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Analyses of Porphyria Caused by Environmental Pollutants : Concerted Reaction and Tempo of Heme and Porphyrin Syntheses

Research Project

Project/Area Number 14208066
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field 環境影響評価(含放射線生物学)
Research InstitutionTohoku University

Principal Investigator

SHIMIZU Toru  Tohoku University, Institute of Multidisciplinary Research for Advanced Materials, Professor, 多元物質科学研究所, 教授 (40118956)

Co-Investigator(Kenkyū-buntansha) KUROKAWA Hirofumi  Tohoku University, Institute of Multidisciplinary Research for Advanced Materials, Research Associate, 多元物質科学研究所, 助手 (80359546)
IGARASHI Jotaro  Tohoku University, Institute of Multidisciplinary Research for Advanced Materials, Research Associate, 多元物質科学研究所, 助手 (80375162)
佐上 郁子  東北大学, 多元物質科学研究所, 講師 (10143033)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥37,960,000 (Direct Cost: ¥29,200,000、Indirect Cost: ¥8,760,000)
Fiscal Year 2004: ¥11,960,000 (Direct Cost: ¥9,200,000、Indirect Cost: ¥2,760,000)
Fiscal Year 2003: ¥11,960,000 (Direct Cost: ¥9,200,000、Indirect Cost: ¥2,760,000)
Fiscal Year 2002: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000)
KeywordsHeme / Sensor enzyme / Protein translation / synthesis / NO synthase / Environmental pollutants / Circadian rhythms / Transcription factor / Signal transduction / センサー / 蛋白翻訳・合成 / 部位特異的変異 / NO / 軸配位子 / 赤血球 / 一酸化窒素 / キナーゼ / 蛋白合成 / 遺伝子工学 / ポルフィリン
Research Abstract

In eukaryotes, protein synthesis is terminated when cells face an emergency such as a shortage of amino acids, stress to the endoplasmic reticulum, and viral infection. Translation initiation in the red cell is regulated by eukaryotic initiation factor 2a (a-subunit of eukaryotic initiation factor 2 ; eIF2α) kinases or HRI (heme-regulated inhibitor). In the red cell, protein synthesis is terminated when cells face an emergency such as shortage of the heme iron complex. HRI senses and mediates responses to changes in the Fe(II)-protoporphyrin IX (heme) concentration. Under normal conditions when there is sufficient heme, HRI does not phosphorylate eIF2α, but when there is a shortage of heme, it acts to maintain the heme-to-globin ratio at 1:1 by phosphorylating eIF2a, which initiates the termination of protein synthesis. Although HRI is reported to sense the heme concentration in reticulocytes or red blood cells the molecular mechanisms, in particular the role of the N-terminal domain in its oligomerization, kinase function, and heme sensing, have remained elusive. In addition, little is known regarding how heme binds to the catalytic domain and regulates catalysis, the stoichiometry of heme binding, and which residues are axial ligands for the heme iron. In the present study, we attempted to elucidate how the concerted reactions of the heme and protein syntheses are coupled by generating the N-terminal truncated mutants, His mutants, Cys mutants and examining the catalytic function, heme affinities, and heme coordination structures. We also examined effects of environmentally polluted heavy metal cations on the kinase activities of HRI. It was found that NO enhances catalysis of HRI, NO recovers inhibited calysis by heme and bilirubin and heavy metal cations inhibit catalysis. The results obtained will be helpful to understand the molecular mechanism of porphyria caused by environmental pollutants.

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (19 results)

All 2005 2004 Other

All Journal Article (14 results) Publications (5 results)

  • [Journal Article] Investigation of the Relationship between Protein-Protein Interactions2005

    • Author(s)
      笹倉 由貴江 他
    • Journal Title

      Biochemistry 44(28)

      Pages: 9598-9605

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Dual Effects of the Substrate and Pterins on the Kinetics of CO Binding2005

    • Author(s)
      Bengea, Simona 他
    • Journal Title

      Chemistry Letters 34(6)

      Pages: 752-753

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Spectroscopic Characterization of the Isolated Heme-bound PAS-B Domain2005

