Bioactive secondary metabolites produced by sponge symbiont Entotheonella

• Project/Area Number: 15H03112
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biomolecular chemistry
• Research Institution: Hokkaido University
• Principal Investigator: WAKIMOTO Toshiyuki 北海道大学, 薬学研究院, 教授 (70363900)
• Co-Investigator(Renkei-kenkyūsha): KURANAGA Takefumi 北海道大学, 大学院薬学研究院, 講師 (70625201) ; EGAMI Yoko 北海道大学, 大学院薬学研究院, 助教 (50758612)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2016: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2015: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 海綿動物 / 生合成遺伝子 / 生物活性物質 / 生合成 / 共生微生物 / 海綿共生微生物 / 二次代謝産物 / ペプチド / 海綿 / Entotheonella

Outline of Final Research Achievements

Marine sponges are prolific sources of bioactive molecules as well as highly complex consortia, including significantly large populations of symbiotic bacteria. The symbiotic bacteria often cannot be cultured under normal laboratory conditions. To access the gene clusters responsible for the biosynthesis of sponge-derived bioactive natural products, homology-based screening of the sponge metagenome library has been implemented. We successfully obtained the biosynthetic gene clusters of cytotoxic compounds, calyculins isolated from the Japanese sponge Discodermia calyx by a metagenome mining approach. The single cell analysis revealed that all these gene clusters were encoded by the same filamentous bacterium, which was identified as Candidatus “Entotheonella sp.” based on the 16S rRNA sequence. In this study, we investigated new metabolites as well as other gene clusters responsible for the biosynthesis of bioactive peptides derived from Discodermia kiiensis and Theonella swinhoei.

Research Products

• [Int'l Joint Research] ETH Zurich(Switzerland)
• [Int'l Joint Research] ETH, Zurich(Switzerland)
• [Journal Article] Diastereoselective total synthesis and structural confirmation of surugamide F (2018)
  • Author(s): Kuranaga Takefumi、Fukuba Atsuki、Ninomiya Akihiro、Takada Kentaro、Matsunaga Shigeki、Wakimoto Toshiyuki
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 66
  • NAID: 130007382323
  • Peer Reviewed
• [Journal Article] Biosynthetic insights of calyculin- and misakinolide-type compounds in “Candidatus Entotheonella sp.” (2018)
  • Author(s): Uria Agustinus、Piel Joern、Wakimoto Toshiyuki
  • Journal Title: Methods in Enzymology Volume: 604
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Palmitoyl lactic acid induces adipogenesis and a brown fat-like phenotype in 3T3-L1 preadipocytes (2018)
  • Author(s): Uno Yuka、Yamamoto Hirona、Shuto Takatsuki、Sato Yoshinori、Kuranaga Takefumi、Yazawa Kazunaga、Ono Yasuo、Wakimoto Toshiyuki
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids Volume: 1863 Issue: 7 Pages: 772-782
  • DOI: 10.1016/j.bbalip.2018.04.003
  • Peer Reviewed
• [Journal Article] Protein phosphatases 1 and 2A and their naturally occurring inhibitors: current topics in smooth muscle physiology and chemical biology (2017)
  • Author(s): Takai Akira、Eto Masumi、Hirano Katsuya、Takeya Kosuke、Wakimoto Toshiyuki、Watanabe Masaru
  • Journal Title: J Physiol Sci Volume: 68 Issue: 1 Pages: 1-17
  • DOI: 10.1007/s12576-017-0556-6
  • NAID: 40021443577
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Total synthesis of theonellapeptolide Id (2017)
  • Author(s): Kuranaga, T., Enomoto, A., Tan, H., Fujita, K., Wakimoto, T.
  • Journal Title: Org. Lett. Volume: 19 Issue: 6 Pages: 1366-1369
  • DOI: 10.1021/acs.orglett.7b00249
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Toward dark matter of natural products” (2017)
  • Author(s): Wakimoto, T.
  • Journal Title: Chem. Rec. Volume: 17 Issue: 11 Pages: 1124-1134
  • DOI: 10.1002/tcr.201700009
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of pyridinium with three indole moieties as an antimicrobial agent (2017)
  • Author(s): Okada, M., Sugita, T., Wong, C. P., Wakimoto, T., Abe, I.
