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

基本信息

批准号：
10797888
负责人：
Sidney E Creutz
金额：
$ 1.87万
依托单位：
MISSISSIPPI STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

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，是天然存在的六组氨酸的第一个结构特征实例金属蛋白中的锰金属结合位点。钙卫蛋白是少数的锰之一结合金属蛋白具有“全 N”（His4 或 His6）配位环境，与 Mn2+结合位点通常倾向于含有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，它具有 His4 锰位点并催化烯烃的氧化裂解。这里提出的研究将开发仿生功能和使用新型聚咪唑螯合配体构建这些位点的结构模型。这项工作意义重大因为两个重要的科学问题将得到解决：对选择性锰螯合剂的需求这将具有作为潜在的金属结合疗法或生物医学工具的应用研究以及基于地球丰富的和对氧化烯烃裂解的催化方法的需求无毒金属。拟议的研究分为两个具体目标：（1）识别并建模负责钙卫蛋白中 Mn2+ 强结合的结构和电子因素。通过一个合成、结构表征、光谱学、结合研究和计算的结合，新型六齿聚咪唑配体将用于测试选择性、高亲和力的锰螯合。这些结构将针对抗生素活性进行测试锰依赖性病原体肺炎链球菌，以确定是否锰依赖性这种病原体的粘附和毒力可以减弱。 (2) 聚咪唑配位模型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、优化和在氧化双键裂解的背景下进行研究；这种仿生方法的动机是事实上，金属酶中的 His4Mn 和 His4Fe 位点都可以参与该反应。这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种不寻常的金属蛋白位点的忠实仿生模型具有生物医学和技术上重要的属性。此外，通过利用部门之间的协作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，密歇根州立大学的研究环境将得到改善，高素质的学生将得到接触与 NIH 使命相关的生物无机化学研究。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synthesis and Characterization of Bipyridyl-(Imidazole)n Mn(II) Compounds and Their Evaluation as Potential Precatalysts for Water Oxidation.

联吡啶-(咪唑)n Mn(II)化合物的合成和表征及其作为水氧化潜在预催化剂的评估。

DOI：
发表时间：
2023-10-23
期刊：
影响因子：
0
作者：
Mu, Ge;Gaynor, Ryan B;McIntyre, Baylee N;Donnadieu, Bruno;Creutz, Sidney E
通讯作者：
Creutz, Sidney E

Steric Effects on the Chelation of Mn2+ and Zn2+ by Hexadentate Polyimidazole Ligands: Modeling Metal Binding by Calprotectin Site 2.

六齿聚咪唑配体对 Mn2 和 Zn2 螯合的空间效应：模拟钙卫蛋白位点 2 的金属结合。

DOI：
发表时间：
2023-07-03
期刊：
影响因子：
0
作者：
Gaynor, Ryan B;McIntyre, Baylee N;Lindsey, Shelby L;Clavo, Kaylee A;Shy, William E;Mees, David E;Mu, Ge;Donnadieu, Bruno;Creutz, Sidney E
通讯作者：
Creutz, Sidney E

(4-(Adamantan-1-yl)-1-(isopropyl)-1H-imidazol-2-yl)methanol.

(4-(金刚烷-1-基)-1-(异丙基)-1H-咪唑-2-基)甲醇。