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Biosynthetic redesign of small molecules aimed for the concurrent improvements of cell permeability and water solubility

Planned Research

Project AreaCreation of Complex Functional Molecules by Rational Redesign of Biosynthetic Machineries
Project/Area Number 16H06445
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Science and Engineering
Research InstitutionFukui Prefectural University

Principal Investigator

Hamano Yoshimitsu  福井県立大学, 生物資源学部, 教授 (50372834)

Co-Investigator(Kenkyū-buntansha) 丸山 千登勢  福井県立大学, 生物資源学部, 准教授 (20452120)
山中 一也  関西大学, 化学生命工学部, 准教授 (30756870)
Project Period (FY) 2016-06-30 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥72,020,000 (Direct Cost: ¥55,400,000、Indirect Cost: ¥16,620,000)
Fiscal Year 2020: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000)
Fiscal Year 2019: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000)
Fiscal Year 2018: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000)
Fiscal Year 2017: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000)
Fiscal Year 2016: ¥15,860,000 (Direct Cost: ¥12,200,000、Indirect Cost: ¥3,660,000)
Keywordsポリリジン / 細胞膜透過性 / CPP / cell penetrating peptide / ポリカチオン / 生体膜 / 生体膜透過性 / アミノ酸ポリマー / 生合成 / 応用微生物 / 有機化学 / 生理活性
Outline of Final Research Achievements

Our research aims include chemical modification (polycationic modification) of small molecule compounds with bacterial polycationic peptides to improve the water solubility and the cell membrane permeability simultaneously. New small compounds generated by biosynthetic re-design and known small compounds were our target molecules for the polycationic modification approach, and biosynthetic studies were performed to generate new peptide compounds in this study. In addition, we identified novel bacterial polycationic peptides and demonstrated their biosynthetic mechanisms. The polycationic modification of known compounds were achieved with clickable ε-poly-α-L-lysine and ε-oligo-β-L-lysine, which were produced by microbial transformation and enzymatic reaction, respectively.

Academic Significance and Societal Importance of the Research Achievements

薬物である機能性低分子・中分子化合物の細胞膜透過性を改善できれば、生理活性の増強が期待できる。細胞膜透過性を改善するための一般的な戦略は、化合物の疎水化である。しかし、その反面生じる水溶性の低下は、予期しない副作用の出現や製剤調製の複雑化など新たな問題を生む。したがって、生体膜透過性と水溶性を一挙に改善させる薬剤の化学修飾技術を開発できれば、現在の創薬スピードを加速させることができる。そこで本研究では、細胞膜透過性と水溶性を一挙に改善する化学修飾分子として、微生物由来ポリカチオン性ペプチドに着目し、実践的なポリカチオン化修飾法を確立した。

Report

(6 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (43 results)

All 2021 2020 2019 2018 2017

All Journal Article (10 results) (of which Peer Reviewed: 10 results,  Open Access: 5 results,  Acknowledgement Compliant: 2 results) Presentation (30 results) (of which Int'l Joint Research: 12 results,  Invited: 9 results) Patent(Industrial Property Rights) (3 results) (of which Overseas: 1 results)

  • [Journal Article] Molecular and mechanistic characterization of PddB, the first PLP-independent 2,4-diaminobutyric acid racemase discovered in an actinobacterial D-amino acid homopolymer biosynthesis2021

    • Author(s)
      Kazuya Yamanaka, Ryo Ozaki, Yoshimitsu Hamano, Tadao Oikawa
    • Journal Title

      Front. Microbiol.

      Volume: in press

    • DOI

      10.3389/fmicb.2021.686023

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] tRNA-dependent amide bond?forming enzymes in peptide natural product biosynthesis2020

    • Author(s)
      Maruyama Chitose、Hamano Yoshimitsu
    • Journal Title

      Current Opinion in Chemical Biology

      Volume: 59 Pages: 164-171

    • DOI

      10.1016/j.cbpa.2020.08.002

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] C-Methylation of S-adenosyl-L-Methionine Occurs Prior to Cyclopropanation in the Biosynthesis of 1-Amino-2-Methylcyclopropanecarboxylic Acid (Norcoronamic Acid) in a Bacterium2020

