• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Elucidation of the construction mechanism of porphyrin ring essential for organisms: Formation and cyclization of tetrapyrrole

Research Project

Project/Area Number 18K05326
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 37010:Bio-related chemistry
Research InstitutionKurume University

Principal Investigator

Sato Hideaki  久留米大学, 医学部, 准教授 (60271996)

Co-Investigator(Kenkyū-buntansha) 杉島 正一  久留米大学, 医学部, 准教授 (30379292)
塚口 舞 (古澤舞)  久留米大学, 医学部, 助教 (40624094)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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)
Keywordsヘム生合成 / ポルフィリン生合成 / テトラピロール / X線結晶構造解析 / 酵素反応機構 / 結晶構造解析 / タンパク質間相互作用
Outline of Final Research Achievements

In the animal heme biosynthesis pathway catalyzed by eight enzymes, hydroxymethylbilane synthase (HMBS) that catalyzes the third step forms a product by sequentially condensing four molecules of substrate with dipyrromethane cofactor. In this study, in order to well-understand the construction of tetrapyrrole, the reaction mechanism of HMBS was investigated by structural biology techniques. Holo-HMBS and reaction intermediates (ES1 ~ ES4), in which 1 to 4 molecules of substrate are linked to the cofactor, were isolated, and crystal structures of holo-HMBS, ES2, and the complexes of them with a substrate derivative were analyzed. From the obtained crystal structures, the molecular mechanism of the HMBS reaction was considered. In particular, it was found that the construction of the pyrrole chain proceeds by repeating the condensation reaction at a single substrate-binding site.

Academic Significance and Societal Importance of the Research Achievements

ヘム生合成経路においてピロール環を含む基質4分子からテトラピロールを構築する酵素HMBSが、どのように基質を捕らえて連結していくのかについて、基質誘導体との複合体の立体構造に基づいて示すことができた。このHMBSの基質結合部位に基質誘導体が結合した複合体の立体構造は、本研究で初めて明らかになったものである。研究成果は、ヘム生合成が遺伝的に障害されてポルフィリン前駆体が蓄積するポルフィリン症の原因の理解につながるものと期待される。

Report

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

    (32 results)

All 2021 2020 2019 2018 Other

All Journal Article (9 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 9 results,  Open Access: 6 results) Presentation (20 results) (of which Int'l Joint Research: 2 results) Remarks (3 results)

  • [Journal Article] Crystal structures of hydroxymethylbilane synthase complexed with a substrate analog: a single substrate-binding site for four consecutive condensation steps2021

    • Author(s)
      Sato Hideaki、Sugishima Masakazu、Tsukaguchi Mai、Masuko Takahiro、Iijima Mikuru、Takano Mitsunori、Omata Yoshiaki、Hirabayashi Kei、Wada Kei、Hisaeda Yoshio、Yamamoto Ken
    • Journal Title

      Biochemical Journal

      Volume: 478 Issue: 5 Pages: 1023-1042

    • DOI

      10.1042/bcj20200996

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Conformational equilibrium of NADPH-cytochrome P450 oxidoreductase is essential for heme oxygenase reaction2020

    • Author(s)
      Sugishima M., Taira J., Sagara T., Nakao R., Sato H., Noguchi M., Fukuyama K., Yamamoto K., Yasunaga T., Sakamoto H.
    • Journal Title

      Antioxidants

      Volume: 9 Issue: 8 Pages: 1-13

    • DOI

      10.3390/antiox9080673

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional diversification of two bilin reductases for light perception and harvesting in unique cyanobacterium Acaryochloris marina MBIC 110172020

    • Author(s)
      Miyake Keita、Fushimi Keiji、Kashimoto Tomonori、Maeda Kaisei、Ni‐Ni‐Win、Kimura Hiroyuki、Sugishima Masakazu、Ikeuchi Masahiko、Narikawa Rei
    • Journal Title

      The FEBS Journal

      Volume: - Issue: 18 Pages: 4016-4031

    • DOI

      10.1111/febs.15230

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Bilin-metabolizing Enzymes: Site-specific Reductions Catalyzed by Two Different Type of Enzymes2019

    • Author(s)
      Sugishima, M., Wada, K., Unno, M., Fukuyama, K.
    • Journal Title

      Current Opinion in Structural Biology

      Volume: 59 Pages: 73-80

    • DOI

      10.1016/j.sbi.2019.03.005

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Coupling of Redox and Structural States in Cytochrome P450 Reductase Studied by Molecular Dynamics Simulation2019

    • Author(s)
      Iijima Mikuru、Ohnuki Jun、Sato Takato、Sugishima Masakazu、Takano Mitsunori
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 9341-9341

