Physiological roles of hydrogen sulfide and polysulfide

• Project/Area Number: 17K08331
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: Tokyo University of Science, Yamaguchi (2019-2020); National Center of Neurology and Psychiatry (2017-2018)
• Principal Investigator: KIMURA HIDEO 山陽小野田市立山口東京理科大学, 薬学部, 教授 (30321889)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 硫化水素 / ポリサルファイド / TRPA1チャネル / 神経伝達調節 / 過硫化 / 海馬長期増強 / 3MST / 統合失調症 / ノックアウトラット / 亜硫酸 / 神経保護作用 / ３MST / TRPA1 / 記憶 / 一酸化窒素 / 質量分析 / 蛍光プローブ / 阻害剤 / シグナル分子 / 酸化還元

Outline of Final Research Achievements

3-Mercaptopyruvate sulfurtransferase (3MST) produces hydrogen sulfide (H2S) and polyfulfides (H2Sn). H2Sn S-sulfurate cysteine residues of the target proteins, while H2S S-sulfurates the oxidized cysteie residues such as Cys-SOH to generate Cys-SSH. It correlate well with the increase in the amount of bound sulfane sulfur. We elucidated that 3MST increases S-sulfurated proteins, namely the levels of bound sulfane sulfur by using 3MST knockout mice. We also showed that the two cysteine residues of TRPA1 channels are S-sulfurated to activate the channels.

Academic Significance and Societal Importance of the Research Achievements

これまで、硫化水素（H2S）とポリサルファイド（H2Sn）による標的タンパクの活性化機構についてはよくわかっていなかった。今回、これら分子の生合成酵素である3-メルカプトピルビン酸イオウ転移酵素（３MST）ノックアウトマウスを使い、標的分子としては、TRPA1チャネルに注目して、その活性機構を明らかにした。本チャネルは血圧調節や記憶に関わるチャネルで、本研究によって、H2SやH2Snを放出する分子の開発によって血圧や記憶の改善に寄与する薬物の創生が期待される。

Research Products

• [Int'l Joint Research] LSU Health Science Center(米国)
• [Journal Article] From neurotransmission to neuronal disorders. (2021)
  • Author(s): Hideo Kimura
  • Journal Title: Br J Pharmacol. Volume: 178 Issue: 4 Pages: 747-749
  • DOI: 10.1111/bph.15354
  • Peer Reviewed / Open Access
• [Journal Article] 生体内シグナル分子としての硫化水素とポリサルファイド (2021)
  • Author(s): 木村英雄
  • Journal Title: ファルマシア Volume: 57 Pages: 34-38
  • NAID: 130007965111
• [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
  • Peer Reviewed / Open Access
• [Journal Article] Hydrogen sulfide signaling in the central nervous system -Comparison with nitric oxide- (2020)
  • Author(s): Hideo Kimura
  • Journal Title: Br J Pharmacol. Volume: 177 Issue: 22 Pages: 5031-5045
  • DOI: 10.1111/bph.15246
  • 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
  • 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
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Alternative pathway of H2S and polysilfides production form reaction intermediate of 3-mercaptopyruvate sulfurtransferase (2018)
  • 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
  • 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 Persulfide (2017)
  • 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
  • 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 Application (2017)
  • 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
  • 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
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hydrogen sulfide and polysalfide signaling (2017)
  • Author(s): Kimura Hideo
  • Journal Title: Antioxid. Redox Signal. Volume: 27 Issue: 10 Pages: 619-621
  • DOI: 10.1089/ars.2017.7076
  • Peer Reviewed
• [Journal Article] Polysulfides (H2Sn) produced from the interaction of hydrogen sulfide (H2S) and nitric oxide(NO) activate TRPA1 channels (2016)
  • 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
  • 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、渋谷典広、木村英雄
  • Organizer: 第93回日本薬理学会年会
• [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 (2020)
  • 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、花岡健二郎
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 生理活性物質硫化水素の産生経路 (2020)
  • 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
• [Presentation] 硫化水素（H2S）とポリサルファイド（H2Sn）による標的タンパク過硫化によるシグナル伝達 (2020)
  • Author(s): 木村英雄
  • Organizer: 第93回日本生化学会大会
• [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 (2020)
  • 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
• [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 (2020)
  • 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
• [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
• [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
• [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
• [Presentation] Hydrogen sulfide (H2S) and Polysulfides (H2Sn) Signaling Though S-sulfuration of Target Proteins (2019)
  • Author(s): Hideo Kimura
  • Organizer: Gordon Research Conference
  • Int'l Joint Research / Invited
• [Presentation] Signaling molecules hydrogen sulfide (H2S), polysulfides (H2Sn) and sulfite H2SO3. (2019)
  • Author(s): 木村英雄
  • Organizer: 第92回日本薬理学会年会
• [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
• [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
• [Presentation] Signaling by hydrogen polysulfides (H2Sn) produced by the chemical interaction between hydrogen sulfide (H2S) and nitric oxide (NO). (2019)
  • Author(s): 木村英雄
  • Organizer: 92回日本薬理学会年会
• [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.
  • Int'l Joint Research / Invited
• [Presentation] Hydrogen sulfide (H2S) and Polysulfides (H2Sn) as signaling molecules. (2018)
  • Author(s): Hideo Kimura
  • Organizer: WCP2018 Kyoto
  • 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
• [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.
• [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,
  • Organizer: The 41th Annual Meeting of the Japan Neuroscience Society.
• [Presentation] 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
• [Presentation] Mechanisms of polysulfide production: enzymatic biosynthesis and chemical interaction between hydrogen sulfide and nitric oxide (2017)
  • Author(s): Yuka Kimura
  • Organizer: ConBio2017
• [Presentation] Signaling molecules: H2S and H2Sn (2017)
  • Author(s): Hideo Kimura
  • Organizer: ConBio2017
• [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
• [Remarks] 日本医療研究開発機構 成果情報 木村英雄博士がトムソン・ロイター第4回リサーチフロントアワードを受賞
  • URL: https://www.amed.go.jp/news/seika/jyusho/20160725.html
• [Remarks] 日本医療研究開発機構 プレスリリース 酸化還元制御因子生合成経路の解明ー治療等応用に期待ー
  • URL: https://www.amed.go.jp/news/release_20170905-03.html
• [Remarks] 日本医療研究開発機構 事業の成果 受賞記事一覧
  • URL: https://www.amed.go.jp/seika/jusyo_list.html
• [Remarks] 日本医療研究開発機構 成果情報 2016年(平成28)年 成果情報一覧
  • URL: https://www.amed.go.jp/news/seika/2016_index.html
• [Remarks] 国立精神・神経医療研究センター シグナル分子H2SとNOの相乗効果がH2Sn生成によることを解明
  • URL: https://www.ncnp.go.jp/press/release.html?no=342