    • Author(s)
      Maruyama Chitose、Chinone Yukiko、Sato Shusuke、Kudo Fumitaka、Ohsawa Kosuke、Kubota Junya、Hashimoto Junko、Kozone Ikuko、Doi Takayuki、Shin-ya Kazuo、Eguchi Tadashi、Hamano Yoshimitsu
    • Journal Title

      Biomolecules

      Volume: 10 Issue: 5 Pages: 775-775

    • DOI

      10.3390/biom10050775

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Stereocontrolled Biosynthesis of Mirror-Symmetric 2,4-Diaminobutyric Acid Homopolymers Is Critically Governed by Adenylation Activations2020

    • Author(s)
      Yamanaka Kazuya、Fukumoto Hibiki、Takehara Munenori、Hamano Yoshimitsu、Oikawa Tadao
    • Journal Title

      ACS Chemical Biology

      Volume: 15 Issue: 7 Pages: 1964-1973

    • DOI

      10.1021/acschembio.0c00321

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Partition of amines and lysine oligomers between organic solvent and water under a controlled interfacial potential difference2018

    • Author(s)
      Katano, H., Maruyama, M., Kuroda, Y., Uematsu, K., Maruyama, C., Hamano, Y.
    • Journal Title

      J. Electroanal. Chem.

      Volume: 820 Pages: 97-102

    • DOI

      10.1016/j.jelechem.2018.05.001

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Promotion Effect of Streptothricin on a Glucose Oxidase Enzymatic Reaction and Its Application to a Colorimetric Assay2018

    • Author(s)
      UEMATSU Kohei、UENO Takaaki、KAWASAKI Haruka、MARUYAMA Chitose、HAMANO Yoshimitsu、KATANO Hajime
    • Journal Title

      Analytical Sciences

      Volume: 34 Issue: 2 Pages: 143-148

    • DOI

      10.2116/analsci.34.143

    • NAID

      130006341964

    • ISSN
      0910-6340, 1348-2246
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional analysis of methyltransferases participating in streptothricin-related antibiotic biosynthesis2018

    • Author(s)
      Niikura Haruka、Maruyama Chitose、Ogasawara Yasushi、Shin-ya Kazuo、Dairi Tohru、Hamano Yoshimitsu
    • Journal Title

      J. Biosci. Bioeng.

      Volume: 125 Issue: 2 Pages: 148-154

    • DOI

      10.1016/j.jbiosc.2017.09.004

    • NAID

      40021471176

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Colorimetric Microtiter Plate Assay of Polycationic Aminoglycoside Antibiotics in Culture Broth Using Amaranth2017

    • Author(s)
      H. Katano, Y. Kuroda, S. Taira, C. Maruyama, Y. Hamano
    • Journal Title

      Analytical Sciences

      Volume: 33 Issue: 4 Pages: 499-504

    • DOI

      10.2116/analsci.33.499

    • NAID

      130005587977

    • ISSN
      0910-6340, 1348-2246
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Imaging mass spectrometry analysis of ubiquinol localization in the mouse brain following short-term administration2017

    • Author(s)
      Tatsuta Yukina、Kasai Kazuaki、Maruyama Chitose、Hamano Yoshimitsu、Matsuo Kazuhiko、Katano Hajime、Taira Shu
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 12990-12296

    • DOI

      10.1038/s41598-017-13257-8

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Antimicrobial Activity of ε-Poly-l-lysine after Forming a Water-Insoluble Complex with an Anionic Surfactant2017

    • Author(s)
      Kazunori Ushimaru, Yoshimitsu Hamano, Hajime Katano
    • Journal Title

      Biomacromolecules

      Volume: 18 Issue: 4 Pages: 1387-1392

    • DOI

      10.1021/acs.biomac.7b00109

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] ε-poly-L-lysine修飾による抗体の細胞内送達法の確立2020

    • Author(s)
      武内 大和,牛丸和乗,加藤康夫,丸山千登勢,濱野吉十
    • Organizer
      2020年度日本農芸化学会大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 抗生物質resormycin生合成遺伝子群の同定および機能解析2020

    • Author(s)
      茅根千湖,山中一也,五十嵐雅之,濱野吉十,丸山千登勢
    • Organizer
      2020年度日本農芸化学会大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 細胞膜透過に寄与する抗生物質 streptothricinのoligo(β-Lys)構造2020

