Identification of biosynthetic gene clusters of bioactive natural products and their producing bacteria based on sponges life cycle

• Project/Area Number: 16H04980
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Aquatic life science
• Research Institution: Kitasato University (2018-2019); The University of Tokyo (2016-2017)
• Principal Investigator: Takada Kentaro 北里大学, 海洋生命科学部, 准教授 (90455353)
• Co-Investigator(Kenkyū-buntansha): 松永 茂樹 東京大学, 大学院農学生命科学研究科(農学部), 教授 (60183951)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2019: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2018: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2017: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2016: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
• Keywords: 海洋天然物 / 共生微生物 / 生物活性物質 / メタゲノム解析

Outline of Final Research Achievements

Marine sponges have been recognized as critical marine biochemical resources because some sponge-derived natural products are used as research reagents and chemotherapeutic agents. However, the lack of a sufficient supply of bioactive compounds for clinical development has been a problem. In this study, we focus on the sponge life cycle to identify biosynthetic gene clusters of bioactive natural products and their producers. As a result, we found the biosynthetic gene cluster of mycalolides, inhibitors of actin depolymerization, and its producing bacteria. We also revealed that the Mycale sponge inherits symbiotic bacteria producing mycalolides from parents to offspring via microbial transmission.

Academic Significance and Societal Importance of the Research Achievements

本研究は、海洋生物由来の有用物質の生産者および生合成機構を明らかにすることに成功し、創薬における医薬品候補化合物の応用開発に向けた大きな知見を得ることができた。また、活性物質の生産微生物が新規であったことより、海洋には未利用で有用な微生物資源が存在していることを明らかにした。

