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Isomerization of Aspartate residue as a new indicator of aging

Research Project

Project/Area Number 17K13221
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Applied health science
Research InstitutionKyoto University

Principal Investigator

Takata Takumi  京都大学, 複合原子力科学研究所, 准教授 (80379007)

Project Period (FY) 2017-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Keywordsクリスタリン / 白内障 / アスパラギン酸 / 翻訳後修飾 / 異性化 / 加齢 / 質量分析 / MRM法 / Asp異性化 / 結合型D-アミノ酸 / D-アミノ酸 / 脱アミド化 / 加齢性疾患 / タンパク質異常凝集 / 老化 / 水晶体 / プロテオーム
Outline of Final Research Achievements

The purpose of this study is to define the spontaneous chemical alterations (Asp isomerization) of aspartic acid residues in proteins as a new aging index for proteins containing them. Asp residue in protein is isomerized during life. Along with this, isomerized Asp causes structural changes in proteins including itself, and may cause the onset of age-related diseases (cataract, Alzheimer's disease, etc.). Therefore, quantitative analysis of isomerized Asp in proteins may lead to early detection of diseases. In this study, we succeeded in developing a method for finding a very small amount of isomerized Asp present in the protein, and also succeeded in demonstrating the importance of the site where isomerization was observed.

Academic Significance and Societal Importance of the Research Achievements

眼の水晶体内部における加齢分子マーカーを確立した。
水晶体内部における『タンパク質分子年齢』の提唱により、年齢や、測定した眼機能評価による組織年齢以外に、組織(水晶体)の状態や機能を蛋白質分子レベルで評価することができる。これまでにない眼機能の多次元評価が可能となり、また該当部位を疾患予想部位と定め、新たな予防法や薬剤の標的部位とすることができる。本研究で得られた成果は、80歳以上ほぼ全ての人類が罹患する、加齢性白内障の早期症状発見や発症抑制につながる。

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

    (47 results)

All 2021 2020 2019 2018 2017

All Journal Article (12 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 12 results,  Open Access: 6 results) Presentation (35 results) (of which Int'l Joint Research: 13 results,  Invited: 13 results)

  • [Journal Article] Elucidation of the mechanism of subunit exchange in αB crystallin oligomers2021

    • Author(s)
      Inoue Rintaro、Sakamaki Yusuke、Takata Takumi、Wood Kathleen、Morishima Ken、Sato Nobuhiro、Okuda Aya、Shimizu Masahiro、Urade Reiko、Fujii Noriko、Sugiyama Masaaki
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 1-9

    • DOI

      10.1038/s41598-021-82250-z

    • NAID

      120006956390

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Site‐specific rapid deamidation and isomerization in human lens αA‐crystallin in vitro2020

    • Author(s)
      Takata Takumi、Ha Seongmin、Koide Tamaki、Fujii Noriko
    • Journal Title

      Protein Science

      Volume: 29 Issue: 4 Pages: 941-951

    • DOI

      10.1002/pro.3821

    • Related Report
      2020 Annual Research Report 2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Asp isomerization increases aggregation of α-crystallin and decreases its chaperone activity in human lens of various ages2020

    • Author(s)
      Fujii Noriko、Takata Takumi、Kim Ingu、Morishima Ken、Inoue Rintaro、Magami Kousuke、Matsubara Toshiya、Sugiyama Masaaki、Koide Tamaki
    • Journal Title

      Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

      Volume: 1868 Issue: 9 Pages: 140446-140446

    • DOI

      10.1016/j.bbapap.2020.140446

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Simultaneous and Rapid Detection of Multiple Epimers and Isomers of Aspartyl Residues in Lens Proteins Using an LC-MS-MRM Method2020

    • Author(s)
      Fujii Noriko、Takata Takumi、Kim Ingu、Matsubara Toshiya
    • Journal Title

      ACS Omega

      Volume: 5 Issue: 42 Pages: 27626-27632

    • DOI

      10.1021/acsomega.0c04197

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effect of a Lens Protein in Low-Temperature Culture of Novel Immortalized Human Lens Epithelial Cells (iHLEC-NY2).2020

    • Author(s)
      Yamamoto N, Takeda S, Hatsusaka N, Hiramatsu N, Nagai N, Deguchi S, Nakazawa Y, Takata T, Kodera S, Hirata A, Kubo E, Sasaki H.
    • Journal Title

      Cells.

