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Studies on terpenoids produced by actinomycetes-Screening for new bioactive compounds

Research Project

Project/Area Number 14360067
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Bioproduction chemistry/Bioorganic chemistry
Research InstitutionTokyo University of Agriculture

Principal Investigator

SETO Haruo  Tokyo University of Agriculture, Biological Applied Chemistry, Professor, 応用生物科学部・生物応用化学科, 教授 (10013335)

Co-Investigator(Kenkyū-buntansha) SUE Masayuki  Tokyo University of Agriculture, Biological Applied Chemistry, Assistant Professor, 応用生物科学部・生物応用化学科, 助手 (10328544)
FURIHATA Kazuo  University of Tokyo, Graduate School of Agricultural and Life Sciences, 大学院・農学系研究科, 助手 (20219091)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2002: ¥3,100,000 (Direct Cost: ¥3,100,000)
Keywordsterpenoid / actinomycetes / pimaradiene / mevalonate pathway / mevashuntin / HMG-CoA reductase / mevalonate pathway gene / diterpene / テルペン / pimaradiene / mevinolin / フラキノシン / Sterptomyces sp.CL190 / naphterpin / phenazinomycin / furaquinocin / MEP経路 / トリテルペン化合物 / helvolic acid
Research Abstract

The purpose of this project is to isolate new terpenoids from Actinomycetes and to investigate their chemical and biological properties. In order to achieve this purpose, we first attempted to isolate actinomycetes possessing the mevalonate pathway by using the HMG-CoA reductase gene as a probe for PCR, the key enzyme of the mevalonate pathway, and then to isolate terpenoids from the microorganisms. Contrary to our expectation, the number of positive strains isolated was very small, but we succeeded in purification of several new terpenoids. Among them, one compound proved to be a new diterpene derivative with the isopimaradiene skeleton that has never been isolated as actinomycetes metabolites. Although detail properties of this new compound can not be disclosed due to patent application, it showed strong inhibitory activity to EGF protein tyrosine kinase and its detailed biological activities are now under investigation. Another new terpenoid was also isolated from another strain of Streptomyces.
In order to disclose the relationship between the mevalonate pathway and terpenoid biosynthesis, the relevant genes of actinomycetes producing terpenoids were investigated in this project. As a result, it turned out that genes related to terpenoid biosynthesis existed around the mevalonate pathway gene cluster. This finding shows that the mevalonate pathway is strictly linked to production of terpenoids. Expression of these gene was observed at the later stage of the growth of the producing organisms when the production of secondary metabolites started.
Inhibition of the mevalonate pathway in one Streptomyces strain with the mevalonate pathway caused accumulation of a new compound, mevashuntin. The obtained information is expected to be important for studies related to production of terpenoids by actinomycetes.

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (29 results)

All 2005 2004 2003 2002 Other

All Journal Article (15 results) Patent(Industrial Property Rights) (2 results) Publications (12 results)

  • [Journal Article] Studies on terpenoids produced by Actinomycetes. Isolation and structural elucidation of antioxidative agents, naphterpins B and C2005

    • Author(s)
      H.Takagi, K.Motohashi, K.Shin-ya, K.Furihata, H.Seto
    • Journal Title

      J.Antibiot. 58

      Pages: 275-278

    • NAID

      10015525623

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mevashuntin, a novel metabolite produced by inhibition of the mevalonate pathway in Streptomyces prunicolor2005

    • Author(s)
      K.Shin-ya.Y.Umeda, S.Chijiwa, K.Furihata, K.Furihata.H.Seto
    • Journal Title

      Tetrahedron Lett. 46

      Pages: 1273-1276

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mevashuntin, a novel metabolite produced by inhibition of the mevalonate pathway in Streptomyces prunicolor2005

    • Author(s)
      K.Shin-ya, Y.Umeda, S.Chijiwa, K.Furihata, K.Furihata, H.Seto
    • Journal Title

