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Laboratory of Microbial Engineering

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Research Synopsis

      We are currently carrying out molecular genetic analysis on the biosynthesis and regulation of production of antibiotics and bioactive materials using Streptomyces avermitilis, a species isolated at the Kitasato Institute. S. avermitilis is a microorganism that produces avermectin, which is a polyketide antibiotic with anti-parasitic and anti-insect activities used as an anthelmintic. We determined the complete nucleotide sequence of the linear chromosome of S. avermitilis(9,025,608 base pairs) in 2003 (http://avermitilis.ls.kitasato-u.ac.jp).

     The most interesting characteristic (from both industrial and academic viewpoints) of actinomycetes, particularly streptomycetes, is the ability to produce a wide variety of secondary metabolites including antibiotics and bioactive materials. With the completion of genome analysis, close analysis of the material-producing ability of actinomycetes on the molecular level has become possible. We are conducting research primarily by the post-genome analysis of secondary metabolite production processes.

     Basic and applied studies for drug discovery based on the genetic information of microorganisms.

(1) Genome analysis of useful microorganisms and the functional analysis
     of interesting genes

(2) Production of useful compounds based on the genomic information
     of microorganisms

(3) Comprehensive analysis of secondary metabolites produced by
     S. avermitilis.

(4) Analysis of the regulation of expression of the 33 types of
     cytochrome P450 genes of S. avermitilis

(5) Basic research on the structural prediction of secondary metabolites
     based on genomic information

(6) Preparation of the DNA microarrays of all ORFs of S. avermitilis
     and various analyses using them

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Staff

Name position
Ikeda Haruo   Professor iChief of a Laboratoryj
Komatsu Mamoru   Assistant Professor

Student

Name Student
Yamada Yuki   Student, Doctoral Program
Kashima Yui   Student, Master's Program

Researcher

Name Researcher
Miyamoto Seiko   Researcher
Komatsu Kyoko   Assistant Researcher
Koiwai Hanae   Assistant Researcher

Research Results

  1. Komatsu, M. Komatsu, K. Koiwai, H. Yamada, Y. Kozone, I. Izumikawa, M. Hashimoto, J. Takagi, M. Omura, S. Shin-ya, K. Cane, D.E. Ikeda, H. : Engineered Streptomyces avermitilis Host for Heterologous Expression of Biosynthetic Gene Cluster for Secondary Metabolites. ACS Synth. Biol. 2013 dx.doi.org/10.1021/sb3001003.
  2. Zhu, D. Wang, Y. Zhang, M. Ikeda, H. Den, Z. Cane, D.E. : Product-Mediated Regulation of Pentalenolactone Biosynthesis in Streptomyces by the MarR/SlyA Family Activators PenR and PntR. J. Bacteriol. 2013 doi:10.1128/JB.02079-12.
  3. Aroonsri, A, Kitani, S. Hashimoto, J. Kosone, I, Izumikawa, M. Komatsu, M. Fujita, N. Takahashi, Y. Shin-ya, K. Ikeda, H. Nihira, T. Pleiotropic control of secondary metabolism and morphological development by KsbC, a butyrolactone-autoregulator receptor homologue in Kitasatospora setae. Appl. Environ. Microbiol. 2012 78, 8015-8024.
  4. Yamada, Y. Cane, D.E. Ikeda, H. : Diversity and Analysis of Bacterial Terpene Synthases. In David A. Hopwood, ed. Natural Product Biosynthesis by Microorganisms and Plants, Part A, Methods in Enzymology 2012 Vol. 515, pp.123-162, Burlington, Academic Press.
  5. Aroonsri, A. Kitani, S. Ikeda, H. Nihira, T. Kitasataline, : a novel beta-carboline alkaloid from Kitasatospora setae NBRC 14216. J. Biosci. Bioeng. 2012 114, 56-58.
  6. Inokoshi, J. Matsuhama, M. Miyake, M. Ikeda, H. Tomoda, H. : Molecular cloning of the gene cluster for lariatin biosynthesis of Rhodococcus jostii K01-B0171. Appl. Microbiol. Biotechnol. 2012 95, 451-460.
  7. Koyama, N. Tokura, Y. Munch, D. Sahl, H. Schneider, T. Shibagaki, Y. Ikeda, H. Tmoda, H. : The Nonantibiotic Small Molecule Cyslabdan Enhances the Potency of ƒΐ-Lactams against MRSA by Inhibiting Pentaglycine Interpeptide Bridge Synthesis. PLoS ONE 7, e48981.

