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2002 Fiscal Year Final Research Report Summary

Targeted Pursuit of Bioactive Molecules That Show Inhibitory Activity Against Fungal Polyketide Synthases

Research Project

Project/Area Number 13480184
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Bioorganic chemistry
Research InstitutionThe University of Tokyo

Principal Investigator

EBIZUKA Yutaka  The University of Tokyo, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学系研究科, 教授 (90107384)

Project Period (FY) 2001 – 2002
KeywordsFilamentous Fungi / Polyketide / Polyketide Synthase / Mycotoxin / Mycosis / Inhibitor / 植物病原菌
Research Abstract

Aspergillus fumigatus, a ubiquitous fungus, causes allergy, noninvasive colonization or life-threatening invasive pulmonary aspergillosis in human beings. Its bluish-green conidial pigmentation has been shown to be a critical virulence factor and is resulted by polymerization of 1,8-dihydroxynaphthalene. Alb1p, a poiyketide synthase of this fungus, is the initial enzyme of the biosynthetic pathway leading to the pigment and has been chosen as the target for screening of novel inhibitors from natural sources in this study. In the first year, construction of in vivo screening method for inhibitors was pursued with heterologous expression of Alb1 gene in fungal host, Asp. Oryzae. However, several drawbacks including poor reproducibility in growth of transformant, relatively long culture period, and etc, had hampered the use of this fungal transformant for the practical screening for large number of samples. In the second year, expression of the same enzyme gene in yeast was attempted. Yeast expression vector harboring Alb1 gene was introduced into yeast together with the second vector with phosphopanthethenyl transferase gene by the established procedures. The double transformant produced yellow pigment YWA1, the Alb1p reaction product, as confirmed by LC/APCIMS. With this transformant, test samples of some 240 kinds of microbial cultures were tested for their in vivo inhibitory activity against Alb1p reaction, which was estimated by the decrease of YWA1 production as monitored by absorption at 406 nm. Five of them showed potent inhibition comparable to that of a positive control, cerulenin. Two microbial starins were cultured in large scale to isolate active principles. Activity guided fractionation of the extracts, however, resulted in separation of the inhibitory activity in several fractions and so far none of the pure compound has been obtained yet.

  • Research Products

    (7 results)

All Other

All Publications (7 results)

  • [Publications] H.-F.g Tsai, I.Fujii, A.Watanabe, M.H.Wheeler, Y.-C.Chang, Y.Yasuoka, Y.Ebizuka, K.J.K.-Chung: "Pentaketide-Melanin Biosynthesis in Aspergillus fumigatus Requires Chain-length Shortening of a Heptaketide Precursor"J. Biol. Chem. 276. 29292-29298 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] S.Okamoto, M.Sakurada, Y.Kubo, G.Tsuji, I.Fujii, Y.Ebizuka, M.ono, H.Nagasawa, S.Sakuda: "Inhibitory effect of Aflastatin A on Melanin Biosynthesis by Colletotrichum lagenarium"Microbiology. 147. 2623-2628 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Akira Watanabe, Yutaka Ebizuka: "A Novel Hexaketide Naphthalene Synthesized by a Chimeric Polyketide Synthase Composed of Fungal Pentaketide and Heptaketide Synthases"Tetrahedron Letters.. 43. 843-846 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Isao Fujii, Akira Watanabe, Yutaka Ebizuka: "More Functions for Multifunctional Polyketide Synthases"Advances in Fungal Biotechnology for Industry, Agriculture and Medicine (Klewer Academic/Plenum Publishers). (印刷中). (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Huei-Fung Tsai, Isao Fujii, Akira Watanabe, Michael H. Wheeler, Yun C. Chang, Yoshinori Yasuoka, Yutaka Ebizuka, and K. J. Kwon-Chung: "Pentaketide-melanin Biosynthesis in Aspergillus fumigatus Requires Chain-length Shortening of a Heptaketide Precursor"J. Biol. Chem.. 276. 29292-29298 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Susumu Okamoto, Masaru Sakurada, Yasuyuki Kubo, Gento Tsuji, Isao Fujii, Yutaka Ebizuka, Makoto Ono, Hiromichi Nagasawa, and Shohei Sakuda: "Inhibitory Effect of Aflastatin A on Melanin Biosynthesis by Colletotrichum lagenarium"Microbiology. 147. 2623-2628 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Akira Watanabe, and Yutaka Ebizuka: "A Novel Hexaketide Naphthalene Synthesized by a Chimeric Polyketide Synthase Composed of Fungal Pentaketide and Heptaketide Synthases"Tetrahedron Lett.. 43. 843-846 (2002)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2004-04-14  

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