Destruction of the biological clock system by environmental contaminants : Crosstalk between heme, NO, protein synthesis and clock genes

2009 Fiscal Year Final Research Report

• Project/Area Number: 17101002
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Risk sciences of radiation/Chemicals
• Research Institution: Tohoku University
• Principal Investigator: SHIMIZU Toru Tohoku University, 多元物質科学研究所, 教授 (40118956)
• Co-Investigator(Kenkyū-buntansha): KUROKAWA Hirofumi 東北大学, 多元物質科学研究所, 助手 (80359546) ; TANAKA Atsunari 東北大学, 多元物質科学研究所, 教育研究支援者 (20431471) ; IGARASHI Jotaro 東北大学, 多元物質科学研究所, 助教 (80375162)
• Project Period (FY): 2005 – 2009
• Keywords: NO,ヘム / 環境汚染物質 / 時計遺伝子 / 蛋白合成

Research Abstract

[1] Molecular mechanisms of NO- and heme-sensing of heme-regulated kinase (HRI) and heme-regulated transcriptional factors were elucidated and mercury was found to break the heme-protein interactions.; [2] Thiolate and α-lipoic acid remedied depressive behavior of mice induced by methyl-mercury.; [3] Gas-recognition sites and molecular mechanism of gas-induced catalytic enhancement of the heme-regulated gas-sensor enzymes were elucidated.

Research Products

• [Journal Article] Thiolate with alpha-lipoic acid remediates depressive behavior of mice induced by methyl-mercury (2010)
  • Author(s): K. Kitanishi, J. Igarashi, T. Shimizu
  • Journal Title: Current Topic in Toxicology (in press)
• [Journal Article] The FG loop of a heme-based gas sensor enzyme, Ec DOS, functions in heme binding, autoxidation and catalysis (2009)
  • Author(s): S. Ito, J. Igarashi, T. Shimizu
  • Journal Title: J.Inorg.Biochem. 103 Pages: 1380-1385
  • Peer Reviewed
• [Journal Article] Role of Phe113 at the distal side of the heme domain of an oxygen-sensor (Ec DOS) in the characterization of the heme environment (2009)
  • Author(s): S. Ito, Y. Araki, A. Tanaka, J. Igarashi, T. Wada, T. Shimizu
  • Journal Title: J.Inorg.Biochem. 103 Pages: 989-996
  • Peer Reviewed
• [Journal Article] Ligand binding to the Fe(III)-protoporphyrin IX complex of phosphodiesterase from Escherichia coli (Ec DOS) markedly enhances catalysis of cyclic di-GMP : Roles of Met95, Arg97, and Phe113 of the putative heme distal side in catalytic regulation and ligand binding (2008)
  • Author(s): A. Tanaka, T. Shimizu
  • Journal Title: Biochemistry 47 Pages: 13438-13446
  • Peer Reviewed
• [Journal Article] Arg97 at the heme distal side of the isolated heme-bound PAS domain of a heme-based oxygen sensor from Escherichia coli (Ec DOS) plays critical roles in auto-oxidation and binding to gases, particularly O_2 (2008)
  • Author(s): Y. Ishitsuka, Y. Araki, A. Tanaka, J. Igarashi, O. Ito, T. Shimizu
  • Journal Title: Biochemistry 47 Pages: 8874-8884
  • Peer Reviewed
• [Journal Article] Resonance Raman investigation of redox-induced structural changes of protein and heme in the sensor domain of Ec DOS protein (2008)
  • Author(s): S. F. El-Mashtoly, H. Takahashi, H. Kurokawa, A. Sato, T. Shimizu, T. Kitagawa
  • Journal Title: J.Raman Spectrosc. 39 Pages: 1614-1626
  • Peer Reviewed
• [Journal Article] Elucidation of the heme-binding site of heme-regulated eIF2alpha kinase (HRI) and the role of the regulatory motif in heme sensing by spectroscopic and catalytic studies of mutant proteins (2008)
  • Author(s): J. Igarashi, M. Murase, A. Iizuka, F. Pichierri, M. Martinkova, T. Shimizu
  • Journal Title: J.Biol.Chem. 283 Pages: 18782-18791
