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Regulation of glutathione production by sulfuration induced by polysulfide/hydrogen sulfide

Research Project

Project/Area Number 17K08613
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General pharmacology
Research InstitutionTokyo University of Science, Yamaguchi (2019-2020)
National Center of Neurology and Psychiatry (2017-2018)

Principal Investigator

Kimura Yuka  山陽小野田市立山口東京理科大学, 薬学部, 研究員 (60425692)

Project Period (FY) 2017-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords硫化水素 / ポリサルファイド / MPST / 過硫化 / TRPA1 / 結合型硫黄 / ノックアウト / D-セリン / 統合失調症 / ノックアウトラット / 亜硫酸 / 酸化ストレス / グルタチオン / システイン / 生理活性
Outline of Final Research Achievements

3-Mercaptopyruvate sulfurtransferase (MPST) biosynthesizes hydrogen sulfide (H2S) and polysulfides (H2Sn), which sulfurate (addition of sulfur) cysteine residues of proteins to increase amount of bound sulfane sulfur. We made clear that MPST is required to produce bound sulfane sulfur by using MPST knock out mice. In addition, we demonstrated that 1) MPST sulfurates endogenous cysteine or glutathione (GSH) to produce redox regulators, cysteine persulfide (Cys-SSH) or glutathione persulfide (GSSH), 2) Sulfite (H2SO3), an oxidative product of H2S and H2Sn, protects neuronal cells from oxidative stress, 3) H2Sn produced from interaction between H2S and nitric oxide (NO), activate TRPA1 channel to synergically induce calcium response.

Academic Significance and Societal Importance of the Research Achievements

H2S、H2Snはシグナル分子として確立してきたが、そのターゲットやシグナル経路については不明な点が多い。本研究からH2S、H2Snに加えて、Cys-SSH、GSSH、過硫化蛋白質などが生体内に存在し、シグナル分子としてレドックス制御に関わることがわかってきた。H2S、H2Snは不安定だが、その酸化物亜硫酸(H2SO3)に強力な酸化ストレス防御作用があることがわかり、H2S、H2Snの下流の分子が生物作用を担う可能性も見えてきた。この知見が既に始まっているH2S、H2Snの創薬に生かされことを期待する。

Report

(5 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (37 results)

All 2020 2019 2018 2017 2016

All Journal Article (13 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 12 results,  Open Access: 10 results,  Acknowledgement Compliant: 2 results) Presentation (24 results) (of which Int'l Joint Research: 6 results,  Invited: 2 results)

  • [Journal Article] Signalling by hydrogen sulfide and polysulfides via protein S-sulfuration.2020

    • Author(s)
      Kimura H.
    • Journal Title

      Br J Pharmacol.

      Volume: 177 Issue: 4 Pages: 720-733

    • DOI

      10.1111/bph.14579

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sulfite protects neurons from oxidative stress.2019

    • Author(s)
      Kimura Y, Shibuya N, Kimura H.
    • Journal Title

      British Journal of Pharmacology

      Volume: 176 Issue: 4 Pages: 571-582

    • DOI

      10.1111/bph.14373

    • NAID

      130007812611

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Signaling by hydrogen sulfide (H2S) and polysulfides (H2Sn) in the central nervous system.2019

    • Author(s)
      Kimura, H.
    • Journal Title

      Neurochem Int

      Volume: 126 Pages: 118-125

    • DOI

      10.1016/j.neuint.2019.01.027

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology.2019

    • Author(s)
      Ide M, et al. .... Kimura H, Yoshikawa T.
    • Journal Title

      EMBO Mol Med.

      Volume: 11(12) Issue: 12

    • DOI

      10.15252/emmm.201910695

    • NAID

      120007132855

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pharmacological polysulfide suppresses glucose-stimulated insulin secretion in an ATP-sensitive potassium channel-dependent manner.2019

    • Author(s)
      4.Shoji T, Hayashi M, Sumi C, Kusunoki M, Uba T, Matsuo Y, Kimura H, Hirota K
    • Journal Title

      Sci Rep.

