Elucidation of Molecular Mechanism for Activation of High-Valent Metal-Oxo species through their interaction with G-Quadruplexes and Creation of Novel DNAzymes
Project/Area Number |
19H02824
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Basic Section 37010:Bio-related chemistry
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Research Institution | University of Tsukuba |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
鈴木 秋弘 長岡工業高等専門学校, 物質工学科, 教授 (60179190)
百武 篤也 筑波大学, 数理物質系, 准教授 (70375369)
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Project Period (FY) |
2019-04-01 – 2022-03-31
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Project Status |
Completed (Fiscal Year 2021)
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Budget Amount *help |
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2021: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥10,270,000 (Direct Cost: ¥7,900,000、Indirect Cost: ¥2,370,000)
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Keywords | 四重鎖DNA / Gカルテット / ヘム / 酸化触媒作用 / 機能性核酸 / G-カルテット / 分子認識 / 触媒機構 / テロメア / 軸配位子 / 高原子価金属オキソ種 |
Outline of Research at the Start |
四重鎖DNAまたは四重鎖RNAとヘムの複合体が示す酸化触媒作用の分子機構を、反応中間体として生成するオキソ鉄4価ポルフィリンπカチオンラジカル錯体の反応性の制御機構の解明を通して明らかにする研究である。そして、高温および有機溶媒との混合水溶液中でも利用できると共に、簡便に大量合成可能な画期的酵素を創製するために有用な知見を得る。本研究を通して、ヘムをもつ核酸酵素の酸化触媒活性の発現で鍵となる反応中間体である高酸化状態の鉄ポルフィリン錯体が生成する分子機構が解明されることになり、生物無機化学における革新的ブレークスルーにつながる研究成果が得られる。
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Outline of Final Research Achievements |
Heme(Fe3+) binds to non-canonical G-quadruplex DNAs to form complexes (heme-DNAzymes) that exhibit peroxidase and peroxygenase activities. We found that the catalytic cycle of the heme-DNAzyme involves an iron(IV)oxo porphyrin π-cation radical intermediate known as Compound I formed through heterolytic O-O bond cleavage of an Fe-bound hydroperoxo ligand (Fe-OOH) in Compound 0. We also found that heme(Fe3+) binds selectively to the 3’-terminal G-quartet of the DNA, and a water molecule (AxH2O) sandwiched between the heme and G-quartet planes is coordinated to the heme Fe atom as an axial ligand. The polarization of AxH2O is thought to be considerably greater than that of an ordinary H2O molecule. Such unique electronic nature of AxH2O was found to be responsible for the catalytic activity of the heme-DNAzyme. We also found that the peroxidase activity of the heme-DNAzyme can be controlled through the local heme environment.
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Academic Significance and Societal Importance of the Research Achievements |
本研究により、ヘムDNA酵素におけるヘムの機能の調節機構が解明された。ヘムDNA酵素の触媒サイクルでは、酵素ペルオキシダーゼとは異なる分子機構で、オキソ鉄4価ポルフィリンπカチオンラジカル錯体(Compound I)が反応中間体として生成することが明らかになった。ヘムDNA酵素のヘム鉄の軸配位子である水分子が、Compound Iの生成に重要な役割を担っていること、ヘムDNA酵素が示すヘムタンパク質類似の様々な分光学的性質をもたらしていることを発見した研究成果は、水分子の新しい機能および疎水性空間で孤立する水分子のユニークな物理化学的性質が解明されたという観点から、学術的な意義は大きい。
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Report
(4 results)
Research Products
(60 results)
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[Presentation] Characterization of Myoglobins Where Exogenous Ligands Replace the Proximal Histidine2021
Author(s)
R. Murata, T. Sugita, T. Matsuo, S. Hirota, S. Yanagisawa, S. Neya, A. Suzuki, O. Shoji, Y. Watanabe, A. Momotake, and Y. Yamamoto
Organizer
Joint Conference of 22nd ISMAR, 9th APNMR, 60th NMRSJ(2021), and 60th SEST
Related Report
Int'l Joint Research
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[Presentation] Deoxyribozyme Possessing Heme2019
Author(s)
Y. Yamamoto, H. Araki, K. Hayasaka, S. Nakamura,T. Shibata, A. Momotake, and H. Hemmi
Organizer
61st Experimental Nuclear Magnetic Resonance Conference
Related Report
Int'l Joint Research
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[Presentation] Heme-DNAzyme2019
Author(s)
Y. Yamamoto, R. Shinomiya, H. Araki, T. Shibata, A. Momotake, S. Yanagisawa, T. Ogura, A. Suzuki, S. Neya, and H. Hemmi
Organizer
Commemorative International Symposium of the Japan Society of Nucleic Acids Chemistry
Related Report
Int'l Joint Research
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[Presentation] Heme Meets DNA.2019
Author(s)
Y. Yamamoto, R. Shinomiya, H. Kotani, H. Araki, A. Momotake, T. Shibata, S. Yanagisawa, T. Ogura, H. Hemmi, A. Suzuki, S. Neya, and T. Kojima
Organizer
19th International Conference on Biological Inorganic Chemistry (ICBIC-19)
Related Report
Int'l Joint Research / Invited
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[Presentation] DNAzyme Possessing Heme2019
Author(s)
Y. Yamamoto, R. Shinomiya, H. Araki, T. Shibata, A. Momotake, S. Yanagisawa, T. Ogura, A. Suzuki, and S. Neya
Organizer
The 46th International Symposium on Nucleic Acids Chemistry
Related Report
Int'l Joint Research
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[Presentation] Electronic Control of Myoglobin Function2019
Author(s)
T. Sugita, T. Matsuo, S. Hirota, S. Yanagisawa, T. Ogura, O. Shoji, Y. Watanabe, A. Suzuki, S. Neya, A. Momotake, and Y. Yamamoto
Organizer
17th International Symposium on Blood Substitutes & Oxygen Therapeutics (XVII-ISBS-2019)
Related Report
Int'l Joint Research
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