    • DOI

      10.1038/s41598-019-45690-2

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Crystal structure of phytochromobilin synthase in complex with biliverdin IXα, a key enzyme in the biosynthesis of phytochrome2019

    • Author(s)
      Sugishima Masakazu、Wada Kei、Fukuyama Keiichi、Yamamoto Ken
    • Journal Title

      Journal of Biological Chemistry

      Volume: 295 Issue: 3 Pages: 771-782

    • DOI

      10.1074/jbc.ra119.011431

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Crystal structure of a NADPH-cytochrome P450 oxidoreductase (CYPOR) and heme oxygenase 1 fusion protein implies a conformational change in CYPOR upon NADPH/NADP+ binding2019

    • Author(s)
      Sugishima Masakazu、Sato Hideaki、Wada Kei、Yamamoto Ken
    • Journal Title

      FEBS Letters

      Volume: 593 Issue: 8 Pages: 868-875

    • DOI

      10.1002/1873-3468.13360

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Recent Advances in the Understanding of the Reaction Chemistries of the Heme Catabolizing Enzymes HO and BVR Based on High Resolution Protein Structures2018

    • Author(s)
      Sugishima M, Wada K, Fukuyama K.
    • Journal Title

      Current Medicinal Chemistry

      Volume: 26 Issue: 21 Pages: 3499-3518

    • DOI

      10.2174/0929867326666181217142715

    • Related Report
      2020 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Crystal Growth of a Bilin Reductase PcyA I86D Mutant-Substrate Complex for Neutron Crystallography2018

    • Author(s)
      Igarashi Keisuke、Hagiwara Yoshinori、Sugishima Masakazu、Wada Kei、Fukuyama Keiichi、Ikeda Atsushi、Yano Naomine、Kusaka Katsuhiro、Ostermann Andreas、Unno Masaki
    • Journal Title

      Crystal Growth & Design

      Volume: 18 Issue: 9 Pages: 5174-5181

    • DOI

      10.1021/acs.cgd.8b00607

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] 光応答タンパク質フィトクロムの発色団合成機構2020

    • Author(s)
      杉島 正一、和田 啓、福山 恵一、山本 健
    • Organizer
      第93回日本生化学会大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] フィトクロム発色団合成酵素HY2の結晶大型化に向けて2020

    • Author(s)
      杉島正一、和田啓、齋藤夏希、海野昌喜、福山恵一、山本健
    • Organizer
      日本結晶学会 令和2年(2020年)度年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] ヒドロキシメチルビラン合成酵素の反応中間体と基質誘導体との複合体の結晶構造解析2019

    • Author(s)
      佐藤 秀明,杉島 正一,塚口 舞,増子 隆博,小俣 義明,和田 啓,久枝 良雄,山本 健
    • Organizer
      2019年度日本生化学会九州支部例会
    • Related Report
      2019 Research-status Report
  • [Presentation] フィトクロム発色団合成酵素のX線結晶構造解析2019

    • Author(s)
      杉島 正一,和田 啓,山本 健
    • Organizer
      2019年度日本生化学会九州支部例会
    • Related Report
      2019 Research-status Report
  • [Presentation] 基質誘導体を結合したヒト由来ヒドロキシメチルビランシンターゼ反応中間体の結晶構造解析2019

    • Author(s)
      佐藤 秀明,杉島 正一,塚口 舞,増子 隆博,小俣 義明,和田 啓,久枝 良雄,山本 健
    • Organizer
      第19回日本蛋白質科学会年会 第71回日本細胞生物学会大会 合同年次大会
    • Related Report
      2019 Research-status Report
  • [Presentation] 基質誘導体を結合したヒドロキシメチルビランシンターゼ反応中間体の構造解析2019

    • Author(s)
      佐藤 秀明,杉島 正一,塚口 舞,増子 隆博,小俣 義明,和田 啓,久枝 良雄,山本 健
    • Organizer
      第43回蛋白質と酵素の構造と機能に関する九州シンポジウム
    • Related Report
      2019 Research-status Report
  • [Presentation] フィトクロモビリン合成酵素の酵素反応と立体構造2019

    • Author(s)
      杉島 正一,和田 啓,山本 健
    • Organizer
      第43回蛋白質と酵素の構造と機能に関する九州シンポジウム
    • Related Report
      2019 Research-status Report
  • [Presentation] ヘム生合成経路におけるピロール結合反応の分子機構2019

    • Author(s)
      佐藤 秀明
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] ヘム分解酵素HO-1によるCOとO2の厳密な識別機構2019

