Production of polysulfidated protein and regulation mechanism of its structure/functions

• Project/Area Number: 17K08619
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: Ida Tomoaki 東北大学, 医学系研究科, 助教 (70570406)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ポリスルフィド化タンパク質 / 活性イオウ分子種 / プロテオーム / 質量分析装置 / タンパク質ポリスルフィド化 / レドックス / 活性イオウ分子 / メタボローム / 生理活性物質

Outline of Final Research Achievements

A specific and highly sensitive polysulfide protein analysis system, which is essential for elucidating the protein polysulfide level, biosynthesis, structure, and regulation mechanism, has not been established. In this research project, we showed the unique chemical reactivity of reactive sulfur species. Furthermore, an analysis system using a mass spectrometer was developed to detect polysulfided proteins with high specificity. Using this analysis system, the dynamics, structure and function of polysulfated proteins were clarified.

Academic Significance and Societal Importance of the Research Achievements

本研究により構築したポリスルフィド化タンパク質解析システムは、タンパク質科学や分子生物学、生理学、各種疾患の分子病態論など基礎生物学から医学・臨床科学など様々な学術分野で求められている極めて重要な解析ツールであることが示された。本ポリスルフィド解析システムによるポリスルフィド化タンパク質の生合成、構造機能の解明は、様々な疾患病態の分子メカニズムの理解に寄与するのみならず、ポリスルフィド化タンパク質の生理機能に基づいた新規治療薬・治療法の開発応用の基盤となることが期待された。

Research Products

• [Int'l Joint Research] Sonoma State University/Washington State University(米国)
• [Int'l Joint Research] University of Southampton/King's College of London(英国)
• [Int'l Joint Research] National Institute of Oncology(ハンガリー)
• [Int'l Joint Research] Karolinska Institutet(スウェーデン)
• [Int'l Joint Research] National Institute of Oncology(ハンガリー)
• [Int'l Joint Research] Sonoma State University/University of Vermont(米国)
• [Int'l Joint Research] University of Southampton/King's College London(英国)
• [Journal Article] 8-Nitro-cGMP modulates exocytosis in adrenal chromaffin cells (2020)
  • Author(s): Tsutsuki Hiroyasu、Kasamatsu Shingo、Kunieda Kohei、Ida Tomoaki、Sawa Tomohiro、Sasakawa Nobuyuki、Akaike Takaaki、Ihara Hideshi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: in press Issue: 1 Pages: 225-230
  • DOI: 10.1016/j.bbrc.2020.03.045
  • Peer Reviewed / Open Access
• [Journal Article] Control of Protein Function Through Oxidation and Reduction of Persulfidated States (2020)
  • Author(s): E Doka, T Ida, M Dagnell, Y Abiko, N C Luong, N Balog, T Takata, B Espinosa, A Nishimura, Q Cheng, Y Funato, H Miki, J M Fukuto, J R Prigge, E E Schmidt, E S J Arner, Y Kumagai, T Akaike, P Nagy
  • Journal Title: Sci Adv Volume: 6 Issue: 1 Pages: 8358-8358
  • DOI: 10.1126/sciadv.aax8358
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long-lasting blood pressure lowering effects of nitrite are NO-independent and mediated by hydrogen peroxide, persulfides, and oxidation of protein kinase G1α redox signalling (2019)
  • Author(s): Feelisch Martin、Akaike Takaaki、Griffiths Kayleigh、Ida Tomoaki、Prysyazhna Oleksandra、Goodwin Joanna J、Gollop Nicholas D、Fernandez Bernadette O、Minnion Magdalena、Cortese-Krott Miriam M、Borgognone Alessandra、Hayes Rosie M、Eaton Philip、Frenneaux Michael P、Madhani Melanie
  • Journal Title: Cardiovascular Research Volume: 116 Issue: 1 Pages: 51-62