  • Journal Title: J. Nat. Prod., Volume: 80 Issue: 4 Pages: 1205-1209
  • DOI: 10.1021/acs.jnatprod.6b01152
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Characterization of giant modular PKSs provides insight into genetic mechanism for structural diversification of aminopolyol polyketides (2017)
  • Author(s): Zhang, L., Hashimoto, T., Qin, B., Hashimoto, J., Kozone, I., Kawahara, T., Okada, M., Awakawa, T., Ito, T., Asakawa, Y., Ueki, M., Takahashi, S., Osada, H., Wakimoto, T., Ikeda, H., Shin-ya, K., Abe, I.
  • Journal Title: Angew. Chem. Int. Ed. Volume: 56 Issue: 7 Pages: 1740-1745
  • DOI: 10.1002/anie.201611371
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Calyculin: Nature’s way of making the sponge-derived cytotoxin (2016)
  • Author(s): T. Wakimoto, Y. Egami, I. Abe
  • Journal Title: Nat. Prod. Rep. Volume: 未定 Issue: 6 Pages: 751-760
  • DOI: 10.1039/c5np00123d
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] An unusual chimeric diterpene synthase from Emericella varicolor and its functional conversion into a sesterterpene synthase by domain swapping (2016)
  • Author(s): B. Qin, Y. Matsuda, T. Mori, M. Okada, Z. Quan, T. Mitsuhashi, T. Wakimoto, I. Abe
  • Journal Title: Angew. Chem. Int. Ed. Volume: 55 Issue: 5 Pages: 1658-1661
  • DOI: 10.1002/anie.201509263
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Metagenomic analysis of the sponge Discodermia reveals the production of the cyanobacterial natural product kasumigamide by 'Entotheonella' (2016)
  • Author(s): Nakashima, Y., Egami, Y., Kimura, M., Wakimoto, T., Abe, I.
  • Journal Title: PLoS ONE Volume: 11 Issue: 10 Pages: e0164468-e0164468
  • DOI: 10.1371/journal.pone.0164468
  • NAID: 120005893293
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Sulfoureido lipopeptides from the marine sponge Discodermia kiiensis (2016)
  • Author(s): Tan, K. C., Wakimoto, T., Abe, I.
  • Journal Title: J. Nat. Prod. Volume: 79 Issue: 9 Pages: 2418-2422
  • DOI: 10.1021/acs.jnatprod.6b00586
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Structural diversification of lyngbyatoxin A by host-dependent heterologous expression of the tleABC biosynthetic gene cluster (2016)
  • Author(s): Zhang, L., Hoshino, S., Awakawa, T., Wakimoto, T., Abe, I.
  • Journal Title: ChemBioChem Volume: 17 Issue: 15 Pages: 1407-1411
  • DOI: 10.1002/cbic.201600229
  • Peer Reviewed / Acknowledgement Compliant
• [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
• [Journal Article] Concise synthesis of anserine: efficient solvent tuning in asymmetric hydrogenation reaction (2016)
  • Author(s): M. Yamashita, K. Shimizu, Y. Koizumi, T. Wakimotoa, Y. Hamashima, T. Asakawa, M. Inai, T. Kan
  • Journal Title: Synlet Volume: 27 Issue: 19 Pages: 2734-2736
  • DOI: 10.1055/s-0035-1562796
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Syntheses of methylated catechins and theaflavins using the Ns group to protect and deactivate the phenol (2016)
  • Author(s): T. Asakawa, Y. Kawabe, A. Yoshida, Y. Aihara, T. Manabe, Y. Hirose, A. Sakurada, M. Inai, Y. Hamashima, T. Furuta, T. Wakimoto, T. Kan
  • Journal Title: J. Antibiot. Volume: 69 Issue: 4 Pages: 299-312
  • DOI: 10.1038/ja.2016.14
  • Peer Reviewed
• [Journal Article] 海綿共生微生物による生物活性物質の生産 (2016)
  • Author(s): 江上蓉子, 脇本敏幸, 阿部郁朗
  • Journal Title: バイオインダストリー Volume: 33 Pages: 11-17
  • Peer Reviewed
• [Journal Article] Uncovering the unusual D-ring construction in terretonin biosynthesis by collaboration of a multifunctional cytochrome P450 and a unique isomerase (2015)
  • Author(s): Matsuda, Y., Iwabuchi, T., Wakimoto, T., Awakawa, T., Abe, I.
