理論計算を基盤とした生合成経路の探索と生合成リデザインへの挑戦

• Project Area: Creation of Complex Functional Molecules by Rational Redesign of Biosynthetic Machineries
• Project/Area Number: 17H05430
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: The University of Tokyo
• Principal Investigator: 内山 真伸 東京大学, 大学院薬学系研究科(薬学部), 教授 (00271916)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000); Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2017: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 理論計算 / 生合成経路 / 遷移状態制御 / テルペン / 計算化学 / 実験科学

Outline of Annual Research Achievements

多種多様な構造を持つテルペノイドは、テルペン環化酵素により基本骨格構築がなされており、その閉環反応機構の解明は分子多様性解明の鍵となる。しかしながら、酵素内部での複雑な連続多段階反応のため、中間体の単離や反応機構の全容解明は実験科学のみでは困難である。
計算化学は実則困難な化学現象を解明できるポテンシャルを秘めている。本研究では、異なる数種のテルペノイドの環化反応の理論解析を通して構造多様性創
出の原理（反応経路、選択性発現機構など）を明らかにし、実験化学者との共同研究を通じて遷移状態制御により新規セスタテルペン骨格構築への発展を目指している。
テルペン閉環反応は複雑な連続する多段階反応であるため、遷移状態・中間体構造の正確な予測が困難である。本研究では、まず、セスタテルペンSesterfisherol、Quiannulatene、Astellatol を取り上げ、理論計算を用いて閉環反応経路の網羅的探索を行った。取得した全ての遷移状態・中間体構造に対し、電荷解析、軌道解析などを行い、反応駆動力、カチオンの反応性、立体・化学選択性について定量的に評価した。セスタテルペンの閉環反応は、共通の中間体を分岐点とし、各生成物へと分化していくと考えられてきた。そこで、各閉環経路を理論解析により比較することにより、反応経路の分岐点と閉環反応への酵素の寄与について情報が得られた。これらについて、実験化学者の方々との共同研究を通じて、その裏付け研究を進めて行く。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Structural and computational bases for dramatic skeletal rearrangement in anditomin biosynthesis (2018)
  • Author(s): Nakashima, Y., Mitsuhashi, T., Matsuda, Y., Senda, M., Sato, H., Yamazaki, M., Uchiyama, M., Senda, T. & Abe, I.
  • Journal Title: JACS Volume: 140 Issue: 30 Pages: 9743-9750
  • DOI: 10.1021/jacs.8b06084
  • Peer Reviewed
• [Journal Article] Stable Thiele’s Hydrocarbon Derivatives Exhibiting Near-Infrared Absorption/Emission and Two-Step Electrochromism (2018)
  • Author(s): Yuta Okamoto, Masaru Tanioka, Atsuya Muranaka, Kazunori Miyamoto, Tetsuya Aoyama, Xingmei Ouyang, Shinichiro Kamino, Daisuke Sawada, Masanobu Uchiyama
  • Journal Title: J. Am. Chem. Soc. Volume: 140 Issue: 51 Pages: 17857-17861
  • DOI: 10.1021/jacs.8b11092
  • Peer Reviewed
• [Journal Article] Development of a Series of Practical Fluorescent Chemical Tools to Measure pH Values in Living Samples (2018)
  • Author(s): Takahashi Shodai、Kagami Yu、Hanaoka Kenjiro、Terai Takuya、Komatsu Toru、Ueno Tasuku、Uchiyama Masanobu、Koyama-Honda Ikuko、Mizushima Noboru、Taguchi Tomohiko、Arai Hiroyuki、Nagano Tetsuo、Urano Yasuteru
  • Journal Title: Journal of the American Chemical Society Volume: 140 Issue: 18 Pages: 5925
  • DOI: 10.1021/jacs.8b00277
  • Peer Reviewed
• [Journal Article] N-Alkynylpyridinium Salts: Highly Electrophilic Alkyne?Pyridine Conjugates as Precursors of Cationic Nitrogen-Embedded Polycyclic Aromatic Hydrocarbons (2018)
  • Author(s): Toriumi Naoyuki、Asano Norihito、Miyamoto Kazunori、Muranaka Atsuya、Uchiyama Masanobu
  • Journal Title: J. Am. Chem. Soc. Volume: 140 Issue: 11 Pages: 3858-3862
  • DOI: 10.1021/jacs.8b00356
  • Peer Reviewed
• [Journal Article] Computational Studies on Biosynthetic Carbocation Rearrangements Leading to Quiannulatene: Initial Conformation Regulates Biosynthetic Route, Stereochemistry, and Skeleton Type (2018)
  • Author(s): Sato Hajime、Mitsuhashi Takaaki、Yamazaki Mami、Abe Ikuro、Uchiyama Masanobu
  • Journal Title: Angewandte Chemie International Edition Volume: 57 Issue: 45 Pages: 14752-14757
  • DOI: 10.1002/anie.201807139
  • Peer Reviewed
• [Journal Article] Control of the stereochemical course of [4+2] cycloaddition during trans-decalin formation by Fsa2-family enzymes (2018)
