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Systems biology approach to unravel biosynthesis and evolution of camptothecin, a potent anti-cancer natural product

Research Project

Project/Area Number 19K16391
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 47050:Environmental and natural pharmaceutical resources-related
Research InstitutionInstitute of Physical and Chemical Research (2020-2021)
Chiba University (2019)

Principal Investigator

Rai Amit  国立研究開発法人理化学研究所, 環境資源科学研究センター, 研究員 (60760535)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsCamptothecin / Medicinal plants / MIAs / Whole genome sequencing / Phytogenomics / Ophiorrhiza pumila / Comparative genomics / Systems biology / Metabolic gene clusters / Pangenome / Ophiorrhiza japonica / Evolution / Nothapodytes foetida / STR / Secoiridoids / Metabolic gene cluster / OpCYP1 / Pan-Genome / Genome analysis / Metabolite profiling / Specialized metabolites / Systems Biology / Indole Alkaloids / Biosynthesis
Outline of Research at the Start

Camptothecin (CPT) is one of the most potent anti-cancer compound derived from the plant source. Lack of stable supply for CPT is a grave concern and the reason for the exorbitant cost for cancer treatment. This study aims to understand camptothecin biosynthesis in order to derive a sustainable source of its production.

Outline of Final Research Achievements

During this study, we finalized high-quality genome assemblies of Ophiorrhiza pumila (genome size 440Mb), Ophiorrhiza japonica (genome size 800Mb), and Nothapodytes foetida (genome size 9.79Mb). We also used complete carbon labeling and nitrogen labeling of the Ophiorrhiza pumila metabolome to establish a high-quality metabolome resource to discover unknown intermediates of camptothecin biosynthesis.
Comparative genome analysis showed strictosidine synthase (STR) as the key enzyme that guided the emergence of camptothecin biosynthesis, loss of which resulted in losing the ability of its biosynthesis in coffee. We showed the importance of metabolic gene clusters towards the evolution and retaining the ability to synthesize specialized metabolites in plants. We also identified putative metabolite intermediates from camptothecin biosynthesis. Finally, we established STR knockout lines, which block camptothecin biosynthesis to identify candidate genes associated with biosynthesis pathways.

Academic Significance and Societal Importance of the Research Achievements

This study have produced three high quality genome assemblies of important medicinal plants to explore evolutionary basis of camptothecin biosynthesis, one of the most potent anti-cancer drug in the world. Results and resources will be useful to establish sustainable source of camptothecin.

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (13 results)

All 2021 2020 2019 Other

All Journal Article (5 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 5 results,  Open Access: 4 results) Presentation (6 results) (of which Int'l Joint Research: 6 results,  Invited: 3 results) Remarks (2 results)

  • [Journal Article] A multi-objective hybrid machine learning approach-based optimization for enhanced biomass and bioactive phycobiliproteins production in Nostoc sp. CCC-4032021

    • Author(s)
      Saini Dinesh Kumar、Rai Amit、Devi Alka、Pabbi Sunil、Chhabra Deepak、Chang Jo-Shu、Shukla Pratyoosh
    • Journal Title

      Bioresource Technology

      Volume: 329 Pages: 124908-124908

    • DOI

      10.1016/j.biortech.2021.124908

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Chromosome-level genome assembly of Ophiorrhiza pumila reveals the evolution of camptothecin biosynthesis2021

    • Author(s)
      Rai Amit、Hirakawa Hideki、Nakabayashi Ryo、Kikuchi Shinji、Hayashi Koki、Rai Megha、Tsugawa Hiroshi、Nakaya Taiki、Mori Tetsuya、Nagasaki Hideki、Fukushi Runa、Kusuya Yoko、Takahashi Hiroki、Uchiyama Hiroshi、Toyoda Atsushi、Hikosaka Shoko、Goto Eiji、Saito Kazuki、Yamazaki Mami
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 405-405

    • DOI

      10.1038/s41467-020-20508-2

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Metabolomics and complementary techniques to investigate the plant phytochemical cosmos2021

    • Author(s)
      Tsugawa Hiroshi、Rai Amit、Saito Kazuki、Nakabayashi Ryo
    • Journal Title

      Natural Product Reports

      Volume: 38 Issue: 10 Pages: 1729-1759

    • DOI

      10.1039/d1np00014d

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Gene-Metabolite Network Analysis Revealed Tissue-Specific Accumulation of Therapeutic Metabolites in Mallotus japonicus2021

    • Author(s)
      Rai Megha、Rai Amit、Mori Tetsuya、Nakabayashi Ryo、Yamamoto Manami、Nakamura Michimi、Suzuki Hideyuki、Saito Kazuki、Yamazaki Mami
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 16 Pages: 8835-8835

    • DOI

      10.3390/ijms22168835

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Multiomics-based characterization of specialized metabolites biosynthesis in Cornus Officinalis2020

    • Author(s)
      Rai Amit、Rai Megha、Kamochi Hidetaka、Mori Tetsuya、Nakabayashi Ryo、Nakamura Michimi、Suzuki Hideyuki、Saito Kazuki、Yamazaki Mami
    • Journal Title

      DNA Research

      Volume: 27 Issue: 2 Pages: 1-15

    • DOI

      10.1093/dnares/dsaa009

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Systems approach to explore emergence of specialized metabolites in medicinal plants2021

    • Author(s)
      Amit Rai
    • Organizer
      National Bioengineering Conference- 2022, India
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Genome-guided multi-omics approach to explore evolution of specialized metabolites in plants2020

    • Author(s)
      Amit Rai, Hideki Hirakawa, Ryo Nakabayashi, Shinji Kikuchi, Koki Hayashi, Megha Rai, Hiroshi Tsugawa Tetsuya Mori, Mami Yamazaki, and Kazuki Saito
    • Organizer
      International plant systems biology, EMBO workshop, April 26-27
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Integrated Omics for Hypothesis Generation2020

    • Author(s)
      Amit Rai
    • Organizer
      The 69th Annual Conference on Mass Spectrometry, Japan, May 19-21
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Predicting genes related to the biosynthesis of Camptothecin by integrating promoter similarity score with gene co-expression analysis2019

    • Author(s)
      Koki Hayashi, Amit Rai, Kazuki Saito, Mami Yamazaki
    • Organizer
      The 61th Annual Meeting of the Japanese Society of Plant Physiologists, Osaka
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Integration of cis-element motif analysis with co-expression analysis to predict genes related to Camptothecin biosynthesis2019

    • Author(s)
      Koki Hayashi, Amit Rai, Kazuki Saito, Mami Yamazaki
    • Organizer
      Genome Support Meeting, PAG 2019, Nagoya, Japan
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] シス調節配列のモチーフ解析と共発現解析の統合による カンプトテシン生合成候補遺伝子の探索2019

    • Author(s)
      Koki Hayashi, Amit Rai, Kazuki Saito, Mami Yamazaki
    • Organizer
      The 56th Plant Chemistry Symposium
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Remarks] Ophiorrhiza pumila Genome DataBase.

    • URL

      http://pumila.kazusa.or.jp/

    • Related Report
      2021 Annual Research Report
  • [Remarks] Ophiorrhiza pumila Genome DataBase

    • URL

      http://pumila.kazusa.or.jp/

    • Related Report
      2020 Research-status Report

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Published: 2019-04-18   Modified: 2024-12-25  

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