The Bioinorgainic Chemistry and Nickel: The Ureases and NikR

描述（由申请人提供）：我们的长期目标是提高我们对金属蛋白结构，功能和抑制的理解。我们将使用的工具是那些理论，计算和药物化学。本项目的目标是在分子水平上了解镍的稳态、调控以及含镍金属蛋白的结构和功能。特别是，我们建议研究脲酶的催化机制，稳定性和抑制作用，并通过这种理解增强我们对酶催化，酶在极端环境中的稳定性和小分子疗法的发展的理解。尿素酶参与了广泛的疾病状态，对这个酶家族的结构和功能的深入了解将影响我们改变尿素酶行为的能力。镍离子进入细胞的调控是由镍依赖性转录因子NikR控制的，NikR抑制E.杆菌我们建议详细了解NikR的结构，功能和动力学，以便深入了解细胞中镍离子浓度是如何调节的。主要研究的酶是K. aerogenes，B. pasteurii和H. pylori中的转录因子NikR。杆菌在尿素酶的情况下，我们要解决的生物学问题是尿素酶如何催化尿素转化为氨和氨基甲酸酯，其速率至少是未催化反应的10 × 14倍，以及尿素酶如何从H.幽门螺杆菌使这种细菌能够在肠道的低pH条件下生存。在NikR的情况下，我们正在解决的生物学问题是如何调节细胞中有毒但必要的金属离子浓度。借助量子力学和分子动力学模拟等理论工具，我们将研究尿素的非催化分解和催化分解，H。pylori尿素酶的结构、功能和动力学。coli NikR.对这些过程的深入了解将通过对脲酶催化和抑制的理解以及对细胞内金属离子调节的进一步理解对人类健康产生重大影响。公共卫生相关性：通过对尿素酶和金属调节蛋白NikR的研究，我们将增加对如何控制H. Pylori和我们将增加我们对细胞中金属离子调节的理解，其功能障碍通过阿尔茨海默病和卢伽雷病等疾病对人类健康产生影响。

DESCRIPTION (provided by applicant): Our long-term goal is to enhance our understanding of metalloprotein structure, function and inhibition. The tools we will use are those of theoretical, computational and medicinal chemistry. The goal of this project is to understand, at the molecular-level, nickel homeostatis, regulation and the structure and function of nickel containing metalloproteins. In particular, we propose to study the catalytic mechanism, stability and inhibition of the ureases and through this understanding enhance our comprehension of enzyme catalysis, enzyme stability in extreme environments and the development of small-molecule therapeutics. The ureases are involved in a broad range of diseased states and a thorough understanding of the structure and function of this family of enzymes will impact our ability to modify the behavior of the ureases. The regulation of nickel ion import into a cell is governed by the nickel dependent transcription factor NikR, which represses the expression of the nickel membrane transporter nikABCDE in E. coli. We propose to develop a detailed understanding of the structure, function and dynamics of NikR, in order to gain insights into how nickel ion concentrations are regulated in cells. The primary enzymes that will be studied are the ureases from K. aerogenes, B. pasteurii and H. pylori and we will study the transcription factor NikR from E. coli. In the case of the ureases, the biological questions we are addressing is how do ureases catalyze the conversion of urea to ammonia and carbamate at a rate that is at least 10x14 times greater than the uncatalyzed reaction as well as how does the urease from H. pylori give this bacterium the ability to survive the low-pH conditions of the gut. In the case of NikR the biological question we are addressing is how toxic, yet necessary, metal ion concentrations are regulated in cells. With the aid of theoretical tools like quantum mechanics and molecular dynamics simulations we will study the uncatalyzed and the catalyzed decomposition of urea, the stability of H. pylori urease at low pH's and we will study the structure, function and dynamics of E. coli NikR. The insights obtained into these processes will have a major impact on human health through the understanding of urease catalysis and inhibition and via an enhanced understanding of the regulation of metal ions within cells. PUBLIC HEALTH RELEVANCE: Through the study of the enzyme urease and the metalloregulation protein NikR we will increase our understanding of how to control human ulcers formed by H. Pylori and we will increase our understanding of metal ion regulation in cells, whose dysfunction has an impact on human health through diseases like Alzheimer's and Lou Gehrig's disease.