内因性パ-キンソン病発症物質の探索とその酸化還元特性に関する研究

1989 Fiscal Year Annual Research Report

• Project/Area Number: 01550622
• Research Institution: Osaka University
• Principal Investigator: 福住 俊一 大阪大学, 工学部, 助手 (40144430)
• Keywords: パ-キンソン病 / NADH / 電子伝達系

Research Abstract

1ーメチルー4ーフェニルー1,2,3,6ーテトラヒドロピリジン(MPTP)がパ-キンソン病の症状を引起こすことが報告されて以来、MPTPに関する医化学的研究が活発に行われている。MPTPはモノアミン酵素B型により1ーメチルー4ーフェニルピリジニウムイオン(MPP^+)に酸化され、このMPP^+がミトコンドリア内膜の電子伝達系を阻害することが知られている。本研究ではMPP^+NAD^+(ニコチンアミドアデニンジヌクレオチド)類縁体とみなし得る点に着目し、種々のNAD^+・NADH類縁体の電子伝達反応の機構を明らかにすることによりMPP^+の作用機構について知見を得ることを目的とし、以下の新しい知見を得た。
(1)種々のNAD^+類縁体がビタミンB_<12>補酵素モデル化合物であるアルキルコバルト錯体によって還元され、MPP^+の二電子還元体に類似したアルキル化したNADH類縁体がえられること。(2)NAD^+類縁体の非酵素的還元が種々の脂肪酸あるいは有機金属化合物によって熱反応および光反応で起こること。(3)NADH類縁体は金属ポルフィリン錯体の存在下で非酵素的に酸素分子へ効率的な電子伝達を行い得ること。(4)不安定なNADH類縁体ラジカルカチオンのESRスピクトルを測定することに初めて成功したこと。(5)NADH類縁体から種々の基質への電子伝達反応の機構を明らかにしたこと。
以上の結果により生体内においてもNAD^+が通常とは異なる還元を受けることによりパ-キンソン病発症物質に変成し、正常な電子伝達系を阻害する可能性が示唆された。