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  1. Cane, D.E. Ikeda, H. : Exploration and Mining of the Bacterial Terpenome. Accounts of Chemical Research 2011 45 463-472.
  2. Miyamoto, K.T. Kitani, S. Komatsu, M. Ikeda, H. Nihira, T. : The autoregulator receptor homolog AvaR3 plays a regulatory role in antibiotic production, mecelial aggregation and colony development of Streptomyces avermitilis. Microbiology 2011 157, 2266-2275.
  3. Uchida, M. Takamatsu, S. Arima, S. Miyamoto, K.T. Kitani, S. Nihira, T. Ikeda, H. Nagamitsu, T. : Total synthesis and absolute configuration of avenolide, extracelluar factor in Streptomyces avermitilis. J. Antibiot. 2011 64, 781-787.
  4. Kitani, S. Miyamoto, K.T. Takamatsu, S. Herawati, E. Iguchi, H. Nishitomi, K. Uchida, M. Nagamitsu, T. Omura, S. Ikeda, H. Nihira, T. Avenolide, : a Streptomyceshormone controlling antibiotic production in Streptomyces avermitilis. Proc. Natl. Acad. Sci. USA 2011, 108, 16410-16415.
  5. Chu, W.K.W. Ikeda, H. Cane, D.E. : Cloning and characterization of Pfl_1841, a 2-methylenebornane synthase in Pseudomonas fluorescens PfO-1. Tetrahedron 2011, 67, 6627-6632.
  6. Takahashi, S., Toyoda, A., Sekiyama, Y., Takagi, H., Nogawa, T., Uramoto, M., Suzuki, R., Koshino, H., Kumano, T., Panthee, S., Dairi, T., Ishikawa, J., Ikeda, H., Sakaki, Y., Osada, H. : Reveromycin A biosynthesis uses RevG and RevJ for stereospecific spiroacetal formation. Nat. Chem. Biol. 2011, 7, 461-468.
  7. Miyamoto, T.K., Kitani, S., Komatsu, M., Ikeda, H., Nihira, T. : The autoregulator-receptor homologue AvaR3 plays a regulatory role in antibiotic production, mycelial aggregation and colony development of Streptomyces avermitilis. Microbiology 2011, 157, 2266-2275.
  8. Seo, M-J. Zhu, D. Endo, S. Ikeda, H. Cane, D.E. : Genome mining in Streptomyces. Elucidation of the role of Baeyer-Villiger monooxygenases and non-heme iron-dependent dehydrogenase/oxygenases in the final steps of the biosynthesis of pentalenolactone and neopentalenolactone. Biochemistry 2011, 50, 1739-1754.
  9. Zhu, D. Seo, M-J. Ikeda, H. Cane, D.E. : Genome mining in Streptomyces. Discovery of an unprecedented P450-catalyzed oxidative rearrangement that is the final step in the biosynthesis of pentalenolactone. J. Am. Chem. Soc. 2011, 133, 2128-2131.
  10. Takamatsu, S. Lin, X. Nara, A. Komatsu, M. Cane, D.E. Ikeda, H. : Characterization of a silent sesquiterpenoid biosynthetic pathway in Streptomyces avermitilis controlling epi-isozizaene and albaflavenone biosynthesis and isolation of a new oxidized epi-isozizaene metabolite. Microb. Biotechnol. 2011, 4, 184-191.
  11. Giglio, S. Chou, W.K.W. Ikeda, H. Cane, D.E. Monis, T. : Biosynthesis of 2-methylisoborneol in Cyanobacteria. Environ. Sci. Technol. 2011, 45, 992-998.
  12. Takamatsu, S. Xu, L-H. Fushinobu, S. Shoun, H. Komatsu, M. Cane, D.E. Ikeda, H. : Pentalenic acid is a shunt metabolite in the biosynthesis of the pentalenolactone family of metabolites: Hydroxylation of 1-deoxypentalenic acid mediated by CYP105D7 (SAV_7469) of Streptomyces avermitilis. J. Antibiot. 2011, 64, 65-71.

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  1. Ichikawa, N. Oguchi, A. Ikeda, H. Ishikawa, J. Kitani, S. Watanabe, Y. Nakamura, S. Katano, Y. Sasagawa, M. Ankai, A. Fukui, S. Hashimoto, Y. Kamata, S. Otoguro, M. Tanikawa, S. Nihira, T. Horinouchi, S. Ohnishi, Y. Hayakawa, M. Kuzuyama, T. Arisawa, A. Nomoto, F. Miura, H. Takahashi, Y. Fujita, N. : Genome sequence of Kitasatospora setae NBRC 14216T: An evolutionary snapshot of the family Streptomycetaceae. DNA Res. 2010, 17, 393-406.
  2. Chou, W.K.W. Fanizza, I. Uchiyama, T. Komatsu, M. Ikeda, H. Cane, D.E. : Genome mining in Streptomyces avermitilis: Cloning and characterization of SAV_76, the synthase for a new sesquiterpene, Avermitilol. J. Am. Chem. Soc.. 2010, 132, 8850-8851.
  3. Xu, L. Fushinobu, S. Takamatsu, S. Wakagi, T. Ikeda, H. Shoun, H. : Regio- and stereospecificity of filipin hydroxylation sites revealed by crystal structures of cytochrome P450 105P1 and 105D6 from Streptomyces avermitilis. J. Biol. Chem. 2010, 285, 16844-16853.
  4. Komatsu, M. Uchiyama, T. Omura, S. Cane, D.E. Ikeda, H. : Genome-minimized Streptomyce  shost for the heterologous expression of secondary metabolism. Proc. Natl. Acad. Sci. USA. 2010, 107, 2646-2651.