    • Author(s)
      兼田康平,武内大和,加藤康夫,丸山千登勢,濱野吉十
    • Organizer
      2020年度日本農芸化学会大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Biosynthesis and cell-penetrating activity of bacterial homopoly(amino acid)s2019

    • Author(s)
      Yoshimitsu Hamano
    • Organizer
      Chemistrly department, The University of British Columbia
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Polycationic peptides-discovery, biosynthesis, and application2019

    • Author(s)
      Yoshimitsu Hamano
    • Organizer
      The 4th A3 Foresight Symposium on Chemical & Synthetic Biology of Natural Products 2019 meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Substrate specificity of tRNA-dependent amide-bond forming enzyme2019

    • Author(s)
      Yoshimitsu Hamano
    • Organizer
      The 14th Asian Congress on Biotechnology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 微生物由来の天然ポリカチオンを利用した生体高分子の細胞内送達法2019

    • Author(s)
      濱野 吉十
    • Organizer
      日本農芸化学会2019年度大会(シンポジウム)
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Substrate specificity of tRNA-dependent amide-bond forming enzyme2019

    • Author(s)
      Yoshimitsu Hamano
    • Organizer
      Enzyme Engineering XXV,
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification and characterization of bacterial 1-aminocyclopropane-1-carboxylic acid synthase2019

    • Author(s)
      Yukiko Chinone, Yoshimitsu Hamano, Junko Hashimoto, Ikuko Kozone, Kazuo Shin-ya, Chitose Maruyama
    • Organizer
      The 4th A3 Foresight Symposium on Chemical & Synthetic Biology of Natural Products 2019 meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Intracellular Delivery of Macromolecules Modified with ε-poly-L-lysine2019

    • Author(s)
      Yamato Takeushi, Chitose Maruyama, Yasuo Kato, Yoshimitsu Hamano
    • Organizer
      The 4th A3 Foresight Symposium on Chemical & Synthetic Biology of Natural Products 2019 meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Chemical modification of the bioactive small molecules with ε-poly-L-lysine for improving cell membrane permeability and water solubility2019

    • Author(s)
      Fumika Matsumura, Chitose Maruyama, Yamato Takeuchi, Yasuo Kato, Yoshimitsu Hamano
    • Organizer
      The 4th A3 Foresight Symposium on Chemical & Synthetic Biology of Natural Products 2019 meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Chemical modification of the bioactive small molecules with oligo(β-Lys) for improving cell membrane permeability and water solubility2019

    • Author(s)
      Kohei Kaneda, Chitose Maruyama, Yamato Takeuchi, Yasuo Kato, Yoshimitsu Hamano
    • Organizer
      The 4th A3 Foresight Symposium on Chemical & Synthetic Biology of Natural Products 2019 meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Intracellular Delivery of Macromolecules Modified with ε-poly-L-lysine2019

    • Author(s)
      Yamato Takeushi, Chitose Maruyama and Yoshimitsu Hamano
    • Organizer
      The 14th Asian Congress on Biotechnology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification and characterization of bacterial 1-aminocyclopropane-1-carboxylic acid synthase2019

    • Author(s)
      Yukiko Chinone, Chitose Maruyama, Yoshimitsu Hamano
    • Organizer
      The 14th Asian Congress on Biotechnology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 抗生物質resormycinの生合成遺伝子群の同定および機能解析2019

    • Author(s)
      茅根千湖,山中一也,五十嵐雅之,濱野吉十,丸山千登勢
    • Organizer
      2019年度日本放線菌学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 細胞膜透過に寄与する抗生物質streptothricinのoligo(β-Lys)構造2019

    • Author(s)
      兼田康平,武内大和,加藤康夫,丸山千登勢,濱野吉十
    • Organizer
      2019年度日本放線菌学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 機能性高分子のε-poly-L-lysine修飾による細胞内送達法の確立2019

    • Author(s)
      武内大和,牛丸和乗,加藤康夫,丸山千登勢,濱野吉十
    • Organizer
      2019年度日本放線菌学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 生体膜透過性・水溶性の一挙改善を志向した機能性低分子化合物のoligo(beta-Lys)修飾2019

    • Author(s)
      兼田康平,武内大和,加藤康夫,丸山千登勢,濱野吉十
    • Organizer
      日本生物工学会2019年度大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 機能性高分子のepsilon-poly-L-lysine修飾による細胞内送達法の確立2019