      Volume: 9(1) Issue: 1 Pages: 19377-19377

    • DOI

      10.1038/s41598-019-55848-7

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 亜硫酸の細胞保護作用ー硫化水素、ポリサルファイドに匹敵2019

    • Author(s)
      木村由佳、木村英雄
    • Journal Title

      硫酸と工業

      Volume: 72(11) Pages: 1-10

    • NAID

      40022076249

    • Related Report
      2019 Research-status Report
  • [Journal Article] Alternative pathway of H2S and polysilfides production form reaction intermediate of 3-mercaptopyruvate sulfurtransferase2018

    • Author(s)
      Nagahara N, Koike S, Nirasawa T ,Kimura H, Ogasawara Y
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 496 Issue: 2 Pages: 648-653

    • DOI

      10.1016/j.bbrc.2018.01.056

    • Related Report
      2018 Research-status Report 2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Discovery and Mechanistic Characterization of Selective Inhibitors of H2S-producing Enzyme: 3-Mercaptopyruvate Sulfurtransferase (3MST) Targeting Active-site Cysteine Persulfide2017

    • Author(s)
      K. Hanaoka, K. Sasakura, Y. Suwanai, S. Toma-Fukai, K. Shimamoto, Y. Takano, N. Shibuya, T. Terai, T. Komatsu, T. Ueno, Y. Ogasawara, Y. Tsuchiya, Y. Watanabe, H. Kimura, C. Wang, M. Uchiyama, H. Kojima, T. Okabe, Y. Urano, T. Shimizu, T. Nagano
    • Journal Title

      Sci. Rep.

      Volume: 7 Issue: 1 Pages: 40227-40227

    • DOI

      10.1038/srep40227

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Development of a Reversible Fluorescent Probe for Reactive Sulfur Species, Sulfane Sulfur, and its Biological Application2017

    • Author(s)
      Takano Y, Hanaoka K, Shimamoto K, Miyamoto R, Komatsu T, Ueno T, Terai T, Kimura H, Nagano T, Urano Y
    • Journal Title

      Chem Commun

      Volume: 53 Issue: 6 Pages: 1064-1067

    • DOI

      10.1039/c6cc08372b

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 3-Mercaptopyruvate sulfurtransferase produces potential redox regularots cysteine- and glutathione-persulfide (Cys-SSH and GSSH) together with signaling molecules H2S2, H2S3 and H2S.2017

    • Author(s)
      Kimura, Y., Koike, S., Shibuya, N., Lefer, D., Ogasawara, Y., Kimura, H.
    • Journal Title

      Sci. Rep.

      Volume: 7 Issue: 1 Pages: 10459-10459

    • DOI

      10.1038/s41598-017-11004-7

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Analysis of endogenous H2S and H2Sn in mouse brain by high-performance liquid chromatography with fluorescence and tandem mass spectrometric detection.2017

    • Author(s)
      Koike, S., Kawamura, K., Kimura, Y., Shibuya, N., Kimura, H., Ogasawara, Y.
    • Journal Title

      Free Rad. Biol. Med.

      Volume: 113 Pages: 355-362

    • DOI

      10.1016/j.freeradbiomed.2017.10.346

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Hydrogen sulfide and polysalfide signaling2017

    • Author(s)
      Kimura Hideo
    • Journal Title

      Antioxid. Redox Signal.

      Volume: 27 Issue: 10 Pages: 619-621

    • DOI

      10.1089/ars.2017.7076

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Polysulfides (H2Sn) produced from the interaction of hydrogen sulfide (H2S) and nitric oxide(NO) activate TRPA1 channels2016

    • Author(s)
      R Miyamoto, S Koike, Y Takano, N Shibuya, Y Kimura, K Hanaoka, Y Urano, Y Ogasawara,H Kimura
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 45995-45995

    • DOI

      10.1038/srep45995

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] 亜硫酸(H2SO3)による酸化ストレスからの神経細胞保護作用2020

    • Author(s)
      木村由佳、澁谷典弘、木村英雄
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 硫化水素(H2S)及びポリサルファイド(H2Sn)によるシグナル伝達2020

    • Author(s)
      木村英雄、澁谷典弘、木村由佳、小笠原祐樹、小池伸、永原則之、長野哲夫、浦野泰照、花岡健二郎
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 生理活性物質硫化水素の産生経路2020

    • Author(s)
      澁谷典弘、木村由佳、木村英雄
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 亜硫酸による神経細胞の酸化ストレス保護作用:硫化水素、ポリサルファイドとの関係2020

    • Author(s)
      木村由佳、澁谷典弘、木村英雄
    • Organizer
      第93回日本生化学大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Signaling molecules hydrogen sulfide, polysulfides and sulfite.2019

    • Author(s)
      Hideo Kimura, Yuka Kimura, Norihiro Shibuya
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Sulfite protects neurons from oxidative stress.2019

