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

描述(申请人提供)：摘要：本提案重点关注作为NxSy-Mn+金属蛋白模型的小分子金属络合物的合成和反应活性。金属酶的多肽脱甲酰基酶(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盐和两个或四个组氨酸配体配位。PDF类的酶是抗菌、抗疟疾和抗癌治疗的重要靶点。大多数细菌PDF利用His2Cys配体结合的铁(11)中心，并催化新生多肽N-末端甲酰基的水解性裂解。锌(11)取代铁(11)使PDF在大多数情况下失去活性，即使锌(11)通常是自然首选的催化水解反应的选择。然而，锌离子在真核生物PDF以及一种细菌PDF中是活跃的。这些观察导致了以下问题：为什么酶利用氧化还原活性铁(11)离子来发挥非氧化还原作用？是什么导致了锌的活性变化？罕见的硫酸盐供体的影响是什么？机制是什么？SOR酶含有一个独特的铁(II)活性中心，具有一个半胱氨酸和四个组氨酸配体，并催化O2“还原为H_2O_2。超氧化物的基本化学已被认为与许多疾病有关。关于SOR的问题包括：O2结合部位的性质是什么？在O2~被Fe还原的过程中形成了哪些中间产物？是什么因素(如氧化还原电位、自旋态、施主集)控制O2~的还原？哪些因素对过氧化氢的释放起关键作用？将利用配位设计和配位化学原理合成PDF和SOR的模型络合物。将检查PDF模型的水解性。SOR模型将在与O2~及相关含氧物种的反应中进行研究。将对这两种类型的络合物进行询问，以确定N/S连接的金属中心的反应性、机理和结构/功能关系的广泛模式。关于新的NxSy配体及其金属络合物的合成和反应活性的知识将被推进。相关性：从这项工作中获得的信息可能有助于设计新的抗生素，以及治疗与活性氧类有关的各种疾病(例如帕金森氏症、阿尔茨海默氏症、癌症)。

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).