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

生物学中 N/S 连接金属中心的合成模型

• 批准号: 7922428
• 负责人: David P Goldberg
• 金额: $ 4.41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-26 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922428
• 关键词: Active Sites; Address; Air; Alzheimer' s Disease; Anti-Bacterial Agents; Antibiotics; Antimalarials; Antineoplastic Agents; Archaea; Bacteria; Bacterial Typing; Binding; Binding Sites; Biochemistry; Biological; Biological Models; Biology; Chemistry; Complex; Defense Mechanisms; Dependence; Development; Disease; Drops; Drug Metabolic Detoxication; Electronics; Elements; Environment; Enzymes; Esters; Eukaryota; Exhibits; Family; Formates; Goals; Health; Histidine; Human; Hydrogen Bonding; Hydrogen Peroxide; Hydrolysis; Ions; Iron; Kinetics; Knowledge; Lactams; Lead; Ligand Binding; Ligands; Light; Malignant Neoplasms; Metalloproteins; Metals; Methods; Modeling; Mononuclear; N-terminal; Nature; Oxidation-Reduction; Parkinson Disease; Pattern; Property; Reaction; Reactive Oxygen Species; Reporting; Research Personnel; Role; Structure; Structure-Activity Relationship; Study models; Superoxides; Syphilis; System; Techniques; Testing; Treponema pallidum; Variant; Work; Zinc; abstracting; analog; base; cancer therapy; cold temperature; design; divalent metal; formamide; inhibitor/antagonist; metal complex; metalloenzyme; novel; peptide deformylase; polypeptide; small molecule; superoxide reductase

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).

描述（由申请人提供）：摘要：该提案的重点是小分子金属复合物作为NXSY-MN+金属蛋白的模型的合成和反应性。金属酶肽畸形酶（PDF）和超氧化物还原酶（SOR）具有共同的结构元素。它们都包含一个单一核铁心中心，该中心由不常见的半胱氨酸硫醇酸盐和两个或四个组氨酸配体配位。 PDF类酶是抗菌，抗疟疾和抗癌疗法的重要靶标。大多数细菌PDF使用His2Cys配体约束的铁（LL）中心，并催化新生多肽的N端甲基的水解裂解。在大多数情况下，Zn（LL）代替Fe（LL）在大多数情况下会使PDF无效，即使Zn（LL）通常是自然的催化水解反应的首选选择。但是，锌（LL）离子在真核PDF以及一种类型的细菌PDF中具有活性。这些观察结果导致了以下问题：为什么酶使用氧化还原活性铁（LL）离子执行非雷多斯角色？是什么原因导致Zn的活动变化”？“不常见的硫代硫酸盐供体的影响是什么？该机制是什么？酶SOR包含一个带有一个Cys和四个配体的独特铁（LL）活性位点，并将O2降低到H2O2。超氧化物的基本化学与多种疾病有关。有关SOR的问题包括：O2“绑定位点的性质？在减少o2〜时形成哪些中间体”？哪些因素（例如氧化还原电位，自旋状态，供体集）控制O2〜降低？哪些因素对于释放H2O2至关重要？配体设计和协调化学原理将用于合成PDF和SOR的模型复合物。将检查PDF模型的水解反应性。 SOR模型将在与O2〜和相关的氧化物种的反应中进行研究。两种类型的复合物将被审问，以确定N/S粘合金属中心中反应性，机理和结构/功能关系的广泛模式。关于新的NXSY配体和金属络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可能对设计新抗生素的设计以及对涉及活性氧涉及的多种疾病的治疗（例如，帕金森氏症，阿尔茨海默氏症，癌症）。