      Volume: 9 (12) Issue: 12 Pages: 2670-2670

    • DOI

      10.3390/cells9122670

    • NAID

      130008066407

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Negative charge at aspartate 151 is important for human lens αA-crystallin stability and chaperone function.2019

    • Author(s)
      Takata T, Matsubara T, Nakamura-Hirota T, Fujii N.
    • Journal Title

      Experimental eye research.

      Volume: 5 Pages: 10-18

    • DOI

      10.1016/j.exer.2019.02.023

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] D-Amino acids in protein: The mirror of life as a molecular index of aging2018

    • Author(s)
      Fujii Noriko、Takata Takumi、Fujii Norihiko、Aki Kenzo、Sakaue Hiroaki
    • Journal Title

      Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

      Volume: in press Issue: 7 Pages: 840-847

    • DOI

      10.1016/j.bbapap.2018.03.001

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Identification of Isomeric Aspartate residues in βB2-crystallin from Aged Human Lens2018

    • Author(s)
      Takata Takumi、Murakami Kento、Toyama Atsuhiko、Fujii Noriko
    • Journal Title

      Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

      Volume: in press Issue: 7 Pages: 767-774

    • DOI

      10.1016/j.bbapap.2018.04.002

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Asp 58 modulates lens αA-crystallin oligomer formation and chaperone function2018

    • Author(s)
      Takata Takumi、Nakamura-Hirota Tooru、Inoue Rintaro、Morishima Ken、Sato Nobuhiro、Sugiyama Masaaki、Fujii Noriko
    • Journal Title

      The FEBS Journal

      Volume: in press Issue: 12 Pages: 2263-2277

    • DOI

      10.1111/febs.14475

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Isomeric Replacement of a Single Aspartic Acid Induces a Marked Change in Protein Function: The Example of Ribonuclease A2017

    • Author(s)
      Sakaue H, Kinouchi T, Fujii N, Takumi T, Fujii N.
    • Journal Title

      ACS Omega

      Volume: 2 Issue: 1 Pages: 260-267

    • DOI

      10.1021/acsomega.6b00346

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ferulic Acid Suppresses Amyloid β Production in the Human Lens Epithelial Cell Stimulated with Hydrogen Peroxide.2017

    • Author(s)
      Nagai N, Kotani S, Mano Y, Ueno A, Ito Y, Kitaba T, Takata T and Fujii N.
    • Journal Title

      Biomed. Res. Int.

      Volume: - Pages: 1-9

    • DOI

      10.1155/2017/5343010

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of ?-amino acid-containing peptides in human serum2017

    • Author(s)
      Ha Seongmin、Kim Ingu、Takata Takumi、Kinouchi Tadatoshi、Isoyama Masaharu、Suzuki Minoru、Fujii Noriko
    • Journal Title

      PLOS ONE

      Volume: 12 Issue: 12 Pages: e0189972-e0189972

    • DOI

      10.1371/journal.pone.0189972

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] クリスタリン内部アミノ酸の翻訳後修飾からみる水晶体老化2020

    • Author(s)
      高田 匠
    • Organizer
      第59回日本白内障学会総会・第46回水晶体研究会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] αA-クリスタリン中のAsp151をAsnに置換した組換え体では、同部位の異性化が10倍速く進行する2020

    • Author(s)
      高田 匠 , 藤井 紀子
    • Organizer
      第59回日本白内障学会総会・第46回水晶体研究会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 蛋白質結合型のアスパラギン酸残基の異性化修飾について2020

    • Author(s)
      高田 匠 , 藤井 紀子
    • Organizer
      第71回日本電気泳動学会総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] The Effects of Isomerization and Racemization of Asp Residues for Polypeptide Properties2020

    • Author(s)
      Takumi Takata, Naomi Hachiya and Noriko Fujii
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] CREATION OF ASP-ISOMER-CONTAINING LENS alphaA-CRYSTALLIN USING THE EXPRESSED PROTEIN LIGATION2019

    • Author(s)
      T. Takata, H. Sakaue, and N. Fujii.
    • Organizer
      The 4th International Conference of D-amino acid Research.
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] ISOMERIZATION OF ASP INCREASES THE AGGREGATION OF CRYSTALLIN AND DECREASES THE CHAPERONE FUNCTION OF CRYSTALLIN2019