  • Peer Reviewed
• [Journal Article] Roles of Arg97 and Phe113 in regulation of distal ligand binding to heme in the sensor domain of Ec DOS protein : resonance Raman and mutation study (2008)
  • Author(s): S. F. El-Mashtoly, S. Nakashima, A. Tanaka, T. Shimizu, T. Kitagawa
  • Journal Title: J.Biol.Chem. 283 Pages: 19200-19010
  • Peer Reviewed
• [Journal Article] Heme binding characteristics of the isolated PAS-A domain of mouse Per2, a transcriptional regulatory factor associated with circadian rhythms (2008)
  • Author(s): K. Kitanishi, J. Igarashi, K. Hayasaka, N. Hikage, I. Saiful, S. Yamauchi, T. Uchida, K. Ishimori, T. Shimizu
  • Journal Title: Biochemistry 47 Pages: 6157-6168
  • Peer Reviewed
• [Journal Article] The roles of thiolate-heme proteins, other than the P450 cytochromes, in the regulation of heme-sensor proteins (2008)
  • Author(s): J. Igarashi, K. Kitanishi, M. Martinkova, M. Murase, A. Iizuka, T. Shimizu
  • Journal Title: Acta Chim.Slov. 55 Pages: 67-74
  • Peer Reviewed
• [Journal Article] Eukaryotic initiation factor 2alpha kinase is a nitric oxide-responsive mercury sensor enzyme : Potent inhibition of catalysis by the mercury cation and reversal by nitric oxide (2007)
  • Author(s): M. Martinkova, J. Igarashi, T. Shimizu
  • Journal Title: FEBS Lett. 581 Pages: 4109-4114
  • Peer Reviewed
• [Journal Article] Ultraviolet resonance Raman evidence for utilization of the heme 6-propionate hydrogen-bond network in signal transmission from heme to protein in EcDOS protein (2007)
  • Author(s): S. F. El-Mashtoly, H. Takahashi, T. Shimizu, T. Kitagawa
  • Journal Title: J.Am.Chem.Soc. 129 Pages: 3556-3563
  • Peer Reviewed
• [Journal Article] Critical role of the heme axial ligand, Met95, in locking catalysis of the phosphodiesterase from Escherichia coli (Ec DOS) toward cyclic diGMP (2007)
  • Author(s): A. Tanaka, H. Takahashi, T. Shimizu
  • Journal Title: J.Biol.Chem. 282 Pages: 21301-21307
  • Peer Reviewed
• [Journal Article] Phosphodiesterase activity of EcDOS, a heme-regulated enzyme from Escherichia coli, toward 3', 5'-cyclic diguanylic acid is obviously enhanced by O_2 and CO binding (2006)
  • Author(s): H. Takahashi, T. Shimizu
  • Journal Title: Chem.Lett. 35 Pages: 970-971
  • Peer Reviewed
• [Journal Article] Characterization of heme-regulated eIF2 alpha kinase : Roles of the N-terminal domain in the oligomeric state, heme binding, catalysis, and inhibition (2006)
  • Author(s): M. Miksanova, J. Igarashi, M. Minami, I. Sagami, S. Yamauchi, H. Kurokawa, T. Shimizu
  • Journal Title: Biochemistry 45 Pages: 9894-9905
  • Peer Reviewed
• [Journal Article] Spectroscopic and DNA-binding characterization of the isolated heme-bound basic helix-loop-helix-PAS-A domain of neuronal PAS protein 2 (NPAS2), a transcription activator protein associated with circadian rhythms (2006)
  • Author(s): Y. Mukaiyama, T. Uchida, E. Sato, A. Sasaki, Y. Sato, J. Igarashi, H. Kurokawa, I. Sagami, T. Kitagawa, T. Shimizu
  • Journal Title: FEBS J. 273 Pages: 2528-2539
  • Peer Reviewed
• [Journal Article] Critical roles of Leu99 and Leu115 at the heme distal side in auto-oxidation and the redox potential of a heme-regulated phosphodiesterase from Escherichia coli (2006)
  • Author(s): N. Yokota, Y. Araki, H. Kurokawa, O. Ito, J. Igarashi, T. Shimizu
  • Journal Title: FEBS J. 273 Pages: 1210-1223
  • Peer Reviewed