      Tetrahedron Lett. 46

      Pages: 1273-1276

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mevashuntin, a novel metabolite produced by inhibition of the mevalonate pathway in Streptomyces prunicolor2005

    • Author(s)
      K.Shin-ya, K.Furihata, K.Furihata, Y.Hayakawa, H.Seto
    • Journal Title

      Tetrahedron Lett. 46

      Pages: 1273-1276

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Preparation of highly deuterated zeaxanthin, lycopene, and β-carotene from fully deuterated mevalonate using engineered Eschezichia coli2005

    • Author(s)
      T.Eguchi, H.Aizawa, K.Kakinuma, N.Misawa, T.Kuzuyama, H.Seto
    • Journal Title

      Tetrahedron 61

      Pages: 2027-2035

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Studies on terpenoids produced by Actinomycetes. Isolation and structural elucidation of antioxidative agents, naphterpins B and C2005

    • Author(s)
      H.Takagi, K.Motohashi, K.Shin-ya, K.Furihata, H.Seto
    • Journal Title

      J.Antibiot. 58(in press)

    • NAID

      10015525623

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Bacillus subtilis ypgA gene is fni, a nonessential gene encoding type 2 isopentenyl diphosphate isomerase2004

    • Author(s)
      M.Takagi, K.Kaneda, T.Shimizu, Y.Hayakawa, H.Seto, T.Kuzuyama
    • Journal Title

      Biosci.Biotechnol.Biochem. 68

      Pages: 132-137

    • NAID

      10013141062

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Heterologous mevalonate production in Streptomyces lividans TK232004

    • Author(s)
      T.Kuzuyama, T.Dairi, H.Yamashita, Y.Shoji, H.Seto
    • Journal Title

      Biosci.Biotechnol.Biochem. 68

      Pages: 931-934

    • NAID

      10013144128

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Presence of copalyl diphosphate synthase gene in an actinomycete possessing the mevalonate pathway2004

    • Author(s)
      T.Kawasaki, T.Kuzuyama, N.Itoh, K.Furihata, H.Seto, T.Dairi
    • Journal Title

      J.Antibiot. 57

      Pages: 739-747

    • NAID

      10014024066

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A relationship between the mevalonate pathway and isoprenoid production in actinomycetes2003

    • Author(s)
      T.Kawasaki, T.Kuzuyama, K.Furihata, N.Itoh, H.Seto, T.Dairi
    • Journal Title

      J.Antibiot. 56

      Pages: 957-966

    • NAID

      10012546010

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Diversity of the biosynthesis of the isoprene units2003

    • Author(s)
      T.Kuzuyama, H.Seto
    • Journal Title

      Nat.Prod.Rep. 20

      Pages: 171-183

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Growth-phase dependent expression of the mevalonate pathway in a terpenoid antibiotic-producing Streptomyces strain2002

    • Author(s)
      Y.Hamano, T.Dairi, M.Yamamoto, T.Kuzuyama, N.Itoh, H.Seto
    • Journal Title

      Biosci.Biotechnol.Biochem. 66

      Pages: 808-819

    • NAID

      110002693733

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Detection of the mevalonate pathway in Streptomyces species using the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene2002

    • Author(s)
      T.Kuzuyama, S.Takahashi, T.Dairi, H.Seto
    • Journal Title

      J.Antibiot. 55

      Pages: 919-923

    • NAID

      10010311186

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Growth-phase dependent expression of the mevalonate pathway in a terpenoid antibiotic-producing Streptomyces strain2002

    • Author(s)
      Y.Hamano.T.Dairi.M.Yamamoto.T.Kuzuyama.N.Itoh.H.Seto
    • Journal Title

      Biosci.Biotechnol.Biochem 66

      Pages: 808-819

    • NAID

      110002693733

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Detection of the mevalonate pathway in Streptomyces species using the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene2002

