerases and topoisomerases must have had a pocket to join alpha-eleostearic acid, and this pocket was 12.03 A long and 9.24 A wide.
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: Tsuyoshi
authors.initials: T
authors.lastname: Tsuzuki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Eitsuka
authors.forename: Teruo
authors.initials: T
authors.lastname: Miyazawa
authors.forename: Kanako
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikawa
authors.forename: Isoko
authors.initials: I
authors.lastname: Kuriyama
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yonezawa
authors.forename: Masaharu
authors.initials: M
authors.lastname: Takemura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Kengo
authors.initials: K
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D001665:Binding Sites; D002417:Cattle; D004791:Enzyme Inhibitors / Q000737:chemistry; D006801:Humans; D044243:Linoleic Acids, Conjugated / Q000737:chemistry / Q000494:pharmacology*; D008042:Linolenic Acids / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D044243:Linoleic Acids, Conjugated; D008042:Linolenic Acids; D019384:Nucleic Acid Synthesis Inhibitors; D059003:Topoisomerase Inhibitors; C004934:eleostearic acid