• [Journal Article] Structure-function relationships of EcDOS, a heme-regulated phosphodiesterase from Escherichia coli (2006)
  • Author(s): Y. Sasakura, T. Yoshimura-Suzuki, H. Kurokawa, T. Shimizu
  • Journal Title: Acc.Chem.Res. 39 Pages: 37-43
  • Peer Reviewed
• [Journal Article] Investigation of the relationship between protein-protein interaction and catalytic activity of a heme-regulated phosphodiesterase from Escherichia coli (EcDOS) by protein microarray (2005)
  • Author(s): Y. Sasakura, K. Kanda, T. Yoshimura-Suzuki, T. Matsui, S. Fukuzono, T. Shimizu
  • Journal Title: Biochemistry 44 Pages: 9598-9605
  • Peer Reviewed
• [Journal Article] Spectroscopic characterization of the isolated heme-bound PAS-B domain of neuronal PAS domain protein 2 associated with circadian rhythms (2005)
  • Author(s): R. Koudo, H. Kurokawa, E. Sato, J. Igarashi, T. Uchida, I. Sagami, T. Kitagawa, T. Shimizu
  • Journal Title: FEBS J. 272 Pages: 4153-4162
  • Peer Reviewed
• [Journal Article] CO-dependent activity-controlling mechanism of heme-containing CO-sensor protein, neuronal PAS domain protein 2 (2005)
  • Author(s): T. Uchida, E. Sato, A. Sato, I. Sagami, T. Shimizu, T. Kitagawa
  • Journal Title: J.Biol.Chem. 280 Pages: 21358-21368
  • Peer Reviewed
• [Presentation] Cysteine Thiolate is the Heme Binding Site of Heme-regulated Transcription Regulatory Factors Associated with Circadian Rhythms (2010)
  • Author(s): Kenichi Kitanishi, Jotaro Igarashi, Toru Shimizu
  • Organizer: Gordon Research Conference on Protein Cofactors, Radicals and Quinones
  • Place of Presentation: U.S.A., Ventura, CA
  • Year and Date: 20100124-20100129
• [Presentation] Heme-regulated Eukaryotic Initiation Factor 2α Kinase (2010)
  • Author(s): Jotaro Igarashi, Toru Shimizu
  • Organizer: Gordon Research Conference on Protein Cofactors, Radicals and Quinones
  • Place of Presentation: U.S.A., Ventura, CA
  • Year and Date: 20100124-20100129
• [Presentation] Mechanisms of Gas-sensing and Intra-molecular Signal Transduction of a Heme-based Oxygen-sensor Enzyme, Ec DOS (2009)
  • Author(s): Atsunari Tanaka, Yukako Ishitsuka, Jotaro Igarashi, Toru Shimizu
  • Organizer: Symposium on Avanced Biological Inorganic Chemistry (SABIC-2009)
  • Place of Presentation: India, Mumbai
  • Year and Date: 20091104-20091107
• [Presentation] Heme-sensing Mechanisms of Heme-sensor Proteins Associated with Protein Synthesis and Circadian Rhythms (2009)
  • Author(s): Jotaro Igarashi, Motohiko Murase, Marketa Martinkova, Kenichi Kitanishi, Toru Shimizu
  • Organizer: 14th International Conference on Biological Inorganic Chemistry
  • Place of Presentation: Japan, Nagoya
  • Year and Date: 20090725-20090730
• [Presentation] The Critical Role of the Thiolate-Heme Complex in the Functioning (2009)
  • Author(s): Jotaro Igarashi, Kenichi Kitanishi, Motohiko Murase, Marketa Martinkova, Toru Shimizu
  • Organizer: 16th International Conference on Cytochrome P450, Biochemistry, Biophysics, Biotechnology
  • Place of Presentation: Japan, Nago, Okinawa
  • Year and Date: 20090621-20090625
• [Presentation] Emerging Roles of Heme as the Signal and the Gas-sensing Site : Heme-sensor and Gas-sensor Proteins (2009)
  • Author(s): Toru Shimizu
  • Organizer: Biochemistry Seminar, Department of Medical Biotechnology
  • Place of Presentation: Jagielloninan University, Poland, Krakow
  • Year and Date: 20090612-20090613