    • Author(s)
      N. Fujii, T. Takata, I. Kim, R. Inoue, K. Morishima, K. Magami, and M. Sugiyama.
    • Organizer
      The 4th International Conference of D-amino acid Research.
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] A SINGLE ASP-ISOMER SUBSTITUTION IN AN ALPHA A-CRYSTALLIN-DERIVED PEPTIDE INDUCES A LARGE CHANGE IN PEPTIDE PROPERTIES2019

    • Author(s)
      K. Magami, T. Kinouchi, I. Kim, T. Takata, and N. Fujii.
    • Organizer
      The 4th International Conference of D-amino acid Research.
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 多重反応モニタリング(MRM)法を用いた老化蛋白質中のD-アミノ酸分析2019

    • Author(s)
      藤井紀子, 高田匠, 金仁求, 松原稔哉
    • Organizer
      日本プロテオーム学会2019年大会 第70回日本電気泳動学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Asp151部位へAsp異性体を導入したαA-クリスタリンの作出2019

    • Author(s)
      高田匠, 藤井紀子
    • Organizer
      第58回日本白内障学会総会・第45回水晶体研究会合同大会
    • Related Report
      2019 Research-status Report
  • [Presentation] クリスタリン中の複数箇所で見られるAsp異性体の一斉分析2019

    • Author(s)
      藤井紀子, 高田匠, 金仁求, 松原稔哉
    • Organizer
      第58回日本白内障学会総会・第45回水晶体研究会合同大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Lens β-crystallins preferentially form hetero-oligomers2019

    • Author(s)
      K. J. Lampi, M. Donor, T. Takata, C. Vetter, L. L. David, and J. Prell.
    • Organizer
      The Association For Research in Vision and Ophthalmology.
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] D-アミノ酸で語る新しい老化サイエンス2019

    • Author(s)
      高田匠
    • Organizer
      第14回 京都大学附置研究・センターシンポジウム
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Creation and analysis of isomers-containing lens αA-crystallin2019

    • Author(s)
      Takumi Takata, Ken Morishima, Rintaro Inoue, Masaaki Sugiyama and Noriko Fujii
    • Organizer
      The 6th International Conference on the Lens.
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] The Mutation Studies for Isomerization Hot spots of Aspartate Residues in Lens αA-Crystallin2018

    • Author(s)
      Takumi Takata and Noriko Fujii
    • Organizer
      ISER 2018 XXIII Biennial Meeting of the International Society for Eye Research
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] ヒト水晶体内α A- クリスタリン中における Asp151 部位の重要性2018

    • Author(s)
      高田 匠, 藤井 紀子
    • Organizer
      第57回日本白内障学会総会・第44回水晶体研究会
    • Related Report
      2018 Research-status Report
  • [Presentation] β-クリスタリン中のアスパラギン酸残基の異性化2018

    • Author(s)
      金 仁求, 高田 匠, 加治 優一, 藤井 紀子
    • Organizer
      第57回日本白内障学会総会・第44回水晶体研究会
    • Related Report
      2018 Research-status Report
  • [Presentation] Isomerization and racemization hotspots in lens αA-crystallin2018

    • Author(s)
      Takumi Takata and Noriko Fujii
    • Organizer
      第18回日本蛋白質科学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] The Site-specific Impact of Modifications of Aspartate Residues on Lens αA-Crystallin2018

    • Author(s)
      Takumi Takata, Rintaro Inoue, Ken Morishima, Nobuhiro Sato, Masaaki Sugiyama, and Noriko Fujii
    • Organizer
      The Association for Research in Vision and Ophthalmology 2018 Annual Meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] クリスタリンの凝集とアスパラギン酸の異性化2018

    • Author(s)
      藤井 紀子, 高田 匠, 金 仁求, 守島 健, 井上 倫太郎, 眞上 晃輔, 杉山 正明
    • Organizer
      第14回 D-アミノ酸学会学術講演会
    • Related Report
      2018 Research-status Report
  • [Presentation] ヒト水晶体内αA-クリスタリン中のAsp151残基異性化について2018

    • Author(s)
      高田 匠, 藤井 紀子
    • Organizer
      第14回 D-アミノ酸学会学術講演会
    • Related Report
      2018 Research-status Report
  • [Presentation] β-クリスタリン中のアスパラギン酸残基の異性化2018

