Enzymes: Structure, Mechanism, Function and Inhibition

描述(申请人提供)：细胞膜的结构和功能，以及能量代谢和细胞周期的许多方面，直接依赖于酰基-辅酶A硫酸酯及其辅酶A和脂肪酸成分。辅酶A、短链或长链羧酸盐和酰基辅酶A硫代酯(以及脂类衍生产物)之间在指导细胞功能和反应方面的复杂相互作用，即使在最基本的水平上也不是很清楚。这项研究计划专注于描述细胞过程，其中酰基-辅酶A代谢物或酰基-S-蛋白质的转化起着重要作用。这些转化的催化剂主要存在于热狗折叠超家族中。将使用一种综合的方法，结合不同研究团队的努力，在细胞、化学、机制和结构水平上表征热狗硫代酯酶。总体目标是了解酶结构与底物识别和催化机制之间存在的关系。这些基础知识是开发新药和发现新的生化过程所必需的。理解体外化学功能(即底物的范围和催化效率)和实际细胞化学功能(即生理底物和体内催化效率)之间的关系将有助于深入了解细胞内硫代酯酶活性调节的必要性和机制。此外，关于结构与化学和细胞功能之间的关系的知识应该揭示硫代酯酶如何成功地执行其进化的生物学角色。与公共健康相关：这个项目采用了一种综合的方法，依靠一个多学科的研究团队在细胞、化学、机械和结构水平上定义热狗硫代酯酶。这一努力的结果将有助于开发新的治疗药物和发现新的生化过程。

DESCRIPTION (provided by applicant): The structure and function of the cell membrane, as well as many aspects of energy metabolism and cell cycling, are directly dependent on acyl-CoA thioesters and their CoA and fatty acid constituents. The complex interplay between CoA, short or long chain carboxylates, and acyl-CoA thioesters (and lipid derived products) in directing the functions and responses of cells is not well understood even at the most elementary level. This research program focuses on the delineation of cellular processes in which transformations of acyl-CoA metabolites or acyl-S-proteins play important roles. The catalysts for these transformations reside mainly in the hotdog fold superfamily. An integrated approach that combines the efforts of a diverse research team will be used to characterize hotdog thioesterases at the cellular, chemical, mechanistic, and structural levels. The overall goal is to gain an understanding of the relationships that exist between enzyme structures and the mechanisms of substrate recognition and catalysis in vitro and in vivo. This fundamental knowledge is required for the development of new drugs and for the discovery of new biochemical processes. An understanding of the relationship between in vitro chemical function (i.e., range of substrates and catalytic efficiencies) and the actual cellular chemical function (i.e., physiological substrates and in vivo catalytic efficiencies) will provide insight into the need for and mechanism of regulation of thioesterase activity within the cell. In addition, knowledge about relationships between structure and chemical and cellular functions should reveal how thioesterases successfully execute their evolved biological roles. PUBLIC HEALTH RELEVANCE: This project employs an integrated approach that relies on a multidisciplinary research team to define the hotdog thioesterases at the cellular, chemical, mechanistic, and structural levels. The results of this effort will facilitate the development of new therapeutic drugs and the discovery of new biochemical processes.