  • Journal Title: J. Am. Chem. Soc. Volume: 137 Issue: 9 Pages: 3393-3401
  • DOI: 10.1021/jacs.5b00570
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Structural basis for the β-carboline alkaloids production by the microbial homodimeric enzyme McbB (2015)
  • Author(s): T. Mori, S. Hoshino, S. Sahashi, T. Wakimoto, T. Matsui, H. Morita, I. Abe
  • Journal Title: Chem. Biol. Volume: 17 Issue: 7 Pages: 1501-1504
  • DOI: 10.1016/j.chembiol.2015.06.006
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Chojalactones A-C, Cytotoxic Butanolides Isolated from Streptomyces sp. Cultivated with Mycolic Acid Containing Bacterium. (2015)
  • Author(s): Hoshino S, Wakimoto T, Onaka H, Abe I.
  • Journal Title: Org Lett. Volume: 印刷中 Issue: 6 Pages: 1501-1504
  • DOI: 10.1021/acs.orglett.5b00385
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Production of indole antibiotics induced by exogenous gene derived from sponge metagenome (2015)
  • Author(s): Y. Takeshige, Y. Egami, T. Wakimoto, I. Abe
  • Journal Title: Mol. BioSyst. Volume: 11 Issue: 5 Pages: 1290-1294
  • DOI: 10.1039/c5mb00131e
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dietziamides, novel tetramic acid dimers from Dietzia timorensis MZ-3 with antioxidative activity (2015)
  • Author(s): S. Hoshino, T. Wakimoto, H. Zhang, F. Hayashi, M. Okada, I. Abe
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 25 Issue: 18 Pages: 3953-3955
  • DOI: 10.1016/j.bmcl.2015.07.035
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Niizalactams A-C, multicyclic macrolactams isolated from combined culture of Streptomyces with mycolic acid-containing bacterium (2015)
  • Author(s): S. Hoshino, M. Okada, T. Wakimoto, H. Zhang, F. Hayashi, H. Onaka, I. Abe
  • Journal Title: J. Nat. Prod. Volume: 78 Issue: 12 Pages: 3011-3017
  • DOI: 10.1021/acs.jnatprod.5b00804
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 海綿動物の化学防御を担う共生細菌 (2015)
  • Author(s): 江上蓉子、脇本敏幸、阿部郁朗
  • Journal Title: 細胞工学 Volume: 34 Pages: 412-416
  • NAID: 40020416788
  • Peer Reviewed
• [Presentation] メタゲノムマイニングによる海綿由来新規天然物の探索 (2018)
  • Author(s): 脇本敏幸
  • Organizer: 日本薬学会第138会
  • Invited
• [Presentation] Toward the dark matter of marine natural products (2017)
  • Author(s): Toshiyuki Wakimoto
  • Organizer: International Symposium on Marine Natural Products
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2017-02-28
  • Int'l Joint Research / Invited
• [Presentation] メタゲノムマイニングによる海綿由来新規天然物の探索 (2017)
  • Author(s): 脇本敏幸
  • Organizer: 理研シンポジウム、高磁場・高感度NMR利活用促進のための天然物分野における日中連携シンポジウム2017
  • Int'l Joint Research / Invited
• [Presentation] Marine sponge-derived metagenomes/uncultured bacteria - a rich source of novel natural product biosynthetic genes (2017)
  • Author(s): Wakimoto Toshiyuki
  • Organizer: South China Sea Institute of Oceanology, Chinese Academy of Sciences, China
  • Int'l Joint Research / Invited
• [Presentation] Marine sponge-derived metagenomes/uncultured bacteria - a rich source of novel natural product biosynthetic genes (2017)
  • Author(s): Wakimoto Toshiyuki
  • Organizer: Jinan University, College of Pharmacy, China
  • Int'l Joint Research / Invited
• [Presentation] Marine sponge-derived metagenomes/uncultured bacteria - a rich source of novel natural product biosynthetic genes (2017)
  • Author(s): Wakimoto Toshiyuki
  • Organizer: International Conference on Marine Biodiversity and Biotechnology, Jakarta, Indonesia
