Molecular mechanisms of metal-mediated biological functions for NO, O2, and HNO

金属介导的 NO、O2 和 HNO 生物功能的分子机制

• 批准号: 10291907
• 负责人: Yong Zhang
• 金额: $ 44.67万
• 依托单位: STEVENS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-18 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291907
• 关键词: Acids; Active Sites; Address; Area; Binding; Biological; Biological Availability; Biological Process; Biomedical Research; Blood Vessels; Cardiovascular system; Charge; Clinic; Clinical; Complex; Data; Disease; Drug Design; Electrons; Electrostatics; Environment; Enzymes; Future; Generations; Grant; HIV; Health; Heart failure; Heme; Hemeproteins; Horseradish Peroxidase; Hydrogen Bonding; Immune response; Kinetics; Ligands; Malignant Neoplasms; Mediating; Metabolism; Metalloproteins; Metals; Modeling; Molecular; Mutation; Nervous System Physiology; Oxidation-Reduction; Oxidoreductase; Pathologic Processes; Pathway interactions; Pharmaceutical Preparations; Phosphotransferases; Physiological Processes; Play; Process; Property; Proteins; Reaction; Reagent; Regulation; Relaxation; Reporting; Research; Role; Shapes; Sickle Cell Anemia; Signal Transduction; Stroke; Structure; Therapeutic; Thermodynamics; Work; biological research; catalase; computer studies; denitrification; design; enzyme activity; experimental study; heme a; hydroxyurea; mutant; neurotransmission; nitric oxide reductase; novel; trend

NO has considerable biomedical significance in cardiovascular regulation, immune response, neurotransmission, and global N-cycle. O2 is vital for many fundamental biological functions such as bioenergy, metabolism, and redox signaling. HNO also plays significant roles in vascular relaxation, enzyme activity regulation, and neurological function regulation. Despite numerous progress in this area, many important questions have not been answered. Building on our long-term research on biological complexes of NO, O2, and HNO with metalloproteins and models especially the successful preliminary data in the current grant period, we will provide some novel results to address three significant questions. Our first objective is to determine one- electron NO-to-N2O conversion mechanisms via heme models activated by Lewis acids reported recently, which is different from the conventional two-electron process by bacterial nitric oxide reductases. To provide a complete understanding of the kinetic and thermodynamic factors of this new reaction, systematic computational studies will be done to reveal the full reaction pathways of the reported heme models and explore the pathways for other biologically available metal, ligand environments, and Lewis acids. Our second objective is to determine rewiring mechanisms of NO/O2-sensing functions of a heme enzyme. How enzymes differentiate between two important redox reagents NO and O2 despite their similarity in shape, size, and charge remain unknown. Our experimental collaborator has recently reversed the NO sensing heme protein DosS to be O2 sensing via a triple mutant. The proposed work will reveal specific contributions of each mutation and their combinations on geometric and electronic properties and protein environment effects. The identified correlations of structural and electronic features with sensitivity functions will help rational design to rewire redox sensing functions in future biomedical research. Our third objective is to determine HNO formation mechanisms of a clinical drug hydroxyurea via heme proteins. The reactions have been experimentally studied using horseradish peroxidase (HRP) and catalase (CAT) with different reactivities. However, HNO formation mechanistic details and the origin for such reactivity difference are yet to be elucidated. The proposed work will calculate the complete reaction pathways for HRP and CAT using active site models with varying size of nearby residues and full proteins, to reveal basic mechanisms and roles of active site residues and protein environments for their differential reactivities. Results from this systematic study may also help identify key structural features to assist drug design and understanding of related HNO-generation drugs.

