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

哺乳动物中唯一已知的隔离锰的生物分子--免疫系统蛋白 钙保护素，是第一个结构表征的自然产生的六氢异硫氨酸的例子 金属蛋白中的锰金属结合部位。钙保护素是为数不多的几种锰之一- 结合金属蛋白，具有“全N”(His4或His6)配位环境，而不是 Mn2结合部位一般倾向于含有N-和O-供体氨基酸配体的混合物。一个 第二个例子是Cupin蛋白TM1459，它含有His4锰位点，并催化 烯烃的氧化裂解。这里提出的研究将开发生物灵感功能和 使用新型聚咪唑螯合配体的这些位点的结构模型。这项工作意义重大 因为将解决两个重要的科学问题：选择性锰络合剂的必要性 它将作为潜在的金属结合疗法或作为生物医学的工具而应用 研究，以及基于地球丰富的和催化方法的烯烃氧化裂解的必要性 无毒金属。拟议的研究被组织为两个具体目标：(1)识别和模拟 钙保护素中Mn2结合强的结构和电子因素。通过一个 结合了合成、结构表征、光谱、结合研究和计算， 新型六齿聚咪唑配体将用于测试选择性、 高亲和力的锰络合作用。这些结构将进行抗生素活性测试，以对抗 确定依赖锰的病原体肺炎链球菌是否依赖锰 该病原菌的粘附性和致病力均可减弱。(2)聚咪唑配位模型 参与烯烃氧化裂解的锰和铁中心。锰和铁的络合物 与在目标1中开发的那些相关的富咪唑的螯合配体将被应用、优化和 在氧化双键断裂的背景下研究；这种生物启发的方法是由 金属酶中的His4Mn和His4Fe都能参与该反应。这个 这项研究的贡献预计将是巨大的，因为这些系统将提供更多 这类不同寻常的金属蛋白位点的忠实仿生模型 具有重要技术价值的特性。此外，通过利用部门之间和 直接让密西西比州立大学(MSU)的本科生参与实施 拟议的工作，密歇根大学的研究环境将得到改善，高素质的学生将 接触到与NIH任务相关的生物无机化学研究。

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.