  • Author(s): Kato N, Nogawa T, Takita R, Kinugasa K, Kanai M, Uchiyama M, Osada H, Takahashi S
  • Journal Title: Angew Chem Int Ed Engl Volume: 57 Issue: 31 Pages: 9754-9758
  • DOI: 10.1002/anie.201805050
  • Peer Reviewed
• [Journal Article] In Situ Generation of Silylzinc by Si-B Bond Activation Enabling Silylzincation and Silaboration of Terminal Alkynes (2018)
  • Author(s): Yuki Nagashima, Daiki Yukimori, Chao Wang, Masanobu Uchiyama
  • Journal Title: Angew. Chem. Int. Ed. 2018, 57, 8053-8057 Volume: 57 Issue: 27 Pages: 8053-8057
  • DOI: 10.1002/anie.201802887
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] From Anilines to Aryl Ethers: A Facile, Efficient, and Versatile Synthetic Method Employing Mild Conditions (2018)
  • Author(s): Wang Dong-Yu、Yang Ze-Kun、Wang Chao、Zhang Ao、Uchiyama Masanobu
  • Journal Title: Angew. Chem. Int. Ed. Volume: 57 Issue: 14 Pages: 3641-3635
  • DOI: 10.1002/anie.201712618
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Simultaneous Edge-on to Face-on Reorientation and 1D Alignment of Small π-Conjugated Molecules Using Room-Temperature Mechanical Rubbing (2018)
  • Author(s): Ribierre Jean-Charles、Tanaka Toshihiko、Zhao Li、Yokota Yuki、Matsumoto Shinya、Hashizume Daisuke、Takaishi Kazuto、Muto Tsuyoshi、Heinrich Beno?t、M?ry St?phane、Mathevet Fabrice、Matsushima Toshinori、Uchiyama Masanobu、Adachi Chihaya、Aoyama Tetsuya
  • Journal Title: Adv. Funct. Mater Volume: 28 Issue: 19 Pages: 1707038-1707038
  • DOI: 10.1002/adfm.201707038
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Theoretical Study of Sesterfisherol Biosynthesis: Computational Prediction of Key Amino Acid Residue in Terpene Synthase (2018)
  • Author(s): Sato Hajime、Narita Koji、Minami Atsushi、Yamazaki Mami、Wang Chao、Suemune Hironori、Nagano Shingo、Tomita Takeo、Oikawa Hideaki、Uchiyama Masanobu
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 2473-2473
  • DOI: 10.1038/s41598-018-20916-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] “Dumbbell”- and “Clackers”-Shaped Dimeric Derivatives of Monocarba-closo-dodecaborate (2018)
  • Author(s): Kitazawa Yu、Watanabe Mamoru、Masumoto Yui、Otsuka Mai、Miyamoto Kazunori、Muranaka Atsuya、Hashizume Daisuke、Takita Ryo、Uchiyama Masanobu
  • Journal Title: Angew. Chem. Int. Ed. Volume: 57 Issue: 6 Pages: 1501-1504
  • DOI: 10.1002/anie.201710122
  • Peer Reviewed
• [Journal Article] Mechanistic Study on Aryl-Exchange Reaction of Diaryl-λ3-iodane with Aryl Iodide (2017)
  • Author(s): Masumoto Yui、Miyamoto Kazunori、Iuchi Takuto、Ochiai Masahito、Hirano Keiichi、Saito Tatsuo、Wang Chao、Uchiyama Masanobu
  • Journal Title: J. Org. Chem. Volume: 83 Issue: 1 Pages: 289-295
  • DOI: 10.1021/acs.joc.7b02701
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Radical Multicomponent Carboamination of [1.1.1]Propellane (2017)
  • Author(s): Kanazawa Junichiro、Maeda Katsuya、Uchiyama Masanobu
  • Journal Title: J. Am. Chem. Soc. Volume: 139 Issue: 49 Pages: 17791-17794
  • DOI: 10.1021/jacs.7b11865
  • Peer Reviewed
• [Journal Article] Transition Metal-Free trans-Selective Alkynylboration of Alkynes (2017)
  • Author(s): Nogami Marina、Hirano Keiichi、Kanai Misae、Wang Chao、Saito Tatsuo、Miyamoto Kazunori、Muranaka Atsuya、Uchiyama Masanobu
  • Journal Title: J. Am. Chem. Soc. Volume: 139 Issue: 36 Pages: 12358-12361
  • DOI: 10.1021/jacs.7b06212
  • Peer Reviewed
• [Journal Article] One-step Conversion of Levulinic Acid to Succinic Acid Using I2/t-BuOK System: The Iodoform Reaction Revisited (2017)