  • Int'l Joint Research / Invited
• [Presentation] Marine sponge-derived metagenomes/uncultured bacteria - a rich source of novel natural product biosynthetic genes (2017)
  • Author(s): Wakimoto Toshiyuki
  • Organizer: 1st China-Japan Joint Symposium on Natural Product Biosynthesis, Shanghai, China
  • Int'l Joint Research / Invited
• [Presentation] Activated Chemical Defense of Japanese Marine Sponge Discodermia calyx (2017)
  • Author(s): Wakimoto Toshiyuki
  • Organizer: ISCE/APACE, Kyoto, Japan
  • Int'l Joint Research / Invited
• [Presentation] Marine sponge-derived metagenomes/uncultured bacteria - a rich source of novel natural product biosynthetic genes (2017)
  • Author(s): Wakimoto Toshiyuki
  • Organizer: 9th US-Japan Seminar on Natural Product Biosynthesis, UCLA Lake Arrowhead Conference Center, California, USA
  • Int'l Joint Research / Invited
• [Presentation] A Bacterial Symbiont in Japanese Marine Sponges Produces Biologically Active Metabolites (2016)
  • Author(s): Toshiyuki Wakimoto
  • Organizer: The 3rd Myanmar-Japan International Symposium
  • Place of Presentation: Pathein, Myanmar
  • Year and Date: 2016-12-03
  • Int'l Joint Research / Invited
• [Presentation] 海綿動物由来生物活性物質の探索と生合成研究 (2016)
  • Author(s): 脇本敏幸
  • Organizer: 若手研究者のための有機化学札幌セミナー
  • Place of Presentation: 北海道大学理学部（北海道札幌市）
  • Year and Date: 2016-11-29
  • Invited
• [Presentation] Marine sponge-derived metagenomes/uncultured bacteria - a rich source of novel natural product biosynthetic genes (2016)
  • Author(s): Toshiyuki Wakimoto
  • Organizer: Czech-Japan Joint Workshop
  • Place of Presentation: Prague, Czech Republic
  • Year and Date: 2016-11-09
  • Int'l Joint Research / Invited
• [Presentation] 難培養微生物を起源とする海綿由来生物活性物質の生合成研究 (2016)
  • Author(s): 脇本敏幸
  • Organizer: 日本農芸化学会2016年度大会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2016-03-30
  • Invited
• [Presentation] Recent topics in natural product-derived protein phosphatase inhibitors (2016)
  • Author(s): T. Wakimoto
  • Organizer: 第93回 日本生理学会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2016-03-22
  • Invited
• [Presentation] Activated Chemical Defense of a Sponge-Microbe Association (2016)
  • Author(s): T. Wakimoto
  • Organizer: Gordon Research Conference Marine Natural Products
  • Place of Presentation: Ventura, CA, USA
  • Year and Date: 2016-03-08
  • Int'l Joint Research / Invited
• [Presentation] A Bacterial Symbiont in Japanese Marine Sponges Produces Biologically Active Metabolites (2016)
  • Author(s): T. Wakimoto
  • Organizer: The 4th Frontier Chemistry Center International Symposium
  • Place of Presentation: 北海道大学（北海道札幌市）
  • Year and Date: 2016-02-23
  • Int'l Joint Research / Invited
• [Presentation] 海綿―共生微生物系の化学防御機構 (2015)
  • Author(s): 脇本敏幸
  • Organizer: 第67回 日本生物工学会
  • Place of Presentation: 城山観光ホテル（鹿児島県鹿児島市）
  • Year and Date: 2015-10-27
  • Invited
• [Presentation] 海洋天然物化学が明示した難培養微生物の存在 (2015)
  • Author(s): 脇本敏幸
  • Organizer: 第50回 天然物化学談話会
  • Place of Presentation: グリーンピア岩沼（宮城県岩沼市）
  • Year and Date: 2015-07-03
  • Invited
• [Presentation] 海綿―共生微生物系の化学防御機構 (2015)
  • Author(s): 脇本敏幸
  • Organizer: 第10回 化学生態学研究会
  • Place of Presentation: 湯の川プリンスホテル渚亭（北海道函館市）
  • Year and Date: 2015-06-13
  • Invited
• [Book] 天然物の化学ー魅力と展望ー」上村大輔編 (2016)
  • Author(s): 脇本敏幸
  • Publisher: 東京化学同人
• [Remarks] 北海道大学大学院薬学研究院天然物化学研究室
  • URL: http://www.pharm.hokudai.ac.jp/tennen/index.html