The mechanism regulating the function of a natural cytotoxin

• Project/Area Number: 15K12740
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• 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): EGAMI Yoko 北海道大学, 大学院薬学研究院, 助教 (50758612)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: Calyculin A / リン酸化 / 脱リン酸化 / 海綿動物 / カリクリンA / 生合成 / 海綿共生微生物 / calyculin A

Outline of Final Research Achievements

Marine sponges are prolific sources of highly potent cytotoxic compounds, some of which are promising as anticancer drugs. However, the potent cytotoxicity would be harmful to the host sponge, because marine sponges are also animals. Therefore, it is possible that the self-resistance and activated defense systems underlie their biosynthetic mechanism. Wound-activated chemical defense systems are prevalent among terrestrial plants. The precursor molecule and the activating enzyme are compartmentalized in the tissue, which is readily disrupted by wounding to accomplish chemical defense. The similar activated defense strategy has also been found in a few marine sponges. In previous study, we obtained calyculin biosynthetic gene cluster from the metagenomic DNA of Japanese marine sponge Discodermia calyx and the deactivating enzyme was also clustered. The aim of this work is to identify the as-yet unknown enzyme involved in the activating process of the precursor molecule.

Research Products

• [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] 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] 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] 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] 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] 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] 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）
  • 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, 科学のとびら60 (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