  • DOI: 10.1093/cvr/cvz202
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mitochondrial cysteinyl-tRNA synthetase is expressed via alternative transcriptional initiation regulated by energy metabolism in yeast cells (2019)
  • Author(s): Nishimura Akira、Nasuno Ryo、Yoshikawa Yuki、Jung Minkyung、Ida Tomoaki、Matsunaga Tetsuro、Morita Masanobu、Takagi Hiroshi、Motohashi Hozumi、Akaike Takaaki
  • Journal Title: Journal of Biological Chemistry Volume: 294 Issue: 37 Pages: 13781-13788
  • DOI: 10.1074/jbc.ra119.009203
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Data‐Driven Identification of Hydrogen Sulfide Scavengers (2019)
  • Author(s): Yang Chun‐tao、Wang Yingying、Marutani Eizo、Ida Tomoaki、Ni Xiang、Xu Shi、Chen Wei、Zhang Hui、Akaike Takaaki、Ichinose Fumito、Xian Ming
  • Journal Title: Angewandte Chemie International Edition Volume: 58 Issue: 32 Pages: 10898-10902
  • DOI: 10.1002/anie.201905580
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oxidation of PKGIα mediates an endogenous adaptation to pulmonary hypertension (2019)
  • Author(s): Rudyk Olena、Rowan Alice、Prysyazhna Oleksandra、Krasemann Susanne、Hartmann Kristin、Zhang Min、Shah Ajay M.、Ruppert Clemens、Weiss Astrid、Schermuly Ralph T.、Ida Tomoaki、Akaike Takaaki、Zhao Lan、Eaton Philip
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 116 Issue: 26 Pages: 13016-13025
  • DOI: 10.1073/pnas.1904064116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Environmental Electrophile-Mediated Toxicity in Mice Lacking Nrf2, CSE, or Both (2019)
  • Author(s): Akiyama Masahiro、Unoki Takamitsu、Shinkai Yasuhiro、Ishii Isao、Ida Tomoaki、Akaike Takaaki、Yamamoto Masayuki、Kumagai Yoshito
  • Journal Title: Environmental Health Perspectives Volume: 127 Issue: 6 Pages: 067002-067002
  • DOI: 10.1289/ehp4949
  • NAID: 120007133174
  • Peer Reviewed / Open Access
• [Journal Article] The Uptake and Release of Polysulfur Cysteine Species by Cells: Physiological and Toxicological Implications. (2019)
  • Author(s): Lin J, Akiyama M, Bica I, Long FT, Henderson CF, Goddu RN, Suarez V, Baker B, Ida T, Shinkai Y, Nagy P, Akaike T, Fukuto JM, Kumagai Y.
  • Journal Title: Chem Res Toxicol Volume: 32 Issue: 3 Pages: 447-455
  • DOI: 10.1021/acs.chemrestox.8b00340
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Polysulfide stabilization by tyrosine and hydroxyphenyl-containing derivatives that is important for a reactive sulfur metabolomics analysis. (2019)
  • Author(s): Hamid HA, Tanaka A, Ida T, Nishimura A, Matsunaga T, Fujii S, Morita M, Sawa T, Fukuto JM, Nagy P, Tsutsumi R, Motohashi H, Ihara H, Akaike T.
  • Journal Title: Redox Biol Volume: 21 Pages: 101096-101096
  • DOI: 10.1016/j.redox.2019.101096
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reactive Persulfides from Salmonella Typhimurium Downregulate Autophagy-Mediated Innate Immunity in Macrophages by Inhibiting Electrophilic Signaling (2018)
  • Author(s): Khan Shahzada、Fujii Shigemoto、Matsunaga Tetsuro、Nishimura Akira、Ono Katsuhiko、Ida Tomoaki、Ahmed Khandaker Ahtesham、Okamoto Tatsuya、Tsutsuki Hiroyasu、Sawa Tomohiro、Akaike Takaaki
