MECHANISTIC STUDIES OF GLUTATHIONE METABOLIC ENZYMES

谷胱甘肽代谢酶的机理研究

• 批准号: 7956827
• 负责人: JOSEPH J BARYCKI
• 金额: $ 0.94万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956827
• 关键词: Anabolism; Apoenzymes; Binding; Biological Process; Cell physiology; Commit; Complement; Complex; Computer Retrieval of Information on Scientific Projects Database; Cysteine; Data; Data Set; Enzymes; Funding; Gamma-glutamyl transferase; Gene Expression Regulation; Generations; Glutamate-Cysteine Ligase; Glutamates; Glutathione; Glycine; Grant; Helicobacter pylori; Homeostasis; Housing; Inflammation; Institution; Investigation; Ligands; Maintenance; Metabolic; Modeling; Molecular; Nitrogen; Oxidation-Reduction; Oxygen; Proteins; Publications; Research; Research Personnel; Resolution; Resources; Source; Structure; System; United States National Institutes of Health; Yeasts; design; improved; inhibitor/antagonist; response; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Glutathione is a small tripeptide comprised of glutamate, cysteine, and glycine that is vital for normal cellular function. Glutathione is involved in numerous biological processes including the storage and transport of cysteine, as well as the biosynthesis of molecules involved in the inflammation response. However, its primary function appears to be in the maintenance of intracellular redox homeostasis by affording protection against reactive oxygen and nitrogen species. To attain a comprehensive understanding of glutathione homeostasis, further investigation of the glutathione metabolic enzymes at the protein level is required to complement ongoing studies of gene regulation. The proposed studies will focus on two enzymes: glutamate cysteine ligase (GCL) and γ-glutamyl transpeptidase (GGT), which catalyze the committed steps in glutathione biosynthesis and reclamation respectively. Previously, we have collected several data sets of H. pylori GGT (HpGT) in complex with various ligands. The current studies are focused on HpGT/inhibitor complexes. These structures will be used to aid in second generation inhibitor design. Recently, we determined the structure of yeast GCL by SAD using data collected on our in house system. We are requesting access to APS to collect high resolution data sets of the apoenzyme, various substrate complexes, and inhibitor bound structures. Each of these structures has been successfully solved by molecular replacement and the improved data that we will collect at the APS will aid in model refinement, analysis, and publication.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 谷氨酸是一种由谷氨酸、半胱氨酸和甘氨酸组成的小三肽，对正常细胞功能至关重要。 谷氨酰胺参与许多生物过程，包括半胱氨酸的储存和运输，以及参与炎症反应的分子的生物合成。 然而，它的主要功能似乎是在维持细胞内氧化还原稳态提供保护，防止活性氧和氮物种。 为了获得一个全面的了解谷胱甘肽稳态，需要在蛋白质水平上的谷胱甘肽代谢酶的进一步调查，以补充正在进行的基因调控研究。 拟议的研究将集中在两种酶：谷氨酸半胱氨酸连接酶（GCL）和谷氨酰转肽酶（GGT），催化谷胱甘肽的生物合成和回收的承诺步骤分别。 在此之前，我们已经收集了几组H。pylori GGT（HpGT）与各种配体复合。 目前的研究主要集中在HpGT/抑制剂复合物。这些结构将用于辅助第二代抑制剂设计。 最近，我们确定了酵母GCL的结构SAD使用我们在内部系统收集的数据。 我们正在请求访问APS收集高分辨率数据集的脱辅基酶，各种底物复合物，抑制剂结合结构。 这些结构中的每一个都已经通过分子置换成功地解决了，我们将在APS收集的改进数据将有助于模型的改进、分析和出版。