High efficient production of secondary metabolites on the basis of genomes of Streptomyces

2009 Fiscal Year Final Research Report

• Project/Area Number: 17019009
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kitasato University (2009); The University of Tokyo (2005-2008)
• Principal Investigator: 池田 治生 Kitasato University, 感染制御科学府, 教授 (90159632)
• Co-Investigator(Kenkyū-buntansha): 鮒 信学 東京大学, 大学院・農学生命科学 (70361574) ; 石川 淳 国立感染症研究所 (40202957) ; 堀之内 末治 東京大学, 大学院・農学生命科学 (80143410)
• Project Period (FY): 2005 – 2009
• Keywords: ゲノム / 二次代謝産物 / 物質生産 / 放線菌

Research Abstract

The elucidation of the reaction mechanism of the various second metabolisms, which were observed in actinomycete microorganisms, was systematically examined. The results obtained in this study were applied to the improvement in pathway engineering, metabolic engineering, combinatorial biosynthesis and the creation of the artificial biosynthetic gene cluster for the production of new metabolites. Furthermore, the technology developed in this study was applied to improve the production level of not only known products but also unnatural products. Results would be useful for the development of new bioactive compounds in medical field and industrial materials. For the above purpose, we investigated and evaluated the detailed biosynthetic pathways and regulatory system(s) for their expression from the genome data of avermectin-producing Streptomyces avermitilis, Nocardia farcinia and streptomycin-producing Streptomyces griseus. We have also clarified the reaction mechanism of some biosynthesis gene clusters and novel reactions were identified (Baeyer-Villiger oxidation and new type of benzene ring formation). We also focused on cytochrome P450, flavonoid, and type-III polyketide synthesis and new unnatural flavonoids were discovered by above technology.

