Synthetic Models of N/S-Ligated Metal Centers in Biology

摘要：本课题主要研究作为NxSy-Mn+金属蛋白模型的小分子金属配合物的合成及其反应性。金属酶肽脱甲酰基酶（PDF）和超氧化物还原酶（SOR）具有共同的结构元素。它们都含有一个单核铁中心，由一个罕见的半胱氨酸硫酸酯和两个或四个组氨酸配体配位。PDF类酶是抗菌、抗疟疾和抗癌治疗的重要靶点。大多数细菌pdf使用一个由His2Cys配体结合的铁（ll）中心，并催化新生多肽n端甲酰基的水解裂解。在大多数情况下，用Zn（ll）代替Fe（ll）使PDF失活，尽管Zn（ll）通常是自然催化水解反应的首选。然而，锌离子在真核生物的PDF以及一种细菌的PDF中是活跃的。这些观察结果导致了以下问题：为什么酶利用具有氧化还原活性的铁离子来执行非氧化还原作用？是什么导致了Zn '的活性变化？不常见的硫化物供体有什么影响？它的机制是什么？SOR酶含有一个独特的铁（ll）活性位点，具有1个Cys和4个His配体，并催化O2还原为H2O2。超氧化物的基本化学性质与许多疾病有关。关于SOR的问题包括：O2结合位点的性质是什么？在Fe还原O2~的过程中会形成什么中间产物？哪些因素（如氧化还原电位、自旋态、供体集）控制O2~还原？哪些因素对H2O2的释放至关重要？配体设计和配位化学原理将用于合成PDF和SOR的模型配合物。PDF模型将检验其水解反应性。SOR模型将在与O2~和相关含氧物质的反应中进行研究。这两种类型的配合物都将被研究，以确定N/ s连接金属中心的反应性、机制和结构/功能关系的广泛模式。有关新的NxSy配体和金属配合物的合成和反应性的知识将得到提高。相关性：从这项工作中获得的信息将对新抗生素的设计以及涉及活性氧的各种疾病的治疗（例如帕金森病，阿尔茨海默病，癌症）具有潜在的用途。

DESCRIPTION (provided by applicant): Abstract: This proposal focuses on the synthesis and reactivity of small-molecule metal complexes as models of NxSy-Mn+ metalloproteins. The metalloenzymes peptide deformylase (PDF) and superoxide reductase (SOR) share common structural elements. They both contain a mononuclear iron center coordinated by an uncommon cysteinate thiolate and two or four histidine ligands. The PDF class of enzymes are important targets for antibacterial, antimalarial, and anticancer therapies. Most bacterial PDFs employ an iron(ll) center bound by His2Cys ligands and catalyze the hydrolytic cleavage of the N-terminal formyl group of nascent polypeptides. Substitution of Zn(ll) for Fe(ll) renders PDF inactive in most cases, even though Zn(ll) is normally Nature's preferred choice for catalyzing hydrolysis reactions. However, the zinc(ll) ion is active in eukaryotic PDFs, as well as in one type of bacterial PDF. These observations lead to the following questions: Why does the enzyme utilize a redox-active iron(ll) ion to perform a non-redox role? What causes the variation in activity for Zn"? What is the influence of the uncommon thiolate donor? What is the mechanism? The enzyme SOR contains a unique iron(ll) active site with one Cys and four His ligands, and catalyzes the reduction of O2" to H2O2. The fundamental chemistry of superoxide has been implicated in a number of diseases. Questions regarding SOR include: What is the nature of the O2" binding site? What intermediates are formed during reduction of O2~ by Fe"? What factors (e.g. redox potential, spin state, donor set) control O2~ reduction? What factors are critical for the release of H2O2? Principles of ligand design and coordination chemistry will be used to synthesize model complexes of PDF and SOR. The PDF models will be examined for their hydrolytic reactivity. The SOR models will be studied in reactions with O2~ and related oxygenic species. Both types of complexes will be interrogated in order to determine broad patterns of reactivity, mechanism, and structure/function relationships in N/S-ligated metal centers. Knowledge regarding the synthesis and reactivity of new NxSy ligands and there metal complexes will be advanced. Relevance: The information obtained from this work will be potentially useful for the design of new antibiotics, as well as the treatment of a wide variety of diseases in which reactive oxygen species are implicated (e.g. Parkinson's, Alzheimer's, cancer).