Enzymes: Structure, Mechanism, Function and Inhibition

酶：结构、机制、功能和抑制

• 批准号: 7679047
• 负责人: DEBRA DUNAWAY-MARIANO
• 金额: $ 48.32万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7679047
• 关键词: Acyl Carrier Protein; Acyl Coenzyme A; Acyltransferase; Anabolism; Binding; Biochemical Process; Biochemistry; Biodiversity; Biological; Biological Process; Catalysis; Cell Cycle; Cell Survival; Cell division; Cell membrane; Cell physiology; Cells; Chemical Structure; Chemicals; Chimeric Proteins; Coenzyme A; Complex; Development; Energy Metabolism; Enterobactin; Enzymes; Escherichia coli; Fatty Acids; Future; Glycerol; Goals; Health; Human; Hydrolysis; In Vitro; Interdisciplinary Study; Knowledge; Link; Lipids; Location; Measures; Medicine; Operon; Oxidoreductase; Participant; Performance; Phosphatidylserine Synthase; Physiological; Play; Porphyromonas gingivalis; Prevention; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Research; Role; Site; Solutions; Specificity; Structure; Substrate Domain; System; Testing; Work; acyl group; analog; base; carboxylate; catalyst; chemical function; drug discovery; enzyme structure; falls; human disease; human thioesterase; in vivo; insight; novel; novel therapeutics; programs; protein function; public health relevance; response; thioester

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.

描述（由申请人提供）：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取决于酰基辅酶A硫酯及其辅酶A和脂肪酸成分。CoA、短链或长链羧酸盐和酰基-CoA硫酯（和脂质衍生产物）在指导细胞功能和反应中的复杂相互作用即使在最基本的水平上也没有得到很好的理解。该研究计划的重点是描绘细胞过程中，酰基辅酶A代谢物或酰基-S-蛋白质的转化发挥重要作用。这些转变的催化剂主要存在于热狗折叠超家族中。一个综合的方法，结合了不同的研究团队的努力，将被用来表征热狗硫酯酶在细胞，化学，机械和结构水平。总的目标是了解酶结构与底物识别和催化机制之间的关系。这些基础知识是开发新药和发现新的生物化学过程所必需的。了解体外化学功能（即，底物范围和催化效率）和实际的细胞化学功能（即，生理底物和体内催化效率）将提供对细胞内硫酯酶活性调节的需要和机制的了解。此外，有关结构与化学和细胞功能之间关系的知识应该揭示硫酯酶如何成功地执行其进化的生物学作用。公共卫生相关性：该项目采用了一种综合的方法，依赖于一个多学科的研究团队来定义热狗硫酯酶在细胞，化学，机械和结构水平。这一努力的结果将促进新的治疗药物的开发和新的生物化学过程的发现。