The Bioinorganic Chemistry of Nickel: The Ureases

描述(申请人提供)：本项目的长期目标是在分子水平上了解尿素酶的催化机理、稳定性和抑制作用，并通过这些了解加强我们对酶催化、极端环境下的酶稳定性和小分子疗法的发展的理解。尿素酶涉及广泛的疾病状态，对这一家族酶的结构和功能的彻底了解将影响我们改变尿素酶行为的能力。 用于实现我们长期目标的工具是理论化学工具。将研究的主要酶是产气克雷伯菌、巴氏杆菌和幽门螺杆菌的尿素酶。我们正在解决的首要生物学问题是，尿素酶如何以10/14的速度催化尿素转化为氨和氨基甲酸酯；非催化反应以及来自幽门螺杆菌的尿素酶如何使这种细菌能够在肠道的低pH条件下生存。借助理论工具，我们将研究尿素酶-底物相互作用、尿素酶-抑制剂相互作用以及由尿素酶催化的反应的性质和能量学。此外，我们将研究尿素在水溶液中的非催化分解和水解，以了解尿素酶的催化能力来自哪里。此外，通过分子动力学模拟，我们将更好地了解酶(特别是幽门螺杆菌尿素酶)如何在肠道的低pH环境中生存。通过了解尿素酶的催化和抑制作用，对这些过程的深入了解将对人类健康产生重大影响。

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand, at the molecular-level, the catalytic mechanism, stability and inhibition of 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 tools that will be used to reach our long-term goals are those of theoretical chemistry. The primary enzymes that will be studied are the ureases from K. aerogenes, B. pasteurii and H. pylori. The overarching biological questions we are addressing is how do ureases catalyze the conversion of urea to ammonia and carbamate at a rate that is 10/14> 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. With the aid of theoretical tools the nature and energetics of urease-substrate interactions, urease-inhibitor interactions and reactions catalyzed by the ureases will be examined. Furthermore, we will examine the uncatalyzed decomposition and hydrolysis of urea in aqueous solution in order to understand where the ureases derive their catalytic power from. Moreover via MD simulations we will gain a better understanding of how enzymes (in particular the H. pylori urease can survive the low pH environment of the gut. The insights obtained into these processes will have a major impact on human health through the understanding of urease catalysis and inhibition.