Bioinorganic Copper Coordination Chemistry

生物无机铜配位化学

• 批准号: 9240630
• 负责人: KENNETH D. KARLIN
• 金额: $ 38.74万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240630
• 关键词: Acids; Active Sites; Anions; Basic Science; Behavior; Binding; Biochemical; Biochemistry; Biological; Biology; Carbon Dioxide; Carbonates; Cations; Cellulose; Chelating Agents; Chemistry; Complex; Copper; Coupled; Detection; Development; Dioxygen; Disease; Dissociation; Electron Transport; Electrons; Environment; Enzyme Inhibitor Drugs; Enzymes; Goals; Heme; Histamine; Histidine; Hydrogen Bonding; Hydroxides; Hydroxylation; Imidazole; Injection of therapeutic agent; Investigation; Ions; Isotopes; Kinetics; Lasers; Ligands; Metalloproteins; Metals; Methionine; Mixed Function Oxygenases; Nature; Nitrates; Nitric Oxide; Nitrites; Nitrogen Oxides; Oxidases; Oxidation-Reduction; Oxides; Oxidoreductase; Oxygenases; Pattern; Peptides; Peroxides; Peroxonitrite; Phenols; Photochemistry; Positioning Attribute; Process; Property; Protons; Reaction; Reactive Nitrogen Species; Reagent; Reducing Agents; Research; Role; Solvents; Spectrum Analysis; Structure; Sulfur; Superoxides; System; Therapeutic; Thermodynamics; Time; Water; adduct; base; chelation; copper histidine; cryogenics; electron donor; insight; novel; oxidation; preference; protonation; public health relevance; small molecule; thioether

 DESCRIPTION (provided by applicant): The goal of the proposed research is to further develop aspects of copper coordination chemistry relevant to its essential role in the biochemical processing of O2 and nitrogen oxides (NOx). Research subprojects include: (1) Detailed studies of primary copper(I)-O2 adducts,. For several Cu(II)(O2•-) species we will examine their protonation-reduction chemistry to give Cu(II)-(hydro)peroxides. Acids and reducing agents will be varied and kinetics studied, to provide insights concerning electron-transfer, maybe involving proton-coupled electron-transfer (PCET). Cu(II)(O2•-) complex reactivity with C-H or O-H substrates will be also studied mechanistically to establish their oxidizing capabilities. Cu(II)(O2•-) species with one thioether ligand donor will also be include; we will explore the possibility that O2- chemistry involves methionine sulfur radical cation formation, a possible new paradigm in the field. (2) A specific set of Cu(II)2-OOR complexes with varied R (= H, alkyl or acyl) will be subjected to acids of varying pKa values and investigated for their O-O reductive cleavage chemistry. Kinetic studies, isotope effect determination and product analyses will be carried out in order to elucidate the mechanism of O- O cleavage, homolytic or heterolytic. We hope to identify high-valent copper-oxo intermediates. (3) Particular Histidine (His) containing motifs occur in some Cu monooxygenase enzymes. Cu ion and Cu(I)/O2 reactivity studies will be developed with (i) His-Xaa-His ligands where the availability o N vs. N imidazole tautomeric positions as donors are to be systematically controlled via synthetic means. (ii) The 'histidine-brace' motif, Cu-chelation from a terminal His residue, will b examined for Cu ion and Cu(I)-O2 chemistries employing synthetically varied histamine-based ligands, (4) Short time-scale (ns, s) Cu(I)-O2 chemistry will be probed by laser photo-initiated O2-ejection from discrete Cun-O2 complexes. We will obtain kinetic-thermodynamic descriptions of systems having fast O2-to-Cu(I) binding to form one entity and then transforming to another. Also, these studies may help identify Cun- O2 excited states. (5) Advanced studies will focus on copper/O2/nitric-oxide interactions, following a new paradigm concerning the possible role of copper ion in the biological formation of the reactive nitrogen species peroxynitrite (-OON=O; PN). Cu-PN complexes will be investigated for their transformation to Cu-nitrate, vs Cu-nitrite + O2(g). An emphasis will be placed on Cu-PN reactivity with carbon dioxide, a biologically relevant substrate that enhances PN's damaging effects via formation of the carbonate radical anion and NO2 radical. Overall, the proposed studies will contribute to a broader understanding of copper biochemistry involving O2 and/or NO, activation of O2 and NOx in biology, and associated disease states. Potential long-term applications of this basic research include development of enzyme inhibitors and relevant disease therapeutic strategies.

 描述（由应用提供）：拟议研究的目的是进一步发展与其在O2和氮氧化物（NOX）生化过程中的重要作用相关的铜协调化学方面。研究子项目包括：（1）主要铜（I）-O2加合物的详细研究。对于几种Cu（ii）（O2• - ）物种，我们将检查其质子化还原化学，以给出Cu（II） - （氢）过氧化物。酸和还原剂将被多种多样，动力学研究，以提供有关电子转移的见解，可能涉及质子偶联的电子转移（PCET）。 Cu（II）（O2• - ）与C-H或O-H底物的复杂反应性也将在机械上进行研究以建立其氧化能力。还将包括一个带有一个硫醚配体供体的Cu（ii）（o2• - ）物种；我们将探讨O2-化学涉及甲氧氨基自由基阳离子形成的可能性，这是该领域可能的新范式。 （2）一组具有不同R（= H，烷基或酰基）的Cu（II）2-OOR复合物将受到不同PKA值的酸的酸，并研究 他们的O-O减少裂解化学。动力学研究，同位素效应的测定和产品分析将进行，以阐明O-O裂解，均利性或杂种的机理。我们希望确定高价值的铜中间体。 （3）特定的组氨酸（HIS）含有基序中发生在某些Cu单加掺杂酶中。 Cu ion和Cu（I）/O2反应性研究将使用（i）His-XAA-HIS配体进行，其中可用性ON与n咪唑二唑次分子位置，作为捐助者，将通过合成手段系统地控制捐助者。 (ii) The 'histidine-brace' motif, Cu-chelation from a terminal His residence, will b examined for Cu ion and Cu(I)-O2 chemistries employing synthetically varied histamine-based ligands, (4) Short time-scale (ns, s) Cu(I)-O2 chemistry will be probed by laser photo-initiated 来自离散CUN-O2复合物的O2换次。我们将获得具有快速O2-to-Cu（i）结合的系统以形成一个实体然后转换为另一个实体的系统的动力学描述。同样，这些研究可能有助于鉴定CUN-O2激发态。 （5）高级研究将集中在铜/o2/氮氧的相互作用上，这是关于铜离子在生物形成中的可能作用的新范式，在反应性氮过氧硝酸盐（-oon = o; pn）中的生物形成中的作用。将研究Cu-PN复合物的转化为Cu-硝酸盐，而Cu-硝酸盐 + O2（G）。将重点放在与二氧化碳的Cu-PN反应性上，二氧化碳是一种与生物学相关的底物，通过形成碳酸盐自由基阴离子和NO2自由基来增强PN的破坏作用。总体而言，拟议的研究将有助于更广泛地了解涉及O2和/或NO的铜生物化学，并且在生物学和相关疾病状态中激活O2和NOX。这项基础研究的潜在长期应用包括开发酶抑制剂和相关的疾病疗法策略。