Biomimetic models of manganese- and iron-histidine coordination sites in metalloproteins for chelation, antibiotic activity, and oxidative reactivity

金属蛋白中锰和铁组氨酸配位位点的仿生模型，用于螯合、抗生素活性和氧化反应性

• 批准号: 10292163
• 负责人: Sidney E Creutz
• 金额: $ 41.8万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292163
• 关键词: Address; Adhesions; Affinity; Alkenes; Amino Acids; Antibiotics; Arts; Attenuated; Bacteria; Binding; Binding Sites; Biochemistry; Bioinorganic Chemistry; Biological; Biological Models; Biology; Biomedical Research; Biomimetics; Carotenoids; Catalysis; Chelating Agents; Chemistry; Collaborations; Complex; Data; Development; Dioxygenases; Environment; Exposure to; Family; Funding; Goals; Health; Histidine; Homeostasis; Human; Human body; Imidazole; Immune system; Investigation; Ions; Iron; Leukocyte L1 Antigen Complex; Ligands; Mammals; Manganese; Metal Binding Site; Metalloproteins; Metals; Methods; Mission; Mississippi; Modeling; Nature; Nitrogen; Nutritional Immunity; Organism; Outcome; Pharmacologic Substance; Planet Earth; Problem Solving; Property; Proteins; Public Health; Reaction; Research; Role; Science; Series; Site; Spectrum Analysis; Streptococcus pneumoniae; Structural Models; Structure; Students; Synthesis Chemistry; System; Testing; Therapeutic; Transition Elements; United States National Institutes of Health; Universities; Virulence; Work; base; biological systems; catalyst; chelation; clinical diagnostics; college; design; in vivo; insight; metal complex; metalloenzyme; novel; pathogen; pi bond; prevent; tool; trafficking; undergraduate student; uptake

The only known manganese-sequestering biomolecule in mammals, the immune system protein calprotectin, is the first structurally characterized example of a naturally-occurring hexahistidine manganese metal binding site in a metalloprotein. Calprotectin is one of only a handful of manganese- binding metalloproteins which feature an "all-N" (His4 or His6) coordination environment, in contrast to the general propensity of Mn2+-binding sites to contain a mixture of N- and O-donor amino acid ligands. A second example is the cupin protein TM1459, which hosts a His4 manganese site and catalyzes the oxidative cleavage of alkenes. The research proposed here will develop bioinspired functional and structure models of these sites using novel polyimidazole chelating ligands. This work is significant because two important scientific problems will be addressed: the need for selective manganese chelators which would have applications as potential metal-binding therapeutics or as tools for biomedical research, and the need for catalytic methods for oxidative alkene cleavage based on earth-abundant and non-toxic metals. The proposed research is organized into two specific aims: (1) Identify and model the structural and electronic factors responsible for strong Mn2+ binding in calprotectin. Through a combination of synthesis, structural characterization, spectroscopy, binding studies, and computation, novel hexadentate polyimidazole ligands will be used to test bioinspired design principles for selective, high-affinity manganese chelation. These structures will be tested for antibiotic activity against a manganese-dependent pathogen, S. pneumoniae, to determine whether the manganese-dependent adhesion and virulence of this pathogen can be attenuated. (2) Model the polyimidazole-coordinated manganese and iron centers involved in oxidative alkene cleavage. Manganese and iron complexes of imidazole-rich chelating ligands related to those developed in Aim 1 will be applied, optimized, and studied in the context of oxidative double bond cleavage; this bioinspired approach is motivated by the fact that both His4Mn and His4Fe sites in metalloenzymes are competent in this reaction. The contributions from this research are expected to be significant because these systems will provide more faithful biomimetic models of this unusual class of metalloprotein sites with biomedically and technologically important properties. Additionally, by leveraging collaboration between departments and directly involving undergraduate students from Mississippi State University (MSU) in carrying out the proposed work, the research environment at MSU will be enhanced, and highly qualified students will be exposed to bioinorganic chemistry research relevant to NIH's mission.

哺乳动物中唯一已知的锰螯合生物分子，免疫系统蛋白 钙卫蛋白是天然存在的六聚组氨酸的第一个结构特征的例子 金属蛋白中的锰金属结合位点。钙卫蛋白是为数不多的锰- 结合金属蛋白，其特征在于“全N”（His 4或His 6）配位环境， Mn 2+结合位点含有N-和O-供体氨基酸配体的混合物的一般倾向。一 第二个例子是cupin蛋白质TM 1459，其具有His 4锰位点并催化Cupin蛋白质的磷酸化。 烯烃的氧化裂解。这里提出的研究将开发生物启发的功能和 这些网站的结构模型，使用新的聚咪唑螯合配体。这项工作意义重大 因为两个重要的科学问题将得到解决：需要选择性锰螯合剂 它将作为潜在的金属结合治疗剂或生物医学的工具， 研究，以及对基于地球丰富和 无毒金属。本研究的主要目的有两个：（1）识别和建模 结构和电子因素负责钙卫蛋白中的强Mn 2+结合。通过 合成、结构表征、光谱学、结合研究和计算的组合， 新的六齿聚咪唑配体将用于测试生物启发的设计原理， 高亲和力锰螯合作用。这些结构将被测试针对以下的抗生素活性： 锰依赖型病原菌S.肺炎，以确定是否锰依赖性 可以减弱该病原体的粘附力和毒力。(2)模拟聚咪唑配位 锰和铁中心参与氧化烯烃裂解。锰和铁的络合物 与目标1中开发的那些相关的富含咪唑的螯合配体将被应用、优化， 在氧化双键裂解的背景下研究;这种生物启发的方法是由 事实上，金属酶中的His 4 Mn和His 4Fe位点都能参与该反应。的 这项研究的贡献预计将是显着的，因为这些系统将提供更多的 这类不寻常的金属蛋白位点的忠实仿生模型， 技术上重要的属性。此外，通过利用各部门之间的协作， 直接涉及本科生从密西西比州立大学（MSU）在执行 拟议的工作，在MSU的研究环境将得到加强，高素质的学生将 接触到与NIH的使命相关的生物无机化学研究。