Research Products

• [Journal Article] Metachromins X and Y from a marine sponge Spongia sp. and their effects on cell cycle progression. (2020)
  • Author(s): Hitora Y, Takada K, Ise Y, Woo S.P, Inoue S, Mori N, Takikawa H, Nakamukai S, Okada S, Matsunaga S
  • Journal Title: Bioorg. Med. Chem. Volume: 28 Issue: 2 Pages: 115233-115233
  • DOI: 10.1016/j.bmc.2019.115233
  • Peer Reviewed
• [Journal Article] Heptavalinamide A, an Extensively N-Methylated Linear Nonapeptide from a Cyanobacterium Symploca sp. and Development of a Highly Sensitive Analysis of N,N-Dimethylvaline by LCMS (2020)
  • Author(s): Suo R, Watanabe, R, Takada, K, Suzuki T, Oikawa H, Itoi S, Sugita H, Matsunaga S
  • Journal Title: Org. Lett. Volume: 22 Issue: 4 Pages: 1254-1258
  • DOI: 10.1021/acs.orglett.9b04420
  • Peer Reviewed
• [Journal Article] Microsclerodermins N and O, cytotoxic cyclic peptides containing a p-​ethoxyphenyl moiety from a deep-sea marine sponge Pachastrella sp. (2020)
  • Author(s): Tian T, Takada K, Ise. Y, Ohtsuka S, Okada S, Matsunaga S
  • Journal Title: Tetrahedron Volume: 76 Issue: 10 Pages: 130997-130997
  • DOI: 10.1016/j.tet.2020.130997
  • Peer Reviewed
• [Journal Article] The Revised Structure of the Cyclic Octapeptide Surugamide A (2019)
  • Author(s): Matsuda Kenichi、Kuranaga Takefumi、Sano Ayae、Ninomiya Akihiro、Takada Kentaro、Wakimoto Toshiyuki
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 67 Issue: 5 Pages: 476-480
  • DOI: 10.1248/cpb.c19-00002
  • NAID: 130007641158
  • ISSN: 0009-2363, 1347-5223
  • Year and Date: 2019-05-01
  • Peer Reviewed
• [Journal Article] Miuramides A and B, Trisoxazole Macrolides from a Mycale sp. Marine Sponge, That Induce a Protrusion Phenotype in Cultured Mammalian Cells (2018)
  • Author(s): Rei Suo, Kentaro Takada, Hisanori Kohtsuka, Yuji Ise, Shigeru Okada, and Shigeki Matsunaga
  • Journal Title: Journal of Natural Products Volume: 81(4) Issue: 4 Pages: 1108-1112
  • DOI: 10.1021/acs.jnatprod.8b00101
  • Peer Reviewed
• [Journal Article] Poecillastrin H, a Chondropsin-type Macrolide with a Conjugated Pentaene Moiety, from a Characella sp. Marine Sponge (2018)
  • Author(s): Rei Suo, Kentaro Takada, Raku Irie, Ryuichi Watanabe, Toshiyuki Suzuki, Yuji Ise, Susumu Ohtsuka, Shigeru Okada, and Shigeki Matsunaga
  • Journal Title: Journal of Natural Products Volume: 81(5) Issue: 5 Pages: 1295-1299
  • DOI: 10.1021/acs.jnatprod.8b00180
  • Peer Reviewed
• [Journal Article] Stellatolide H, a cytotoxic peptide lactone from a deep-sea sponge Discodermia sp. (2018)
  • Author(s): Nakamukai Shohei、Takada Kentaro、Furihata Kazuo、Ise Yuji、Okada Shigeru、Morii Yasuhiro、Yamawaki Nobuhiro、Takatani Tomohiro、Arakawa Osamu、Gustafson Kirk R.、Matsunaga Shigeki
  • Journal Title: Tetrahedron Letters Volume: 59 Issue: 26 Pages: 2532-2536
  • DOI: 10.1016/j.tetlet.2018.05.033
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 2.Fukuhara, K., Takada, K.*, Watanabe, R., Suzuki, T., Okada, S., Matsunaga, S.* Colony-wise Analysis of a Theonella swinhoei Marine Sponge with a Yellow Interior Permitted the Isolation of Theonellamide I. (2018)
  • Author(s): 2.Fukuhara, K., Takada, K.*, Watanabe, R., Suzuki, T., Okada, S., Matsunaga, S.*
  • Journal Title: J. Nat. Prod. Volume: 81 Issue: 11 Pages: 2595-2599
  • DOI: 10.1021/acs.jnatprod.8b00591
  • Peer Reviewed
• [Journal Article] Lactomycins A-C, Dephosphorylated Phoslactomycin Derivatives that Inhibit Cathepsin B, from the Marine-derived Streptomyces sp. ACT232 (2018)
  • Author(s): Yi Sun, Rogie Royce Carandang, Yuta Harada, Shigeru Okada, Kazutoshi Yoshitake, Shuichi Asakawa, Yuichi Nogi, Shigeki Matsunaga, Kentaro Takada
  • Journal Title: Mar. Drugs Volume: 16 Issue: 2 Pages: 70-70
  • DOI: 10.3390/md16020070
  • Peer Reviewed / Open Access
• [Journal Article] Poecillastrin E, F, and G, cytotoxic chondropsin-type macrolides from a marine sponge Poecillastra sp. (2018)
  • Author(s): Raku Irie, Yuki Hitora, Yuji Ise, Shigeru Okada, Kentaro Takada, Shigeki Matsunaga
  • Journal Title: Tetrahedron Volume: 74 Issue: 13 Pages: 1430-1434
  • DOI: 10.1016/j.tet.2018.01.037
  • Peer Reviewed
• [Journal Article] Structure Revision of Poecillastrin C and the Absolute Configuration of the β-Hydroxyaspartic Acid Residue (2017)
  • Author(s): Raku Irie, Kentaro Takada, Yuji Ise, Susumu Ohtsuka, Shigeru Okada, Kirk R. Gustafson, Shigeki Matsunaga
  • Journal Title: Org. Lett. Volume: 19 Issue: 19 Pages: 5395-5397
  • DOI: 10.1021/acs.orglett.7b02835
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Resolution of the Confusion in the Assignments of Configuration for the Ciliatamides, Acylated Dipeptides (2017)
  • Author(s): Kentaro Takada, Raku Irie, Rei Suo, Shigeki Matsunaga
  • Journal Title: J. Nat. Prod. Volume: 80 Issue: 10 Pages: 2845-2849
  • DOI: 10.1021/acs.jnatprod.7b00684
  • Peer Reviewed
• [Journal Article] Dragmacidins G and H, Bisindole Alkaloids Tethered by a Guanidino Ethylthiopyrazine Moiety, from a Lipastrotethya sp. Marine Sponge (2016)
  • Author(s): Hitora, H.; Takada, K.; Ise, Y.; Okada, S.; Matsunaga, S.
  • Journal Title: Journal of Natural Products Volume: 79 Issue: 11 Pages: 2973-2976
  • DOI: 10.1021/acs.jnatprod.6b00710
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Curacin E from the Brittle Star Ophiocoma scolopendrina (2016)
  • Author(s): Ueoka, R.; Hitora, U.; Ito, A.; Yoshida, M.; Okada, S.; Takada, K.; Matsunaga, S.
  • Journal Title: Journal of Natural Products Volume: 79 Issue: 10 Pages: 2754-2757
  • DOI: 10.1021/acs.jnatprod.6b00701
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Yakushinamides, polyoxygenated fatty acid amides that inhibit HDACs and SIRTs, from the marine sponge Theonella swinhoei. (2016)
  • Author(s): Takada K, Imae Y, Ise Y, Ohtsuka S, Ito A, Okada S, Yoshida M, Matsunaga S.
  • Journal Title: J. Nat. Prod. Volume: 79 Issue: 9 Pages: 2384-2390
  • DOI: 10.1021/acs.jnatprod.6b00588
  • Peer Reviewed
• [Journal Article] Biosynthetic gene cluster for surugamide A encompasses an unrelated decapeptide, surugamide F (2016)
  • Author(s): Ninomiya, A., Katsuyama, Y., Kuranaga, T., Miyazaki, M., Nogi, Y., Okada, S., Wakimoto, T., Ohnishi, Y., Matsunaga, S., Takada, K.
  • Journal Title: ChemBioChem Volume: 17 Issue: 18 Pages: 1709-1712
  • DOI: 10.1002/cbic.201600350
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 海洋生物の毒を巡る化学コミュニケーション (2019)
  • Author(s): 高田健太郎
  • Organizer: 高磁場・高感度NMR利活用促進のための天然物分野シンポジウム
  • Invited
• [Presentation] 海綿動物の細胞毒性物質を生産する共生微生物と伝播機構の解明 (2019)
  • Author(s): 高田健太郎
  • Organizer: 日本分子生物学会
  • Invited
• [Presentation] 海綿動物の細胞毒性物質を生産する共生微生物と伝播機構の解明 (2018)
  • Author(s): 高田健太郎
  • Organizer: 日本農芸化学会
  • Invited
• [Presentation] Biologically active secondary metabolites from marine-derived actinomycetes (2017)
  • Author(s): Kentaro Takada
  • Organizer: The JSFS 85th Anniversary-Commemorative International Symposium
  • Int'l Joint Research
• [Presentation] Structures and a Function of Surugamides Isolated from Streptomycete (2017)
  • Author(s): Kentaro Takada
  • Organizer: 1st China-Japan Joint Symposium on Natural Product Biosynthesis
  • Int'l Joint Research
• [Presentation] Structures and a function of cyclic peptides isolated from Streptomycete (2016)
  • Author(s): Kentaro Takada
  • Organizer: 15th MaNaPro
  • Place of Presentation: Ceara, Brazil
  • Int'l Joint Research / Invited