NO在心血管调节、免疫调节、免疫调节和免疫调节等方面具有重要的生物学意义， 反应、神经传递和全局N循环。O2对许多基本生物至关重要 功能，如生物能源，新陈代谢和氧化还原信号。HNO也发挥着重要作用 在血管舒张、酶活性调节和神经功能调节中。尽管 在这一领域取得了许多进展，但许多重要问题尚未得到回答。基础上 我们对NO、O2和HNO与金属蛋白的生物复合物的长期研究， 模型，特别是成功的初步数据，在目前的赠款期间，我们将提供 一些新的结果来解决三个重要的问题。我们的首要目标是确定一个- 通过刘易斯酸激活的血红素模型研究了NO-到-N2O的电子转化机理 这一过程不同于传统的细菌一氧化氮的双电子过程 还原酶提供一个完整的了解动力学和热力学因素， 这个新的反应，系统的计算研究将完成，以揭示完整的反应 途径的报告血红素模型，并探讨其他生物可利用的途径 金属、配体环境和刘易斯酸。我们的第二个目标是确定 血红素酶的NO/O2感应功能的机制。酶如何区分 两种重要的氧化还原试剂NO和O2，尽管它们在形状、大小和电荷上相似 仍然未知。我们的实验合作者最近逆转了NO传感血红素 蛋白质DoS通过三重突变体被O2传感。这项工作将揭示具体的 每个突变及其组合对几何和电子性质的贡献 蛋白质环境效应。结构和电子特征的确定的相关性 具有灵敏度功能的传感器将有助于合理的设计，以便在未来重新布线氧化还原传感功能 生物医学研究我们的第三个目标是确定HNO的形成机制， 临床药物羟基脲通过血红素蛋白。对反应进行了实验研究 用辣根过氧化物酶（HRP）和过氧化氢酶（CAT）对不同的反应性。然而，在这方面， HNO生成机理的细节和这种反应性差异的起源还有待于进一步研究。 阐明。这项工作将计算HRP和CAT的完整反应途径 使用具有不同大小的附近残基和完整蛋白质的活性位点模型来揭示基本的 活性位点残基和蛋白质环境对它们的差异的机制和作用 反应性这项系统性研究的结果也可能有助于确定关键的结构特征， 协助药物设计和了解相关HNO生成药物。

项目成果

HNO-Binding in Heme Proteins: Effects of Iron Oxidation State, Axial Ligand, and Protein Environment.

• DOI: 10.1002/anie.201608539
• 发表时间: 2016-11-21
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Khade, Rahul L.;Yang, Yuwei;Shi, Yelu;Zhang, Yong
• 通讯作者: Zhang, Yong

Inhibition of Aβ42 peptide aggregation by a binuclear ruthenium(II)-platinum(II) complex: Potential for multi-metal organometallics as anti-amyloid agents.

• DOI: 10.1021/cn100046m
• 发表时间: 2010-08-23
• 期刊: ACS CHEMICAL NEUROSCIENCE
• 影响因子: 5
• 作者: Kumar, Amit;Moody, LaMaryet;Olaivar, Jason F.;Lewis, Nerissa A.;Khade, Rahul L.;Holder, Alvin A.;Zhang, Yong;Rangachari, Vijayaraghavan
• 通讯作者: Rangachari, Vijayaraghavan

Insights into the binding of pyridines to the iron-sulfur enzyme IspH.

• DOI: 10.1021/ja501127j
• 发表时间: 2014-06-04
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Span, Ingrid;Wang, Ke;Eisenreich, Wolfgang;Bacher, Adelbert;Zhang, Yong;Oldfield, Eric;Groll, Michael
• 通讯作者: Groll, Michael

HNO binding in a heme protein: structures, spectroscopic properties, and stabilities.

• DOI: 10.1021/ja204072j
• 发表时间: 2011-09-07
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Yang, Liu;Ling, Yan;Zhang, Yong
• 通讯作者: Zhang, Yong

Catalytic Role of Conserved Asparagine, Glutamine, Serine, and Tyrosine Residues in Isoprenoid Biosynthesis Enzymes.

在类异丙生素生物合成酶中保守的天冬酰胺，谷氨酰胺，丝氨酸和酪氨酸残基的催化作用。

• DOI: 10.1021/acscatal.8b00543
• 发表时间: 2018-05-04
• 期刊: ACS catalysis
• 影响因子: 12.9
• 作者: Malwal SR;Gao J;Hu X;Yang Y;Liu W;Huang JW;Ko TP;Li L;Chen CC;O'Dowd B;Khade RL;Zhang Y;Zhang Y;Oldfield E;Guo RT
• 通讯作者: Guo RT