Research Products

• [Journal Article] Genomic basis for natural product biosynthetic diversity in the actinomycetes Nat. (2009)
  • Author(s): Nett, M. Ikeda, H. Bradley S. Moore, B.S.
  • Journal Title: Prod. Rep. 26 Pages: 1362-1384
• [Journal Article] Genome mining in Streptomyces avermitilis: A biochemical Baeyer-Villiger reaction and discovery of a new branch of the pentalenolactone family tree. (2009)
  • Author(s): Jiang, J., Tetzlaff, C.N., Yakamatsu, S., Iwatsuki, M., Komatsu, M., Ikeda, H., Cane, D.E.
  • Journal Title: Biochemistry 48 Pages: 6431-6440
• [Journal Article] The site-specific recombination system of actinophage TG1. (2009)
  • Author(s): Morita, K., Yamamoto, T., Fusada, N., Komatsu, M., Ikeda, H., Hirano, N., Takahashi, H.
  • Journal Title: FEMS Microbiol. Lett. 297 Pages: 234-240
• [Journal Article] Antibiotic Overproduction by rpsL and rsmG Mutants of Various Actinomycetes. (2009)
  • Author(s): Tanaka, Y., Komatsu, M., Okamoto, S., Tokuyama, S., Kaji, A., Ikeda, H., Ochi, K.
  • Journal Title: Appl. Environ. Microbiol 75 Pages: 4919-4922
• [Journal Article] Characterization of a regulatory gene, aveR, for the biosynthesis of avermectin in Streptomyces avermitilis. (2009)
  • Author(s): Kitani, K., Ikeda, H., Sakamoto, T., Noguchi, S., Nihira, T.
  • Journal Title: Appl. Microbiol. Biotechnol 82 Pages: 1089-1096
• [Journal Article] Crystal Structures of Cytochrome P450 105P1 from Streptomyces avermitilis: Conformational Flexibility and Histidine Ligation State. (2009)
  • Author(s): Xu, L-H., Fushinobu S., Ikeda, H., Wakagi, T., Shoun, H.
  • Journal Title: J. Bacteriol 191 Pages: 1211-1219
• [Journal Article] Dynamic changes in the extracellular proteome caused by absence of a pleiotropic regulator AdpA in Streptomyces griseus. (2009)
  • Author(s): Akanuma, G., Hara, H., Ohnishi, Y., Horinouchi, S.
  • Journal Title: Mol. Microbiol 73 Pages: 898-912
• [Journal Article] CebR as a master regulator for cellulose/cellooligosaccharide catabolism affects morphological development in Streptomyces griseus. (2009)
  • Author(s): Marushima, K., Ohnishi, Y., Horinouchi, S.
  • Journal Title: J. Bacteriol 191 Pages: 5930-5940
• [Journal Article] Identification and characterization of multiple curcumin synthases from the herb Curcuma longa. (2009)
  • Author(s): Katsuyama, Y., Kita, T., Horinouchi, S.
  • Journal Title: FEBS Lett. 583 Pages: 2799-2803
• [Journal Article] Enzymatic synthesis of bis-5-alkylresorcinols by resorcinol-producing type III polyketide synthases. (2009)
  • Author(s): Miyanaga, A., Horinouchi, S.
  • Journal Title: J. Antibiot 62 Pages: 371-376
• [Journal Article] Physically discrete beta-lactamase-type thioesterase catalyzes product release in atrochrysone synthesis by iterative type I polyketide synthase. (2009)
  • Author(s): Awakawa, T., Yokota, K., Funa, N., Doi, F., Mori, N., Watanabe, H., Horinouchi, S.
  • Journal Title: Chem. Biol. 16 Pages: 613-623
• [Journal Article] Identification and gene disruption of small noncoding RNAs in Streptomyces griseus. (2009)
  • Author(s): Tezuka, T., Hara, H., Ohnishi, Y., Horinouchi, S.
  • Journal Title: J. Bacteriol 191 Pages: 4896-4904
• [Journal Article] Biosynthesis of aliphatic polyketides by type III polyketide synthase and methyltransferase in Bacillus subtilis. (2009)
  • Author(s): Nakano, C., Ozawa, H., Akanuma, G., Funa, N., Horinouchi, S.
  • Journal Title: J. Bacteriol 191 Pages: 4916-4923
• [Journal Article] DNA microarray analysis of global gene regulation by A-factor in Streptomyces griseus. (2009)
  • Author(s): Hara, H., Ohnishi, Y., Horinouchi, S.
  • Journal Title: Microbiology 155 Pages: 2197-2210
• [Journal Article] Combinatorial biosynthesis of plant medicinal polyketides by microorganisms. Curr. (2009)
  • Author(s): Horinouchi, S.
  • Journal Title: Opin. Chem. Biol. 13 Pages: 197-204
• [Journal Article] Curcuminoid biosynthesis by two type III polyketide synthases in the herb Curcuma longa. (2009)
  • Author(s): Katsuyama, Y., Kita, T., Funa, N., Horinouchi, S.
  • Journal Title: J. Biol. Chem. 284 Pages: 11160-11170
• [Journal Article] Organization of the biosynthetic gene cluster for the polyketide antitumor macrolide, pladienolide, in Streptomyces platensis Mer-11107. (2008)
  • Author(s): Machida, K., Arisawa, A., Takeda, S., Tsuchida, T., Aritoku, Y., Yoshida, M., Ikeda, H.
  • Journal Title: Biosci. Biotechnol. Biochem 72 Pages: 2946-2952
• [Journal Article] Identification and functional analysis of genes controlling biosynthesis of 2-methylisoborneol. (2008)
  • Author(s): Komatsu, M., Tsuda, M., Omura, S., Oikawa, H., Ikeda, H.
  • Journal Title: Proc. Natl. Acad. Sci. 105 Pages: 74224-7427
• [Journal Article] Conditionally positive effect of the TetR-family transcriptional regulator AtrA on streptomycin production by Streptomyces griseus. (2008)
  • Author(s): Hirano, S., Tanaka, K., Ohnishi, Y., Horinouchi, S.
  • Journal Title: Microbiology 154 Pages: 905-914
• [Journal Article] Phenolic lipids synthesized by type III polyketide synthase confer penicillin resistance on Streptomyces griseus. (2008)
  • Author(s): Funabashi, M., Funa, N., Horinouchi, S.
  • Journal Title: J. Biol. Chem. 283 Pages: 13983-13991
• [Journal Article] Direct transfer of starter substrates from type I fatty acid synthase to type III polyketide synthases in phenolic lipid synthesis. (2008)
  • Author(s): Miyanaga, A., Funa, N., Awakawa, T., Horinouchi, S.
  • Journal Title: Proc. Natl. Acad. Sci. 105 Pages: 871-876
• [Journal Article] Genome sequence of the streptomycin-producing microorganism Streptomyces griseus IFO 13350. (2008)
  • Author(s): Ohnishi, Y., Ishikawa, J., Hara, H., Suzuki, H., Ikenoya, M., Ikeda, H., Yamashita, A., Hattori, M., Horinouchi, S.
  • Journal Title: J. Bacteriol 190 Pages: 4050-4060
• [Journal Article] A novel pair of terminal protein and telomere-associated protein for replication of the linear chromosome of Streptomyces griseus. (2008)
  • Author(s): Suzuki, H., Marushima, K., Ohnishi, Y., Horinouchi, S.
  • Journal Title: Biosci. Biotechnol. Biochem 72 Pages: 2973-2980
• [Journal Article] Production of curcuminoids by Escherichia coli containing an artificial biosynthesis pathway. (2008)
  • Author(s): Katsuyama, Y., Matsuzawa, M., Funa, N., Horinouchi, S.
  • Journal Title: Microbiology 154 Pages: 2620-2628
• [Remarks]
  • URL: http://avermitilis.ls.kitasato-u.ac.jp
• [Remarks]
  • URL: http://nocardia.nih.go.jp/
• [Remarks]
  • URL: http://streptomyces.nih.go.jp/griseus/