    • Author(s)
      Yuka Kimura, Norihiro Shibuya, Hideo Kimura
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] 硫化水素の産生経路と腎障害の軽減効果2019

    • Author(s)
      渋谷典広、小池 伸、木村由佳、小笠原裕樹、木村英雄
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] 硫化水素(H2S)およびポリサルファイド(H2Sn)によるシグナル伝達2019

    • Author(s)
      木村英雄、渋谷典広、木村由佳、小笠原裕樹、小池 伸、永原則之、長野哲雄、浦野泰照、花野健二郎
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 亜硫酸(H2SO3)による酸化ストレスからの神経細胞保護効果2019

    • Author(s)
      木村由佳、渋谷典広、木村英雄
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 生理活性物質硫化水素の産生経路2019

    • Author(s)
      渋谷典広、木村由佳、木村英雄
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] Hydrogen sulfide (H2S) and Polysulfides (H2Sn) Signaling Though S-sulfuration of Target Proteins” Ventura,2019

    • Author(s)
      Hideo Kimura
    • Organizer
      Gordon Research Conference “Gasotransmitter Cooperation: Chemistry, Physiology and Pathology”
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Signaling molecules hydrogen sulfide (H2S), polysulfides (H2Sn) and sulfite H2SO32019

    • Author(s)
      木村英雄
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] 亜硫酸は酸化ストレスから神経細胞を保護する2019

    • Author(s)
      木村由佳、渋谷典広、木村英雄
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] 生理活性物質硫化水素とポリサルファイドの産生と機能2019

    • Author(s)
      渋谷典広、小池 伸、木村由佳、宮本 亮、小笠原裕樹、木村英雄
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] 「Signaling by hydrogen polysulfides (H2Sn) produced by the chemical interaction between hydrogen sulfide (H2S) and nitric oxide (NO).」シンポジウム 「NO研究の最近の動向」2019

    • Author(s)
      木村英雄
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] Hydrogen sulfide (H2S) and polysulfides (H2Sn) signaling through persulfuration of target proteins.2018

    • Author(s)
      Hideo Kimura,
    • Organizer
      5th World Congress on Hydrogen Sulfide in Biology and Medicine. Plenary Lecture.
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Hydrogen sulfide (H2S) and Polysulfides (H2Sn) as signaling molecules.2018

    • Author(s)
      Hideo Kimura
    • Organizer
      WCP2018 Kyoto
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 3-mercaptopyruvate sulfurtransferase produces potential redox regulators cysteine- and glutathione-persulfide (Cys-SSH and GSSH) together with signaling molecules H2S2, H2S3 and H2S.2018

    • Author(s)
      Kimura Y, Koike S, Shibuya N, Lefer D, Ogasawara Y Kimura H
    • Organizer
      The 41th Annual Meeting of the Japan Neuroscience Society.
    • Related Report
      2018 Research-status Report
  • [Presentation] Hydrogen sulfide and polysulfides as signaling molecules-biosynthesis and function-2018

    • Author(s)
      Kimura H, Kimura Y, Koike S, Shibuya N, Lefer D, Nagahara N, Hanaoka K, Urano Y, Ogasawara Y.
    • Organizer
      The 41th Annual Meeting of the Japan Neuroscience Society.
    • Related Report
      2018 Research-status Report
  • [Presentation] The production and role of hydrogen sulfide and hydrogen polysulfides in mammalian cells.2018

    • Author(s)
      Shibuya N, Koike S, Miyamoto R, Kimura Y, Hanaoka K, Nagahara N, Urano Y, Ogasawara Y, Kimura H.
    • Organizer
      The 41th Annual Meeting of the Japan Neuroscience Society.
    • Related Report
      2018 Research-status Report
  • [Presentation] 活性硫黄種の新展開―硫化水素から過硫化物までー オーガナイザー「硫化水素(H2S)とポリサルファイド(H2Sn)によるシグナル伝達と過硫化タンパク」2018

    • Author(s)
      木村英雄
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] Signaling molecules: H2S and H2Sn.2017

    • Author(s)
      Hideo Kimura
    • Organizer
      ConBio2017 神戸
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 生理活性物質硫化水素とポリサルファイドの産生機構2017

    • Author(s)
      渋谷典広
    • Organizer
      ConBio2017 神戸
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Mechanism of polysulfide production: enzymatic biosynthesis and chemical interaction between hydrogen sulfide and nitric oxide.2017

    • Author(s)
      Yuka Kimura
    • Organizer
      ConBio2017 神戸
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research

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Published: 2017-04-28   Modified: 2022-01-27  

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