    • Author(s)
      武内大和,牛丸和乗,加藤康夫,丸山千登勢,濱野吉十
    • Organizer
      日本生物工学会2019年度大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 放線菌由来1-aminocyclopropane-1-carboxylic acid合成酵素の同定および酵素学的諸性質2019

    • Author(s)
      茅根千湖,橋本絢子,小曽根郁子,新家一男,濱野吉十,丸山千登勢
    • Organizer
      日本農芸化学会2019年度大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 機能性高分子のε-poly-L-lysine修飾による細胞内送達法の確立2019

    • Author(s)
      武内大和,牛丸和乗,加藤康夫,丸山千登勢,濱野吉十
    • Organizer
      日本農芸化学会2019年度大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 機能性分子のε-poly-L-lysine修飾による生体膜透過性・水溶性の一挙改善2018

    • Author(s)
      武内大和,牛丸和乗,加藤康夫,丸山千登勢,濱野吉十
    • Organizer
      酵素工学研究会第80回講演会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 機能性分子のε-poly-L-lysine修飾による生体膜透過性・水溶性の一挙改善2018

    • Author(s)
      武内大和,牛丸和乗,加藤康夫,丸山千登勢,濱野吉十
    • Organizer
      2018年度日本農芸化学会中部支部183回例会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 機能性分子のε-poly-L-lysine修飾による生体膜透過性・水溶性の一挙改善2018

    • Author(s)
      武内大和,牛丸和乗,加藤康夫,丸山千登勢,濱野吉十
    • Organizer
      2018年度日本放線菌学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 機能性低分子化合物のポリリジン化による生体膜透過性・水溶性の一挙改善2018

    • Author(s)
      武内大和,牛丸和乗,加藤康夫,丸山千登勢,濱野吉十
    • Organizer
      日本農芸化学会2018年度大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 膜透過性・水溶性の一挙改善を志向した新規機能性低分子の生合成リデザイン2017

    • Author(s)
      濱野吉十
    • Organizer
      新学術領域研究(研究領域提案型)生物合成系の再設計による複雑骨格機能分子の革新的創成科学,第3回公開シンポジウム
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Amide-bond forming enzymes in the biosynthesis of streptothricin group antibiotics2017

    • Author(s)
      Yoshimitsu Hamano
    • Organizer
      1st US-China Seminar on the Biosyntheis of Natural Products
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Amide-bond forming enzymes in the biosynthesis of streptothricin group antibiotics2017

    • Author(s)
      Yoshimitsu Hamano
    • Organizer
      Society of Industrial Microbiology and Biotechnology (SIMB) 2017 meeting
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Amide-bond Forming Enzymes in the Biosynthesis of Streptothricin Group Antibiotics2017

    • Author(s)
      Yoshimitsu Hamano
    • Organizer
      9th US-Japan Seminar on the Biosyntheis of Natural Products
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] streptothricin類縁抗生物質の生合成研究に見出したtRNA依存性ペプチド合成酵素2017

    • Author(s)
      濱野吉十
    • Organizer
      新学術領域研究(研究領域提案型)生物合成系の再設計による複雑骨格機能分子の革新的創成科学,第1回公開シンポジウム
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Patent(Industrial Property Rights)] クリック官能基をもつε-ポリ-L-リジン誘導体、その製法、及びその用途2018

    • Inventor(s)
      濱野吉十、牛丸和乗
    • Industrial Property Rights Holder
      福井県立大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] クリック官能基をもつε-ポリ-L-リジン誘導体、その製法、及びその用途2017

    • Inventor(s)
      濱野吉十、牛丸和乗
    • Industrial Property Rights Holder
      福井県立大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2017-159848
    • Filing Date
      2017
    • Related Report
      2017 Annual Research Report
  • [Patent(Industrial Property Rights)] クリック官能基をもつε-ポリ-L-リジン誘導体、その製法、及びその用途2017

    • Inventor(s)
      濱野吉十、牛丸和乗
    • Industrial Property Rights Holder
      福井県立大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2017-159849
    • Filing Date
      2017
    • Related Report
      2017 Annual Research Report

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Published: 2016-07-04   Modified: 2024-01-30  

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