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.

免疫系统蛋白质中唯一已知的锰序列生物分子 钙骨蛋白，是一个自然抗六个月的结构表征的第一个示例 金属蛋白中的锰金属结合位点。钙骨蛋白酶是仅有的少数锰之一 具有“ All-N”（HIS4或HIS6）协调环境的具有约束力的金属蛋白，与 MN2+结合位点的一般倾向，含有N-和O-Donor氨基酸配体的混合物。一个 第二个例子是Cupin蛋白TM1459，该蛋白质含有HIS4锰部位并催化 烷烃的氧化裂解。这里提出的研究将发展生物启发的功能，并 这些位点的结构模型使用新型多咪唑螯合配体。这项工作很重要 因为将解决两个重要的科学问题：需要选择性锰螯合剂 将其应用于潜在的金属结合疗法或生物医学的工具 研究，以及基于土壤丰富的和 无毒金属。拟议的研究分为两个具体目的：（1）识别和建模 负责钙骨蛋白中强MN2+结合的结构和电子因素。通过一个 合成，结构表征，光谱，结合研究和计算的结合， 新型己酸酯多咪唑配体将用于测试选择性的生物启发的设计原理， 高亲和力锰螯合。这些结构将测试针对A的抗生素活性 锰依赖性病原体，肺炎链球菌，以确定锰依赖性是否依赖 该病原体的粘附和毒力可以减弱。 （2）建模聚咪唑协调 参与氧化烯烃裂解的锰和铁中心。锰和铁综合体 将应用，优化与AIM 1中开发的咪唑较丰富的螯合配体，并且 在氧化双键裂解的背景下进行了研究；这种生物启发的方法是由 Metalloenzymes中的HIS4MN和HIS4FE站点均具有这种反应的事实。这 预计这项研究的贡献将是重要的，因为这些系统将提供更多 具有生物医学和 技术上重要的特性。此外，通过利用部门之间的合作 直接涉及密西西比州立大学（MSU）的本科生 拟议的工作，MSU的研究环境将得到增强，高素质的学生将是 暴露于与NIH的使命相关的生物无机化学研究。