  • Journal Title: Cell Chemical Biology Volume: 25 Issue: 11 Pages: 1403-1413
  • DOI: 10.1016/j.chembiol.2018.08.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Speciation of reactive sulfur species and their reactions with alkylating agents: do we have any clue about what is present inside the cell? (2018)
  • Author(s): Bogdandi Virag、Ida Tomoaki、Sutton Thomas R、Bianco Christopher、Ditroi Tamas、Koster Grielof、Henthorn Hillary A、Minnion Magda、Toscano John P、van der Vliet Albert、Pluth Michael D、Feelisch Martin、Fukuto Jon M、Akaike Takaaki、Nagy Peter
  • Journal Title: British Journal of Pharmacology Volume: 176 Issue: 4 Pages: 646-670
  • DOI: 10.1111/bph.14394
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The reaction of hydrogen sulfide with disulfides: formation of a stable trisulfide and implications for biological systems (2018)
  • Author(s): Bianco Christopher L、Akaike Takaaki、Ida Tomoaki、Nagy Peter、Bogdandi Virag、Toscano John P、Kumagai Yoshito、Henderson Catherine F、Goddu Robert N、Lin Joseph、Fukuto Jon M
  • Journal Title: British Journal of Pharmacology Volume: 176 Issue: 4 Pages: 671-683
  • DOI: 10.1111/bph.14372
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reactive Cysteine Persulphides: Occurrence, Biosynthesis, Antioxidant Activity, Methodologies, and Bacterial Persulphide Signalling (2018)
  • Author(s): Sawa Tomohiro、Ono Katsuhiko、Tsutsuki Hiroyasu、Zhang Tianli、Ida Tomoaki、Nishida Motohiro、Akaike Takaaki
  • Journal Title: Advances in Microbial Physiology Volume: 72 Pages: 1-28
  • DOI: 10.1016/bs.ampbs.2018.01.002
  • Peer Reviewed / Open Access
• [Journal Article] Biological hydropersulfides and related polysulfides - a new concept and perspective in redox biology (2018)
  • Author(s): Fukuto Jon M.、Ignarro Louis J.、Nagy Peter、Wink David A.、Kevil Christopher G.、Feelisch Martin、Cortese-Krott Miriam M.、Bianco Christopher L.、Kumagai Yoshito、Hobbs Adrian J.、Lin Joseph、Ida Tomoaki、Akaike Takaaki
  • Journal Title: FEBS Letters Volume: 592 Issue: 12 Pages: 2140-2152
  • DOI: 10.1002/1873-3468.13090
  • NAID: 120007133961
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Important role of endothelial caveolin-1 in the protective role of endothelium-dependent hyperpolarization against nitric oxide-mediated nitrative stress in microcirculation in mice (2018)
  • Author(s): Saito H, Godo S, Sato S, Ito A, Ikumi Y, Tanaka S, Ida T, Fujii S, Akaike T, Shimokawa H.
  • Journal Title: Journal of Cardiovascular Pharmacology Volume: 71 Issue: 2 Pages: 113-126
  • DOI: 10.1097/fjc.0000000000000552
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of nitric oxide/reactive oxygen species signaling via 8-nitro-cGMP formation in 1-methyl-4-phenylpyridinium ion-induced neurotoxicity in PC12 cells and rat cerebellar granule neurons (2018)
  • Author(s): Masuda Kumiko、Tsutsuki Hiroyasu、Kasamatsu Shingo、Ida Tomoaki、Takata Tsuyoshi、Sugiura Kikuya、Nishida Motohiro、Watanabe Yasuo、Sawa Tomohiro、Akaike Takaaki、Ihara Hideshi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 495 Issue: 3 Pages: 2165-2170
  • DOI: 10.1016/j.bbrc.2017.12.088
  • Peer Reviewed / Open Access