    • Author(s)
      杉島 正一
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] 赤色光受容体フィトクロムの光受容色素合成に必須な酵素の立体構造と機能2019

    • Author(s)
      杉島 正一,和田 啓,福山 恵一,山本 健
    • Organizer
      日本結晶学会令和元年(2019年)度年会
    • Related Report
      2019 Research-status Report
  • [Presentation] ヒドロキシメチルビランシンターゼの反応中間体と基質類似体との複合体の結晶構造解析2019

    • Author(s)
      佐藤秀明,杉島正一,塚口 舞,増子隆博,小俣義明,和田 啓,久枝良雄,山本 健
    • Organizer
      日本化学会第99春季年会
    • Related Report
      2018 Research-status Report
  • [Presentation] 基質を2分子結合したヒドロキシメチルビラン合成酵素のX線結晶構造解析2018

    • Author(s)
      佐藤秀明,杉島正一,塚口 舞,増子隆博,小俣義明,和田 啓,久枝良雄,山本 健
    • Organizer
      第18回日本蛋白質科学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] NADP添加によるNADPH-シトクロムP450還元酵素とヘムオキシゲナーゼ間の相互作用増大の構造的要因2018

    • Author(s)
      杉島正一,佐藤秀明,和田 啓,平 順一,坂本 寛,山本 健
    • Organizer
      平成30年度日本生化学会九州支部例会
    • Related Report
      2018 Research-status Report
  • [Presentation] 構造変化を伴うNADPH-シトクロムP450還元酵素とヘムオキシゲナーゼ-1の複合体形成の沈降平衡法による解析2018

    • Author(s)
      平 順一、相良達哉、杉島正一、坂本 寛
    • Organizer
      平成30年度日本生化学会九州支部例会
    • Related Report
      2018 Research-status Report
  • [Presentation] ヘム分解関連酵素間の特異的相互作用を基盤とする分子内FRETヘムプローブの開発2018

    • Author(s)
      松田和也、井之上実希、平 順一、小松英幸、杉島正一、坂本 寛
    • Organizer
      平成30年度日本生化学会九州支部例会
    • Related Report
      2018 Research-status Report
  • [Presentation] Coupling of the Redox and Structural States in Cytochrome P450 Reductase Studied by Molecular Dynamics2018

    • Author(s)
      Iijima M, Ohnuki J, Sato T, Sugishima M, Takano M
    • Organizer
      The 32nd Annual Symposium of The Protein Society
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] ヒドロキシメチルビラン合成酵素(HMBS)の酵素反応と構造変化2018

    • Author(s)
      佐藤秀明,杉島正一,塚口 舞,増子隆博,小俣義明,和田 啓,久枝良雄,山本 健
    • Organizer
      第42回蛋白質と酵素の構造と機能に関する九州シンポジウム
    • Related Report
      2018 Research-status Report
  • [Presentation] 2分子の基質を結合したヒトヒドロキシメチルビランシンターゼの結晶構造2018

    • Author(s)
      佐藤秀明,杉島正一,塚口 舞,増子隆博,小俣義明,和田 啓,久枝良雄,山本 健
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] HO-CPR人工融合タンパク質の結晶構造2018

    • Author(s)
      杉島正一,佐藤秀明,和田 啓,平 順一,坂本 寛,山本 健
    • Organizer
      日本結晶学会2018年度年会
    • Related Report
      2018 Research-status Report
  • [Presentation] Crystal structure of the substrate bound form of biliverdin reductase with unpredicted substrate-stacked geometry revealed unique reaction mechanism2018

    • Author(s)
      Haruna Takao, Kei Hirabayashi, Jiro Harada, Hideaki Sato, Keiichi Fukuyama, Masakazu Sugishima, Kei Wada
    • Organizer
      AsCA 2018/CRYSTAL 32: The combined conference of the Asian Crystallographic Association (AsCA) and the Society of Crystallographers in Australia and New Zealand (SCANZ)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Remarks] 久留米大学研究者紹介:佐藤秀明

    • URL

      http://research.kurume-u.ac.jp/data.php?scode=54025632885110

    • Related Report
      2020 Annual Research Report
  • [Remarks] 久留米大学研究者紹介:佐藤秀明

    • URL

      http://research.kurume-u.ac.jp/data.php?scode=54025632885110

    • Related Report
      2019 Research-status Report
  • [Remarks] 久留米大学研究者紹介:佐藤秀明

    • URL

      http://research.kurume-u.ac.jp/data.php?scode=62235632885110

    • Related Report
      2018 Research-status Report

URL: 

Published: 2018-04-23   Modified: 2022-01-27  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi