Bioinorganic Copper Coordination Chemistry

描述（由申请人提供）：拟议研究的目标是进一步发展铜配位化学的基本方面，这些方面与其在分子氧（O2）和氮氧化物（NOx）的生化处理中的重要作用有关。关于铜（I）/O2相互作用、O2-加合物形成的动力学和能量学以及关于结构、相关光谱、O-O键断裂（即，O2活化）和底物氧化化学。这些也可能与氧化应激的情况有关，例如，神经系统疾病如阿尔茨海默氏症铜-NOx研究与亚硝酸盐和一氧化二氮（N2O）还原酶中的活性位点化学以及铜离子在一氧化氮（"NO"）生物化学中的可能作用相关，包括介导O2与-NO过氧亚硝酸盐（O =诺奥~）化学和氧化（和/或硝化）应激。研究方法分为子项目，直接沿着各种主题或化学系统。其中包括（1）O2和一氧化碳的研究（2）关键配体-Cu~（2+）（O~（2-））的研究（超氧化物）溶剂氢键和光化学，（3）主要致力于揭示涉及氢原子转移化学的配体-Cu 2+（O2-）底物反应性的机理细节，（4）与某些Cu-单加氧酶相关的新的四齿配体-Cu络合物（包括与硫醚供体）的研究，强调O2 & CO结合动力学-热力学和与其它系统的结构-光谱比较，（5）先前未观察到的初级Cu/O2 = 1的瞬时吸收光谱检测：1加合物，并阐明其动力学-热力学和光谱学，采用高活性的三齿配体铜络合物系统，（6）研究铜离子与组氨酸-组氨酸肽部分（铜生物化学中的新结合基序）的络合、结构、结合和化学反应性，强调以前未研究的HisHis和阿尔茨海默病相关淀粉样蛋白的已知金属结合部分（残基6 - 14）的铜（I）配位化学。（7）铜硫化物化学的阐述，包括与一氧化二氮还原酶活性位点相关的新簇化合物的产生和表征，另外强调了络合物还原活化N2O的能力，以及（8）配体Cu+与NO和O2的反应的研究，导致过氧亚硝酸盐衍生的化学。拟议的研究有助于更广泛地了解铜生物化学，其他金属蛋白（例如，血红素或非血红素铁）在生物学和相关疾病状态中O2和NOx的活化/还原。这项基础研究的潜在长期应用包括酶抑制剂和相关疾病治疗策略的开发。

DESCRIPTION (provided by applicant): The goal of the proposed research is to further develop fundamental aspects of copper coordination chemistry relevant to its essential role in the biochemical processing of dioxygen (O2) and nitrogen oxides (NOx). Many questions remain concerning copper(l)/O2 interactions, dynamics & energetics of O2-adduct formation, as well as questions concerning structure, associated spectroscopy, O-O bond cleavage (i.e., O2- activation) and substrate oxidation chemistries. These may also be relevant to situations of oxidative stress, e.g., in neurological disorders such as Alzheimer's disease. Copper-NOx investigations are relevant to the active site chemistry in nitrite and nitrous oxide (N2O) reductases, and to the possible role of copper ion in nitrogen monoxide ("NO) biochemistry, including mediation of O2 with -NO peroxynitrite (O=NOO~) chemistry and oxidative (and/or nitrative) stress. The research methods divide into sub-projects, directed along various themes or chemical systems. These include (1) study of O2 and carbon monoxide (CO, as O2-surrogate) kinetics and thermodynamics of binding to tetradentate ligand Cu(l)-chelates, (2) study of key ligand- Cu2+(O2-) (superoxide) solvent hydrogen bonding and photochemistry, (3) a major effort to unravel mechanistic details of ligand-Cu2+(O2-) substrate reactivity involving hydrogen-atom transfer chemistry, (4) study of new tetradentate ligand-Cu complexes including with thioether donors, of relevance to certain Cu- monooxygenases, emphasizing O2 & CO binding kinetics-thermodynamics and structural-spectroscopic comparisons to other systems, (5) transient absorption spectroscopic detection of previously unobserved primary Cu/O2 =1:1 adducts and elucidation of their kinetics-thermodynamics and spectroscopy, employing highly reactive tridentate ligand Cu complex systems, (6) investigation of copper ion complexation, structure, binding and chemical reactivity with histidine-histidine peptide moieties (novel binding motifs in copper biochemistry), emphasizing previously un-researched copper(l) coordination chemistry of HisHis and the known metal binding portion (residues 6-14) of the Alzheimer's disease associated amyloid ??peptide, (7) elaboration of Cu-sulfide chemistry, including generation and characterization of new cluster compounds relevant to the active site of nitrous oxide reductase, with additional emphasis placed on the complexes' ability to reductively activate N2O, and (8) investigation of ligand Cu+ reactions with NO and O2, leading to peroxynitrite-derived chemistry. The proposed studies contribute to a broader understanding of copper biochemistry, other metalloprotein (e.g., heme or non-heme iron) activation/reduction 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.