• [Journal Article] Cysteine perthiosulfenic acid (Cys-SSOH): A novel intermediate in thiol-based redox signaling? (2018)
  • Author(s): Heppner DE, Hristova M, Ida T, Mijuskovic A, Dustin CM, Bogdandi V, Fukuto JM, Dick TP, Nagy P, Li J, Akaike T, van der Vliet A.
  • Journal Title: Redox Biol. Volume: 14 Pages: 379-385
  • DOI: 10.1016/j.redox.2017.10.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics (2017)
  • Author(s): Akaike Takaaki、、、Nishida Motohiro（4）、、、、、、Fujii Shigemoto（20）、、、Motohashi Hozumi（26）
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 1177-1177
  • DOI: 10.1038/s41467-017-01311-y
  • NAID: 120007134656
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 8-Nitro-cGMP promotes bone growth through expansion of growth plate cartilage (2017)
  • Author(s): Hoshino M, Kaneko K, Miyamoto Y, Yoshimura K, Suzuki D, Akaike T, Sawa T, Ida T, Fujii S, Ihara H, Tanaka J, Tsukuura R, Chikazu D, Mishima K, Baba K Kamijo R
  • Journal Title: Free Radic Biol Med. Volume: 110 Pages: 63-71
  • Peer Reviewed / Open Access
• [Journal Article] Exposure to Electrophiles Impairs Reactive Persulfide-Dependent Redox Signaling in Neuronal Cells (2017)
  • Author(s): Ihara Hideshi、Kasamatsu Shingo、Kitamura Atsushi、Nishimura Akira、Tsutsuki Hiroyasu、Ida Tomoaki、Ishizaki Kento、Toyama Takashi、Yoshida Eiko、Abdul Hamid Hisyam、Jung Minkyung、Matsunaga Tetsuro、Fujii Shigemoto、Sawa Tomohiro、Nishida Motohiro、Kumagai Yoshito、Akaike Takaaki
  • Journal Title: Chem. Res. Toxicol Volume: 30 Issue: 9 Pages: 1673-1684
  • DOI: 10.1021/acs.chemrestox.7b00120
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ferulic acid and its water-soluble derivatives inhibit nitric oxide production and inducible nitric oxide synthase expression in rat primary astrocytes (2017)
  • Author(s): Kikugawa M, Ida T, Ihara H, Sakamoto T
  • Journal Title: Bioscience, biotechnology, and biochemistry Volume: 81 Issue: 8 Pages: 1607-1611
  • DOI: 10.1080/09168451.2017.1336925
  • Peer Reviewed / Open Access
• [Journal Article] Production of reactive persulfide species in chronic obstructive pulmonary disease (2017)
  • Author(s): Numakura T, Sugiura H, Akaike T, Ida T, Fujii S, Koarai A, Yamada M, Onodera K, Hashimoto Y, Tanaka R, Sato K, Shishikura Y, Hirano T, Yanagisawa S, Fujino N, Okazaki T, Tamada T, Hoshikawa Y, Okada Y, Ichinose M
  • Journal Title: Thorax Volume: 72 Issue: 12 Pages: 1074-1083
  • DOI: 10.1136/thoraxjnl-2016-209359
  • Peer Reviewed / Open Access
• [Presentation] 活性硫黄メタボロームの新展開 (2020)
  • Author(s): 井田智章、居原 秀、赤池孝章
  • Organizer: 第19回分子予防環境医学研究会大会
  • Invited
• [Presentation] 全生物種横断的に発現されるシステインパースルフィド合成酵素の発見と機能解明 (2020)
  • Author(s): 井田智章、守田匡伸、松永哲郎、西村 明、居原 秀、澤 智裕、本橋ほづみ、赤池孝章
  • Organizer: 第93回日本細菌学会総会
• [Presentation] 活性イオウ安定化と高精度イオウ代謝解析法の確立 (2019)
  • Author(s): 井田智章、松永哲郎、西村 明、守田匡伸、居原 秀、澤 智裕、本橋ほづみ、赤池孝章
  • Organizer: 第92回日本生化学会大会
• [Presentation] Translation-coupled protein polysulfidation, discovery of a novel cysteine persulfide synthase (2019)
  • Author(s): Tomoaki Ida, Masanobu Morita, Akira Nishimura, Tetsuro Matsunaga, Hideshi Ihara, Tomohiro Sawa, Hozumi Motohashi, Takaaki. Akaike