    • Author(s)
      鴻渡 亮次他
    • Journal Title

      FEBS Journal 272(43)

      Pages: 4153-4162

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] DOSEc, a Heme-regualted Phosphodiesterase, Plays an Important Role2005

    • Author(s)
      鈴木 登紀子 他
    • Journal Title

      Journal of Bacteriology 187(19)

      Pages: 6678-6682

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] CO-dependent Activity-controlling Mechanism of Heme-containing CO-sensor2005

    • Author(s)
      内田 毅 他
    • Journal Title

      Journal of Biological Chemistry 280(22)

      Pages: 21358-21368

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Investigation of the Relationship between Protein-Protein Interacation2005

    • Author(s)
      Y.Sasakura
    • Journal Title

      Biochemistry 44(28)

      Pages: 9598-9605

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Dual Effects of the Substrate and Pterins on the Kinetics of CO Binding2005

    • Author(s)
      S.Bengea
    • Journal Title

      Chemistry Letters 34(6)

      Pages: 752-753

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Spectroscopic Characterization of the Isolated Heine-bound PAS-B Domain2005

    • Author(s)
      R.Koudo
    • Journal Title

      FEBS Journal 272(43)

      Pages: 4153-4162

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] DOSEc, a Heme-regualted Phosphodiesterase, Plays an Important Role2005

    • Author(s)
      T.Suzuki
    • Journal Title

      Journal of Bacteriology 187(19)

      Pages: 6678-6682

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] CO-dependent Activity-controlling Mechanism of Heme-Contaning CO sensor2005

    • Author(s)
      T.Uchida
    • Journal Title

      Journal of Biological Chemistry 280(22)

      Pages: 21358-21368

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Activation of Heme-regulated Initiation Factor 2α Kinase by Nitric Oxide Is Inducued by the Formation of a Five-coordinated NO-Heme Complex2004

    • Author(s)
      J.Igarashi
    • Journal Title

      Journal of Biological Chemistry 279(16)

      Pages: 15752-15762

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Arg410 near the Heme Proximal Ligand of Neuronal Nitric Oxide Synthases Is Critical for Both Substrate Recognition and Electron Transfer2004

    • Author(s)
      J.Yadav
    • Journal Title

      Chemistry Letters 33(6)

      Pages: 752-753

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Analysis of the Kinetics of CO Binding to Neuronal Nitric Oxide Synthase by Flash Photolysis : Dual Effects of Substrates, Inhibitors2004

    • Author(s)
      S.Bengea
    • Journal Title

      Journal of Inorganic Biochemistry 98

      Pages: 1210-1216

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Importance of Valine 567 in Substrate Recognition and Oxidation by Neuronal Nitric Oxide Synthase2004

    • Author(s)
      M.Moreau
    • Journal Title

      Journal of Inorganic Biochemistry 98

      Pages: 1200-1209

    • Related Report
      2004 Annual Research Report
  • [Publications] J.Igarashi, A.Sato, T.Kitagawa, I.Sagami, T.Shimizu: "CO Binding Study of Mouse Heme-regulated eIF-2α Kinase : Kinetics and Resonance Raman Spectra"Biochim.Biophys.Acta. 1650. 99-104 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] J.Igarashi, A.Sato, T.Kitagawa, I.Sagami, T.Shimizu: "Activation of Heme-regulated Eukaryotic Initiation Factor 2α Kinase by Nitric Oxide Is Induced by the Formation of NO-heme Complex"J.Biol.Chem.. 279(in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] T.Schimizu, I.Sagami: "Characterization of a Direct Oxygen Sensor Heme Protein from Escherishia coli"J. Biol. Chem. Vol.277. 23821-23827 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] T.Shimizu, I.Sagami: "Stationary and Time-resolved Resonance Raman Spedtra of His77 and Met95Mutants of the Isolated Heme Domain of a Direct Oxygen"J. Biol. Chem. Vol.277. 32650-32658 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] T.Shimizu, I.Sagami: "Unusual Cynide Bindings to a Heme-regulated Phosphodiesterase from Escherichia coli ; Effest of met95 Mutations"Biochem. Biophys. Res. Commun. Vol.299. 169-172 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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