Copper-peptide Chemistry; Alzheimer's Disease Relevance

铜肽化学；

• 批准号: 7234333
• 负责人: RICHARD A HIMES
• 金额: $ 4.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2008-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7234333
• 关键词: Address; Alzheimer' s Disease; Amino Acid Sequence; Amino Acids; Amyloid beta-Protein; Attention; Behavior; Binding; Bioinorganic Chemistry; Biological; Biological Models; Biological Process; Carbon Monoxide; Characteristics; Chemistry; Comparative Study; Complex; Copper; Coupling; Dioxygen; Dipeptides; Dopamine; Environment; Enzymes; Histidine; Human; Hydrogen Peroxide; Hydroxyl Radical; Imidazole; Ions; Ligands; Light; Link; Mediating; Metabolism; Metalloproteins; Metals; Methionine; Methods; Mixed Function Oxygenases; Modeling; Organism; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Peptide Fragments; Peptides; Process; Property; Proteins; Purpose; Reaction; Research; Role; Structure; Sulfur; System; Tyrosine; base; copper-binding protein; crosslink; cytochrome c oxidase; insight; interest; metalloenzyme; neurotoxicity; novel; oxidation; peptide I; protein aminoacid sequence; thioether

DESCRIPTION (provided by applicant): Novel copper-peptide complexes based on fragments of the amyloid beta peptide, implicated in the pathogenesis of Alzheimer's Disease, will be studied structurally and chemically. The purposes of these studies are to elucidate the role of several amino acid sequence motifs of interest found in the A-beta peptide as well as such biologically important metalloenzymes as cytochrome c oxidase, petidylglycine alpha-hydroxylating monoxygenase, and dopamine beta-hydroxygenase. The research will potentially shed light on the role of the sequences of interest on binding copper, determining structure, and activating copper for biological function in these metalloenzymes. In addition, the studies address the roles of copperdioxygen reactivity and copper-peptide interactions in the oxidative stress associated with Alzheimer's Disease and experimentally linked at A-beta. This will be accomplished by structural characterization of copper-peptide complexes in the +1 and +2 oxidation states, as well as reactivity and mechanistic studies of Cu(l) chemistry with dioxygen and hydrogen peroxide.

描述（由申请人提供）： 新的铜肽复合物的基础上的淀粉样β肽的片段，牵连在阿尔茨海默氏病的发病机制，将在结构和化学上进行研究。这些研究的目的是阐明在A-β肽中发现的几种感兴趣的氨基酸序列基序以及生物学上重要的金属酶如细胞色素c氧化酶、小甘氨酸α-羟基化单加氧酶和多巴胺β-羟化酶的作用。该研究将潜在地阐明感兴趣的序列在结合铜、确定结构和激活铜以实现这些金属酶的生物功能方面的作用。此外，这些研究还探讨了铜氧反应性和铜-肽相互作用在与阿尔茨海默病相关的氧化应激中的作用，并在实验上与A-β相关。这将通过+1和+2氧化态的铜-肽复合物的结构表征以及Cu（I）化学与分子氧和过氧化氢的反应性和机理研究来实现。