    • Author(s)
      金 仁求, 高田 匠, 加治 優一, 藤井 紀子
    • Organizer
      第14回 D-アミノ酸学会学術講演会
    • Related Report
      2018 Research-status Report
  • [Presentation] Asp76異性化によるαA-crystallin由来ペプチドαA66-80の機能変化2018

    • Author(s)
      眞上 晃輔, 木野内 忠稔, 金 仁求, 高田 匠, 藤井 紀子
    • Organizer
      第14回 D-アミノ酸学会学術講演会
    • Related Report
      2018 Research-status Report
  • [Presentation] Age-related abnormal Asp 58 isomers distribution in lens αA-crystallin2017

    • Author(s)
      Takumi Takata, Noriko Fujii
    • Organizer
      The 3rd International Conference of D-Amino Acid Research
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] The mechanism of D-amino acid formation in proteins and new method of protein-bound D-amino acid detection2017

    • Author(s)
      Noriko Fujii, Takumi Takata, Norihiko Fujii, Kenzo Aki, Hiroaki Sakaue
    • Organizer
      The 3rd International Conference of D-Amino Acid Research
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] A single aspartyl isomer at a specific site induces a change in protein function2017

    • Author(s)
      Hiroaki Sakaue, Tadatoshi Kinouchi, Takumi Takata, Noriko Fujii
    • Organizer
      The 3rd International Conference of D-Amino Acid Research
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Analysis of the post-translational modifications of the individual amino acids in lens proteins which were induced by irradiation and aging2017

    • Author(s)
      Ingu Kim, Takumi Takata, Noriko Fujii
    • Organizer
      The 3rd International Conference of D-Amino Acid Research
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 水晶体構成タンパク質中のアミノ酸の翻訳後修飾が引き起こす白内障発祥の機構解明に関する研究2017

    • Author(s)
      高田匠
    • Organizer
      第56回日本白内障学会総会・第43回水晶体研究会 合同大会 受賞講演
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] alphaA-クリスタリン相互作用能に関与するAsp異性化2017

    • Author(s)
      高田匠, 金仁求, 藤井紀子
    • Organizer
      第56回日本白内障学会総会・第43回水晶体研究会 合同大会
    • Related Report
      2017 Research-status Report
  • [Presentation] LC-MS/MSによる白内障クリスタリンの翻訳後修飾の一斉分析2017

    • Author(s)
      金仁求, 高田匠, 加治優一, 藤井紀子
    • Organizer
      第56回日本白内障学会総会・第43回水晶体研究会 合同大会
    • Related Report
      2017 Research-status Report
  • [Presentation] Age-related modification of Asp58 and Asp151 in lens αA-crystallin contributes to cataract formation2017

    • Author(s)
      Takumi Takata, Noriko Fujii
    • Organizer
      International Conference on the Lens 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] The loss of chaperone activity of human lens αA-crystallin-derived peptide 66-80 is dramatically recovered by the replacement of Lβisomer at Asp762017

    • Author(s)
      Kosuke Magami, Takumi Takata, Iugu Kim, Noriko Fujii
    • Organizer
      International Conference on the Lens 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 加齢に応じた水晶体機能の低下に関与するアスパラギン酸の異性化修飾2017

    • Author(s)
      高田匠, 藤井紀子
    • Organizer
      第90回 日本生化学会 (ConBio2017)
    • Related Report
      2017 Research-status Report
  • [Presentation] αA-クリスタリン66-80ペプチド中でのAsp76の異性化によるペプチドの機能変化2017

    • Author(s)
      眞上晃輔, 高田匠, 金仁求, 木野内忠稔, 藤井紀子
    • Organizer
      第90回 日本生化学会 (ConBio2017)
    • Related Report
      2017 Research-status Report
  • [Presentation] αA-クリスタリンの部分ペプチドを用いたAsp58の異性化速度に関するpHの影響2017

    • Author(s)
      石原和樹, 金仁求, 高田匠, 藤井紀子
    • Organizer
      第90回 日本生化学会 (ConBio2017)
    • Related Report
      2017 Research-status Report
  • [Presentation] ヒト血清中のD-アミノ酸含有ペプチド同定2017

    • Author(s)
      Seongmin H, Ingu Kim, 高田匠, 藤井紀子
    • Organizer
      第90回 日本生化学会 (ConBio2017)
    • Related Report
      2017 Research-status Report

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

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