• [Presentation] Cysteine thiolate is the heme sensing site in heme-sensor proteins (2009)
  • Author(s): Jotaro Igarashi, Kenichi Kitanishi, Toru Shimizu
  • Organizer: XXII International Conference on Coordination and Bioinorganic Chemistry
  • Place of Presentation: Slovakia, Smolenice
  • Year and Date: 20090607-20090611
• [Presentation] Molecular machanism of NO-induced activation of a heme-sensor, eIF2α kinase (2008)
  • Author(s): Toru Shimizu
  • Organizer: Convegno Nazionale, Gli Aspetti Biologici dell'Ossido Nitrico (Italia National Congress for Biological Aspect of Nitric Oxide)
  • Place of Presentation: Italia, Rimini
  • Year and Date: 20081004-20081006
• [Presentation] NO-induced activation of a heme-sensor, eIF2α kinase, in association with binding to cysteine and heme (2008)
  • Author(s): Jotaro Igarashi, Motohiko Murase, Jun Iwashita, Takehiko Sasaki, Toru Shimizu
  • Organizer: Fifth International Conference, Biology, Chemistry, and Therapeutic Applications of Nitric Oxide
  • Place of Presentation: Austria, Bregenz
  • Year and Date: 20080824-20080828
• [Presentation] Heme-binding proteins associated with transcription of circadian rhythms (2008)
  • Author(s): Toru Shimizu
  • Organizer: Gordon Research Conference on the Chemistry & Biology of Tetrapyrroles
  • Place of Presentation: U.S.A., Newport, RI
  • Year and Date: 20080720-20080725
• [Presentation] Heme-sensing Mechanism of Heme-sensor Proteins Associated with Circadian Rhythms and Protein Synthesis (2008)
  • Author(s): Toru Shimizu
  • Organizer: Biochemistry Meeting at the Department of Morphological-Biomedical Science
  • Place of Presentation: University of Verona, Italy, Verona
  • Year and Date: 2008-10-03
• [Presentation] Structure-function relationships of a thiol-coordinating heme protein, HRI, associated with protein synthesis (2007)
  • Author(s): Marketa Martinkova, Jotaro Igarashi, Toru Shimizu
  • Organizer: 15th International Conference on Cytochrome P450, Biochemistry, Biophysics, Functional Genomics
  • Place of Presentation: Slovenia, Bled
  • Year and Date: 20070617-20070621
• [Presentation] Structure-function relationships of eIF2α kinase (heme-regulated inhibitor, HRI), associated with protein synthesis (2007)
  • Author(s): Toru Shimizu
  • Organizer: VIIIth National Congress of Pharmacology, Therapeutics and Clinical Toxicology
  • Place of Presentation: Romania, Tirgu-Mure
  • Year and Date: 20070606-20070609
• [Presentation] Intramolecular Signal Transduction and Signal Switching of Heme-sensor Proteins through NO and CO Binding (2006)
  • Author(s): Toru Shimizu
  • Organizer: 20th International Congress of Biochemistry and Molecular Biology and 11th FAOBMB
  • Place of Presentation: Japan, Kyoto
  • Year and Date: 20060618-20060623
• [Presentation] Role of the N-terminal Domain in the Structure and Catalysis of Heme-regualted Eukaryotic Initiation Factor 2α Kinase, a Heme-sensor Enzyme (2006)
  • Author(s): Marketa Miksanova, Hirofumi Kurokawa, Jotaro Igarashi, Toru Shimizu
  • Organizer: Biochemistry and Molecular Biology of Sensor Enzymes and Proteins : Satellite Meeting of the 20th IUBMB International Congress of Biochemistry and Molecular Biology
  • Place of Presentation: Japan, Sendai
  • Year and Date: 20060615-20060616
• [Book] 他のヘムーチオレートタンパク質の構造と機能 (2009)
  • Author(s): 五十嵐城太郎, 清水透 (分担執筆)
  • Total Pages: 77-83
• [Remarks] ホームページ等
  • URL: http://www.tagen.tohoku.ac.jp/labo/shimizu/