2020 Fiscal Year Final Research Report
Production of rare bioactive natural products originating from uncultured bacteria
| Project Area | Creation of Complex Functional Molecules by Rational Redesign of Biosynthetic Machineries |
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| Project/Area Number |
16H06448
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| Research Category |
Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
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| Allocation Type | Single-year Grants |
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| Review Section |
Science and Engineering
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| Research Institution | Hokkaido University |
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Principal Investigator |
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| Project Period (FY) |
2016-06-30 – 2021-03-31
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| Keywords | 海綿動物 / ポリケタイド / 細胞毒性物質 |
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| Outline of Final Research Achievements |
Marine sponges often contain potent cytotoxic compounds, which usually target molecules that are likely to be shared with the sponge itself. This fact in turn evokes the principle question of how marine sponges avoid self-toxicity. We previously identified an intriguing mechanism to prevent self-toxicity by the phosphorylation of the highly toxic calyculin A in the sponge holobiont, which is catalyzed by the phosphotransferase CalQ of a producer symbiont, “Candidatus Entotheonella” sp. However, the activating mechanism to dephosphorylate the stored phosphocalyculin A remains elusive. Here we show that the phosphatase specific to phosphocalyculin A is CalL, which is also encoded in the calyculin biosynthetic gene cluster. CalL represents a new clade and unprecedently coordinates the heteronuclear metals Cu and Zn. The CalL is localized in the periplasmic space of the sponge symbiont, where it is ready for the on-demand production of calyculin A in response to sponge tissue disruption.
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| Free Research Field |
天然物化学
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| Academic Significance and Societal Importance of the Research Achievements |
海綿動物からは、これまでに多様な生物活性物質が単離報告されてきた。その中には、特異的かつ極めて低濃度で強力な活性を示す化合物が複数見出されており、それらは医薬品や生化学試薬の開発において重要な天然資源である。しかし海綿動物自体が稀少生物であることから、量的供給が難しく、その代謝物の医薬品開発を目指す上で大きな壁となっている。海綿を起源とする二次代謝産物を実験室下で異種生産した報告例はこれまでにほとんどないため、本研究は稀少な生物資源である海綿動物由来生物活性物質の生合成機構を解明する。本研究で得られる成果は、海綿及びその共生微生物に由来する医薬品資源の異種生産系の確立につながる。
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