title: Formosusin A, a novel specific inhibitor of mammalian DNA polymerase β from the fungus Paecilomyces formosus.
abstract: Variotin (1) and three novel compounds, formosusin A (2), B (3), and C (4), were isolated from the cultures of the fungus Paecilomyces formosus, and their structures were determined by spectroscopic analyses. Compound 2 is (6Z,8E,10E)-variotin, a new cis-olefin analog of compound 1. Compound 2 selectively inhibited the activity of mammalian DNA polymerase β (pol β) in vitro, with an IC50 of 35.6μM. By contrast, compounds 1, 3, and 4 did not influence the activity of pol β. These four compounds showed no effect on the activities of other 10 mammalian pols (i.e., pols α, γ, δ, ε, η, ι, κ, λ, and μ, and terminal deoxynucleotidyl transferase). These compounds also did not inhibit the activities of fish, insect, plant, and prokaryotic pols and other DNA metabolic enzymes tested. These results suggested that compound 2 could be a selective inhibitor of mammalian pol β. The compound 2-induced inhibition of rat pol β activity was competitive and non-competitive with respect to the DNA template-primer substrate and the dNTP substrate, respectively. On the basis of these results, the relationship between the three-dimensional structure and pol β inhibitory mechanism of compound 2 is discussed.
authors.affiliation: Laboratory of Food & Nutritional Sciences, Faculty of Nutrition, Kobe Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan; Cooperative Research Center of Life Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Hyogo 651-8586, Japan. Electronic address: mizushin@nutr.kobegakuin.ac.jp.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mizushina
authors.affiliation: Department of Applied Biological Science, Tokyo University of Science, Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Hiroe
authors.initials: H
authors.lastname: Suzuki-Fukudome
authors.affiliation: Department of Applied Biological Science, Tokyo University of Science, Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Takeuchi
authors.affiliation: Department of Applied Biological Science, Tokyo University of Science, Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Takemoto
authors.affiliation: Laboratory of Food & Nutritional Sciences, Faculty of Nutrition, Kobe Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan.
authors.forename: Isoko
authors.initials: I
authors.lastname: Kuriyama
authors.affiliation: Laboratory of Food & Nutritional Sciences, Faculty of Nutrition, Kobe Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Department of Applied Biological Science, Tokyo University of Science, Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kamisuki
authors.affiliation: Department of Applied Biological Science, Tokyo University of Science, Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Sugawara
mesh_terms: D000818:Animals; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D005233:Fatty Alcohols / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008322:Mammals; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors; D010143:Paecilomyces / Q000737:chemistry*; D011760:Pyrrolidinones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D005233:Fatty Alcohols; D019384:Nucleic Acid Synthesis Inhibitors; D011760:Pyrrolidinones; C000592629:formosusin A; D019951:DNA Polymerase beta; C001405:pecilocin
keywords: Computer simulation; DNA polymerase β; Enzyme inhibitor; Formosusin A