  • Author(s): Kawasumi Ryosuke、Narita Shodai、Miyamoto Kazunori、Tominaga Ken-ichi、Takita Ryo、Uchiyama Masanobu
  • Journal Title: Sci. Rep. Volume: 7 Issue: 1 Pages: 17967-17967
  • DOI: 10.1038/s41598-017-17116-4
  • Peer Reviewed / Open Access
• [Journal Article] Effects of N-Oxidation on Heteroaromatic Macrocycles: Synthesis, Electronic Structures, Spectral Properties, and Reactivities of Tetraazaporphyrin meso-N-Oxides (2017)
  • Author(s): Toriumi Naoyuki、Yanagi Shunsuke、Muranaka Atsuya、Hashizume Daisuke、Uchiyama Masanobu
  • Journal Title: Chem. Eur. J. Volume: 23 Issue: 34 Pages: 8309-8314
  • DOI: 10.1002/chem.201701300
  • Peer Reviewed
• [Journal Article] Organozinc-Mediated Direct C?C Bond Formation via C?N Bond Cleavage of Ammonium Salts (2017)
  • Author(s): Wang Dong-Yu、Morimoto Koki、Yang Ze-Kun、Wang Chao、Uchiyama Masanobu
  • Journal Title: Chem. Asian J. Volume: 12 Issue: 19 Pages: 2554-2557
  • DOI: 10.1002/asia.201701132
  • Peer Reviewed
• [Journal Article] "Naked" Lithium Cation: Strongly Activated Metal Cations Facilitated by Carborane Anions (2017)
  • Author(s): Yu Kitazawa, Ryo Takita, Kengo Yoshida, Atsuya Muranaka, Seijiro Matsubara, Masanobu Uchuyama
  • Journal Title: Journal of Organic Chemistry Volume: 82 Issue: 4 Pages: 1931-1935
  • DOI: 10.1021/acs.joc.6b02677
  • Peer Reviewed
• [Journal Article] Focused genome mining of structurally related sesterterpenes: enzymatic formation of enantiomeric and diastereomeric products (2017)
  • Author(s): Narita, K., Sato, H., Minami, A., Kudo, K., Gao, L., Liu, C., Ozaki, T., Kodama, M.., Lei, X., Taniguchi, T., Monde, K., Yamazaki, M., Uchiyama, M., Oikawa, H.
  • Journal Title: Organic letters Volume: 19 Issue: 24 Pages: 6696-6699
  • DOI: 10.1021/acs.orglett.7b03418
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hitoyol A and B, Two Norsesquiterpenoids from the Basidiomycete Coprinopsis cinerea (2017)
  • Author(s): Otaka Junnosuke、Hashizume Daisuke、Masumoto Yui、Muranaka Atsuya、Uchiyama Masanobu、Koshino Hiroyuki、Futamura Yushi、Osada Hiroyuki
  • Journal Title: Organic Letters Volume: 19 Issue: 15 Pages: 4030-4033
  • DOI: 10.1021/acs.orglett.7b01784
  • Peer Reviewed
• [Journal Article] Revisitation of Organoaluminum Reagents Affords a Versatile Protocol for C?X (X = N, O, F) Bond-Cleavage Cross-Coupling: A Systematic Study (2017)
  • Author(s): Ogawa Hiroyuki、Yang Ze-Kun、Minami Hiroki、Kojima Kumiko、Saito Tatsuo、Wang Chao、Uchiyama Masanobu
  • Journal Title: ACS Catal. Volume: 7 Issue: 6 Pages: 3988-3994
  • DOI: 10.1021/acscatal.7b01058
  • Peer Reviewed
• [Journal Article] Iodoarene-catalyzed oxidative transformations using molecular oxygen (2017)
  • Author(s): Miyamoto K.、Yamashita J.、Narita S.、Sakai Y.、Hirano K.、Saito T.、Wang C.、Ochiai M.、Uchiyama M.
  • Journal Title: Chem. Commun. Volume: 53 Issue: 70 Pages: 9781-9784
  • DOI: 10.1039/c7cc05160c
  • Peer Reviewed
• [Journal Article] Unexpected formation of benziphthalocyanine dimer: An easily synthesizable dimer of phthalocyanine analogue (2017)
  • Author(s): Toriumi Naoyuki、Muranaka Atsuya、Hashizume Daisuke、Uchiyama Masanobu
  • Journal Title: Tetrahedron Lett. Volume: 58 Issue: 23 Pages: 2267-2271
  • DOI: 10.1016/j.tetlet.2017.04.089
  • Peer Reviewed
• [Book] 薬学研究 (2017)
  • Author(s): 日本薬学会
  • Total Pages: 170
  • Publisher: 東京化学同人
  • ISBN: 9784807917228
• [Remarks] 東京大学大学院薬学系研究科 基礎有機化学教室
  • URL: http://www.f.u-tokyo.ac.jp/~kisoyuki/publication.html