The Bioinorganic Chemistry of Nickel: The Ureases

这个项目的长期目标是在分子水平上了解催化机理、稳定性 和对尿素酶的抑制，并通过这种理解增强了我们对酶催化的理解， 酶在极端环境中的稳定性和小分子疗法的发展。尿素酶 涉及多种疾病状态，并对其结构和功能有深入的了解 这一家族的酶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。初级阶段 将要研究的酶是产气克雷伯菌、巴氏杆菌和幽门螺杆菌的尿素酶。最重要的是 我们正在解决的生物问题是尿素酶如何催化尿素转化为氨和 非催化反应以及幽门螺杆菌的尿素酶如何给出 这种细菌具有在肠道低pH条件下生存的能力.在理论工具的帮助下 尿素酶-底物相互作用、尿素酶-抑制剂相互作用和催化的反应的性质和能量学 将对尿素酶进行检查。此外，我们将研究非催化分解和水解 水溶液中的尿素，以便了解尿素酶的催化能力从何而来。更有甚者 通过分子动力学模拟，我们将更好地理解酶(特别是幽门螺杆菌尿素酶)是如何 能在低pH的肠道环境中存活。对这些过程的洞察将具有重大意义 通过了解尿素酶的催化和抑制作用对人体健康的影响。

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_4> 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 majo impact on human health through the understanding of urease catalysis and inhibition.