  • Organizer: The 9th Biennial Meeting of Society for Free Radical Research-Asia
  • Int'l Joint Research
• [Presentation] TRANSLATION-COUPLED PROTEIN POLYSULFIDATION, A UNIQUE BIOSYNTHESIS PATHWAY OF CYSTEINE PERSULFIDE (2018)
  • Author(s): Tomoaki. Ida, Akira. Nishimura, Masanobu. Morita, Hideshi Ihara, Tomohiro Sawa, Shigemoto Fujii, Hozumi Motohashi, Takaaki Akaike
  • Organizer: 10th International Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide
  • Int'l Joint Research
• [Presentation] 種横断的新しいシステインパースルフィド合成酵素の発見とシステインパースルフィドの機能 (2018)
  • Author(s): 井田智章、守田匡伸、松永哲郎、西村 明、居原 秀、澤 智裕、藤井重元、本橋ほづみ、赤池孝章
  • Organizer: 第72回日本細菌学会東北支部総会
• [Presentation] システイニルtRNA合成酵素によるパースルフィド合成制御機構の解明 (2018)
  • Author(s): 井田智章、西村 明、守田匡伸、松永哲郎、澤 智裕、居原 秀、藤井重元、本橋ほづみ、赤池孝章
  • Organizer: 第71回日本酸化ストレス学会 第18回日本NO学会 合同学術集会
• [Presentation] Mechanism of persulfide production by cysteinyl-tRNA synthetase (2018)
  • Author(s): 井田智章、守田匡伸、松永哲郎、西村 明、居原 秀、澤 智裕、藤井重元、本橋ほづみ、赤池孝章
  • Organizer: 第91回生化学会大会
• [Presentation] 種横断的新しいシステインパースルフィド合成酵素の発見 (2018)
  • Author(s): 井田智章、守田匡伸、松永哲郎、西村 明、居原 秀、澤 智裕、藤井重元、本橋ほづみ、赤池孝章
  • Organizer: 第29回生体防御学会学術総会
• [Presentation] システイニルtRNA合成酵素によるシステインパースルフィド合成制御機構の解明 (2018)
  • Author(s): 井田智章、西村 明、守田匡伸、松永哲郎、澤 智裕、居原 秀、藤井重元、本橋ほづみ、赤池孝章
  • Organizer: 生理研レドックス研究会
• [Presentation] 親電子解毒代謝系システインパースルフィドの新しい合成酵素の発見 (2018)
  • Author(s): 井田智章、守田匡伸、西村 明、松永哲郎、居原 秀、澤 智裕、藤井重元、熊谷嘉人、本橋ほづみ、赤池孝章
  • Organizer: 第45回日本毒性学会学術年会
• [Presentation] チロシン、ヒドロキシフェニル基によるポリスルフィドの安定化 (2018)
  • Author(s): 井田智章、松永哲郎、西村 明、守田匡伸、居原 秀、澤 智裕、本橋ほづみ、赤池孝章
  • Organizer: 第18回分子予防環境医学研究会
• [Presentation] 活性イオウ・パースルフィド解析システムの開発と応用 (2018)
  • Author(s): 井田智章、赤池孝章
  • Organizer: ConBio2017
  • Invited
• [Presentation] アルコールデヒドロゲナーゼ5の酵素活性制御におけるタンパク質ポリスルフィド化の機能 (2017)
  • Author(s): 井田智章、笠松真吾、 Md. Morshedul Alam、守田匡伸、居原 秀、 西村 明、松永哲郎、藤井重元、本橋ほづみ、赤池孝章
  • Organizer: 第17回日本NO学会学術集会
• [Presentation] 新規システインパースルフィド合成酵素の同定と機能解析 (2017)
  • Author(s): 井田智章、守田匡伸、魏 研范、松永哲郎、西村 明、Jun Minkyung、赤司壮一郎、居原 秀、澤 智裕、藤井重元、熊谷嘉人、富澤一仁、本橋ほづみ、赤池孝章
  • Organizer: 第70回日本酸化ストレス学会学術集会
• [Presentation] Cysteine hydropersulfide production catalyzed by cysteinyl-tRNA synthetases (2017)
  • Author(s): Tomoaki Ida, Akira Nishimura, Masanobu Morita, Hozumi Motohashi, Takaaki Akaike
  • Organizer: SfRBM 2017
  • Int'l Joint Research
• [Presentation] 新しいシステインパースルフィド産生酵素の同定と機能解析 (2017)
  • Author(s): 井田智章、守田匡伸、魏 研范、松永哲郎、西村 明、Jun Minkyung、赤司壮一郎、居原 秀、澤 智裕、藤井重元、熊谷嘉人、富澤一仁、本橋ほづみ、赤池孝章
  • Organizer: オルガネラ研究会２０１７
• [Presentation] 活性イオウ分子種定量解析システムの開発と新しいシステインパースルフィド合成酵素の発見 (2017)
  • Author(s): 井田智章、守田匡伸、魏 研范、松永哲郎、西村 明、居原 秀、澤 智裕、藤井重元、熊谷嘉人、本橋ほづみ、赤池孝章
  • Organizer: 第17回分子予防環境医学研究会
• [Book] SH(ポリスルフィド)の酸化 (2018)
  • Author(s): 西村 明、井田智章、赤池孝章
  • Total Pages: 2
  • Publisher: 医学書院
• [Book] ポリスルフィド化 (2018)
  • Author(s): 西村 明、井田智章、赤池孝章
  • Total Pages: 2
  • Publisher: 医学書院
• [Book] 活性イオウメタボローム: イオウ代謝物とレドックスバイオマーカー (2018)
  • Author(s): 井田智章、西村 明、守田匡伸
  • Total Pages: 9
  • Publisher: 羊土社
  • ISBN: 9784758103695
• [Book] レドックス疾患学 (2018)
  • Author(s): 井田智章、西村 明、守田匡伸
  • Total Pages: 276
  • Publisher: 羊土社
  • ISBN: 9784758103695
• [Remarks] 東北大学大学院医学系研究科環境医学分野ホームページ
  • URL: http://www.toxicosci.med.tohoku.ac.jp/index.html