    • Author(s)
      T.Kuzuyama.S.Takahashi, T.Dairi, H.Seto
    • Journal Title

      J.Antibiot. 55

      Pages: 919-923

    • NAID

      10010311186

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Patent(Industrial Property Rights)] イソプレノイド化合物およびその製造方法2005

    • Inventor(s)
      瀬戸 治男, 本橋慶一郎
    • Industrial Property Rights Holder
      東京農業大学
    • Industrial Property Number
      2005-047029
    • Filing Date
      2005-02-23
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Patent(Industrial Property Rights)] イソプレノイド化合物およびその製造方法2005

    • Inventor(s)
      瀬戸 治男, 本橋 慶一郎
    • Industrial Property Rights Holder
      東京農業大学
    • Industrial Property Number
      2005-047029
    • Filing Date
      2005-02-23
    • Related Report
      2004 Annual Research Report
  • [Publications] T.Kuzuyama, H.Seto: "Diversity of the biosynthesis of the isoprene units"Natural Products Res.. 20. 171-183 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kawasaki, Y.Hamano, T.Kuzuyama, N.Itoh, H.Seto, T.Dairi: "Interconversion of product specificity of type I eubacterial farnesyl diphosphate synthase and geranylgeranyl diphosphate synthase by one amino acid substitution"J.Biochem.. 133. 83-91 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] T.Eguchi, Y.Dekishima, Y.Hamano, T.Dairi, H.Seto, K.Kakinuma: "A new approach for the investigation of isoprenoid biosynthesis featuring pathway switching, deuterium hyperlabeling, and 1H NMR spectroscopy"J.Org.Chem. 68. 5433-5438 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] H.Matsuura, S.Okamoto, T.Kuzuyama, H.Seto, S.Sakuda: "Nucleotide sequences of genes encoding allosamidin-sensitive and -insensitive chitinases produced by allosamidin-producing Streptomyces"Biosci.Biotechnol.Biochem.. 67. 2002-2005 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] T.Kawasaki, T.Kuzuyama, K.Furihata, N.Itoh, H.Seto, T.Dairi: "A relationship between the mevalonate pathway and isoprenoid production in actinomycetes"J.Antibiot.. 56. 957-966 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] M.Takagi, K.Kaneda, T.Shimizu, Y.Hayakawa, H.Seto, T.Kuzuyama: "Bacillus subtilis ypgA gene is fni, a nonessential gene encoding type 2 isopentenyl diphosphate isomerase"Biosci.Biotechnol.Biochem. 68. 132-137 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] S.Yajima, T.Nonaka, T.Kuzuyama, H.Seto, K.Osawa: "Crystal structure of 1-deoxy-D-xylulose 5-phosphate reductoisomerase complexed with cofactors : implications of a flexible loop movement upon substrate binding"J. Biochem.. 131. 313-317 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Y.Hamano, T.Dairi, M.Yamamoto, T.Kuzuyama, N.Itoh, H.Seto: "Growth-phase dependent expression of the mevalonate pathway in a terpenoid antibiotic-producing Streptomyces strain"Biosci. Biotechnol. Biochem.. 66. 808-819 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] T.Kuzuyama, S.Takahashi, T.Dairi, H.Seto: "Detection of the mevalonate pathway in Streptomyces species using the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene"J. Antibiot.. 55. 919-923 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Y.Hamano, T.Kuzuyama, N.Itoh, K.Furihata, H.Seto, T.Dairi: "Functional analysis of eubacterial diterpene cyclases responsible for biosynthesis of a diterpene antibiotic-terpentecin"J. Biol. Chem.. 277. 37098-37104 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] T.Kawasaki, Y.Hamano, T.Kuzuyama, N.Itoh, H.Seto, T.Dairi: "Interconversion of product specificity of type I eubacterial farnesyl diphosphate synthase and geranylgeranyl diphosphate synthase by one amino acid substitution"J. Biochem.. 133. 83-91 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] T.Kuzuyama, H.Seto: "Diversity of the biosynthesis of the isoprene units"Natural Products Res.. 20. 171-183 (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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