Research Products

• [Publications] S・Fukuzumi: "Selective OneーElectron Reduction of a Cationic Substrate,10ーMethylacrikimium Ion by Group 4B Dimetals, Me_3SnーMMe_3(M=Sn,Ge,Si)Via Radical Chain Reactions" Journal of the American Chemical Society. 112. (1990)
• [Publications] S.Fukuzumi: "Effiicient ElectronーTransfer Catalytic Systems from an NADH Model Compound to Dioxygen" Inorganic Chemistry. 29. (1990)
• [Publications] S.Fukuzumi: "Blue Transient Complex Formation in the Electron Transfer Reaction Betweem Ferric Ions and a NADH Analogue without an Amide Group" Journal of the Chemical Society,Dalton Transactions. (1990)
• [Publications] K.Ishikawa: "Oxygenation and Oxidative Coupling Processes of Alkyl Ligands of cisーDialkylcobalt(III)Complexes with Dioxygen Catalyzed by Coenzyme Analogues in the Presence of Perchloraic Acid" Journal of the American Chemical Society. 112. 1577-1584 (1990)
• [Publications] S.Fukuzumi: "Photocatalytic Reduction of Phenacyl Halides by 9,10ーDihydroー10ーmethylacridine. Control Between the Reductive and Oxidative Quenching Pathways of Trisbipyridineruthenium Complex.." Journal of the Physical Chemistry. 94. 722-726 (1990)
• [Publications] S.Fukuzumi: "Flavinーsensitized photoーoxidation of Unsaturated Fatty Acids" Journal of the Chemical Society,Perkin Transaction 2. 2103-2108 (1989)
• [Publications] K.Isgujawa: "Photoinduced Radical Chain Reactions between Alkylcobalt(III)Complexes and Iodine" Journal of the Chemical Society,Dalton Transactions. 85-90 (1990)
• [Publications] S.Fukuzumi: "Peroxidation of Polyunsaturated Fatty Acids, Initiated by the Direct Interaction between a Cobalt Porphyrin Complex and Polyunsaturated Fatty Acids" Journal of the Chemical Society,Perkin Taransaction 2. 2035-2039 (1989)
• [Publications] M.Ishikawa: "Photochromic Systems Utilizing the Reversible Photoredox Reactions between a Flavin Analogue and Benzenethiol" Chemistry Letters. 2187-2192 (1989)
• [Publications] S.Fukuzumi: "Photoinduced Hydride Reduction of an NAD^+ Analogue with Permethylpolysilanes Acting as Electoron Sources and Water as a Proton Source" Chemistry Letters. 2177-2180 (1989)
• [Publications] S.Fukuzumi: "Acidーcatalysed Reduction of pーBenzoquinone Derivatives by an NADH Analogue,9,10ーDihydroー10ーmethylacridine.The Energetic Comparison of Oneーelectron vs.Twoーelectron Pathways" Journal of the Chemical Society,Perkin Transaction 2. 1811-1816 (1989)
• [Publications] S.Fukuzumi: "Reversibli Transformation between the Oxidized and Reduced Foarms of Redox Coenzyme Analogues" Journal of the Chemical Society,Perkin Transaction 2. 1801-1806 (1989)
• [Publications] S.Fukuzumi: "AcidーCatalyzed ElectronーTransfer Parocesses in Reduction of αーHaloketones by an NADH Model Compound and Ferrocene Derivatives" Jouarnal of the American Chemical Society. 111. 1497-1499 (1989)
• [Publications] M.Ishikawa: "Efficient Reduction of Triphenylmethanol to Triphenylmethane by 9,10ーDihydroー10ーmethylacridine in the Presence of Perchloric Acid" Bulletin of the Chemical Society of Japan. 62. 3754-3756 (1989)
• [Publications] S.Fukuzumi: "Reduction of Dioxytgen by an NADH Model Compound and 1,1'ーDimethyferrocene,Catalysed by Acids in the Homogeneous and Heterogeneous Systems" Journal of the Chemical Society,Perkin Transaction 2. 1417-1423 (1989)
• [Publications] S.Fukuzumi: "Photoreduction of Phenacyl Halides By NADH Model Compounds.Different Mechanistic Pathways" Journal of the Chemical Society,Perkin Transaction 2. 1583-1589 (1989)
• [Publications] S.Fukuzumi: "Complex Formation between NADH Model Compounds and Metallopoarphyrins" Journal of the Chemical Society,Perkin Transaction 2. 1753-1761 (1989)
• [Publications] S.Fukuzumi: "AcidーCatalysed Reduction of Flavin Analogues by an NADH Model Compound,10ーMethylー9,10ーdihydroacridine and cisーDialkylcobalt(III)Complexes" Journal of the Chemical Society,Perkin Transaction 2. 1047-1053 (1989)
• [Publications] S.Fukuzumi: "Mechanisms of Photoーoxidation of NADH Model Compounds by Oxygen" Journal of the Chemical Society,Perkin Transaction2. 1037-1045 (1989)
• [Publications] S.Mochizuki: "Efficient Reduction of αーHaloacetophenone Derivatives to the Corresponding Halohydrins by 9,10ーDihydroー10ーmethylacridine in the Pesence of Titanium Tetrachloride." Bulletin of the Chemical Society of Japan. 62. 3049-3051 (1989)
• [Publications] S.Fukuzumi: "Efficient Reduction of Dioxygen with Ferrocene Derivatives,Catalyzed by 一etalloporphyrins in the Presence of Perchlric Acid" Inorganic Chemistry. 28. 2459-2465 (1989)
• [Publications] K.Ishikawa: "ElectronーTransfer Processes in Electrophilic Cleavage of CobaltーCarbon Bonds of Alkylcobalt(III)Complexes with Iodine" Inorganic Chemistry. 28. 1661-1665 (1989)
• [Publications] S.Fukuzumi: "Reduction of 10ーNethylacridinium Ion with Fatty Acidas by Photoinduced ElectronーTransfer Reactions" Chemistry Letters. 1231-1234 (1989)
• [Publications] S.Fukuzumi: "Reductive Methylation of NAD^+ Analogues by a transーDimethylーcobalt(III)Complex" Chemistry Letters. 1599-1602 (1989)
• [Publications] S.Fukuzumi: "Acidーcataiysed Electronーtransfer Processes in Hydridetransfer Reactions from 10ーMethylaridan to pーBenzoquinone Derivatives" Chemistry Letters. 1227-1230 (1989)
• [Publications] S.Fukuzumi: "Acidーcatalysed Multiーelectron Reduction of Nitrobenzene Derivatives by an NADH Model Compound,10ーMethylacridan" Journal of Chemical Society.Chemical Communications. 941-943 (1989)
• [Publications] S.Fukuzumi: "Protonated Pteridines and Flavin Analogues acting as Efficient and Substrateーselective Photocatalysts in the Oxidation of Benzyl Alcohol Derivatives by Oxygen," Journal of the Chemical Society,Chemical Communications. 816-818 (1989)
• [Publications] S.Fukuzumi: "Twoーeiectron and Fourーelectron Reduction of Dioxygen with an NADH Model Componud,Catalysed by Metalloporphyrins in the Presence of Perchloric Acid Acid in Acetonirils" Journal of the Chemical Society,Chemcal Communications. 391-392 (1989)
• [Publications] S.Fukuzumi: "Photoーcleavage of Cobaltーcarbon Bonds of Alkylcobalt(III)Complexes by Iodine with Extremely Large Quantum Yields" Journal of the Chemical Society,Chemical Communication. 260-261 (1989)
• [Publications] S.Fukuzumi: "AcidーCatalyzed Reduction of Ketones by an NADH Model Compound and the Relation with AcidーCatalyzed Photoinduced ElectronーTransfer Reactions" Chemistry Letters. 31-34 (1989)