N-acetylglutamate Synthase: Structure, Function & Defects

N-乙酰谷氨酸合成酶：结构、功能

• 批准号: 7809804
• 负责人: Mendel Tuchman
• 金额: $ 55.88万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7809804
• 关键词: Acetyl Coenzyme A; Address; Affect; Amino Acid Substitution; Ammonia; Anabolism; Animal Model; Animals; Archives; Arginine; Bacteria; Be++ element; Behavior Therapy; Beryllium; Binding; Biochemical; Biochemistry; Biological; Biology; Birth; Brain; Breeding; CYP21A2 gene; Carbamyl Phosphate; Catalysis; Citrulline; Clinical; Clinical Trials; Communities; Country; Crystallization; DNA Footprint; Data; Defect; Development; Diagnosis; Discipline; Disease; ES Cell Line; Embryo; Engineering; Enzyme Inhibition; Enzymes; Escherichia coli; Evolution; Functional disorder; Funding; Gene Expression; Gene Proteins; Genes; Genetic Transcription; Genotype; Glutamates; Goals; Grant; Health; Hepatic; Homozygote; Hyperammonemia; Hypersensitivity; Inherited; Intestines; Investigation; Kidney; Knock-out; Knockout Mice; Knowledge; Letters; Ligands; Ligase; Liver; Liver diseases; Mammals; Messenger RNA; Metabolism; Methods; Mitochondrial Matrix; Modeling; Molecular; Mus; Mutation; N acetyl L glutamate; N-carbamylglutamate; Neisseria gonorrhoeae; Nitrogen; Occupations; Organ; Organism; Patients; Phenotype; Phosphotransferases; Phylogenetic Analysis; Physiological; Physiology; Plants; Play; Poison; Primer Extension; Production; Property; Proteins; Proteobacteria; Race; Recombinant Proteins; Recombinants; Recovery; Regulation; Reporting; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Site; Small Intestines; Structure; System; Tetraodontidae; Time; Tissues; Toxic effect; Transcription Initiation Site; Transcriptional Regulation; Transgenic Mice; Transgenic Model; United States National Institutes of Health; Urea; Vertebrates; Withdrawal; X-Ray Crystallography; Xanthomonas; Xanthomonas campestris; Xylella; Zebrafish; analog; arginylglutamate; base; chromatin immunoprecipitation; cofactor; fungus; hepatic ureagenesis; in vivo; knock out mouse project; mouse argA protein; mouse model; mutant; nitrogen balance; nitrogen metabolism; novel; parent grant; parent project; postnatal; prenatal; protein K; protein folding; protein profiling; protein structure; public health relevance; repository; research study; response; structural biology; three dimensional structure; tool; urea cycle

DESCRIPTION (provided by applicant): This is a Competitive Revision Application in response to the Recovery Act Funds Notice Number NOT-OD-09- 058. The parent project over goal is to explore the biology, biochemistry and pathophysiology of N- acetylglutamate synthase (NAGS) is an enzyme that produces the cognate cofactor N-acetylglutamate (NAG), an essential allosteric activator in ureagenesis. This revision application adds two new aims to the parent project. 1. To develop a knockout mouse for NAGS deficiency, characterize its phenotype, and explore its use as a conditional hyperammonemia model. 2. To "isolate" and study the in vivo regulation of ureagenesis specifically at the level of NAGS/CPSI by comparing nitrogen metabolism in N-carbamylglutamate (NCG) treated koNAGS mouse vs. wild type littermates. In addition to these new aims to be completed in two years, this project will enhance in the long term two of the existing aims that study the arginine effects on NAGS function and the effect of naturally-occurring mutations in patients with NAGS deficiency. In this revised project, we will develop, study and make available to the research community a novel "titratable mouse model of hyperammonemia. This knockout NAGS mouse will be rescued with NCG and will develop hyperammonemia upon withdrawal of this cofactor analog. We will determine the in vivo differences between nitrogen balance and metabolism in the NAGS "regulation-deprived" koNAGS mice rescued with NCG vs. the naturally-regulated wild type littermates on and off NCG. These studies will use both gene expression and protein profiles methods and will allow for the first time to "isolate" in vivo the regulatory effects of NAGS on ureagenesis. This project will enhance the pace and quality of the parent grant by providing a new tool for in vivo investigations for our group and other investigators studying hyperammonemia. In addition, The contribution of this project to the economy is leveraged by making the koNGAS mouse model available to othr investigators across the country, enhancing their research and promoting new job creation. PUBLIC HEALTH RELEVANCE: This project is dedicated to the investigation of an important gene and protein (NAGS) that determined how much nitrogen we eliminate from our bodies. It is important to know this since one of the main problem in liver disease is the inability to eliminate toxic nitrogen (ammonia) which can poison the brain. We will study an engineered mouse that does not posses NAGS to allow us to better understand this system and how it is regulated. The results from this project could allow the development of new treatments for elevated ammonia levels to protect the brain from its toxic effects.

描述（由申请人提供）：这是响应《恢复法》的竞争修订申请，NOT-OD-09-058。父母项目的目标是探索N-乙酰基谷氨酸的生物学，生物化学和病理生理学的生物学，生物化学和病理生理学尿素发生中的激活剂。此修订应用程序为父项目添加了两个新目标。 1。为了开发一种nag鼻缺乏症的敲除小鼠，表征其表型，并探索其用作条件性高症模型。 2。“分离”并研究NAGS/CPSI水平的体内调节，通过比较N-核甲基谷氨酸（NCG）处理过的Konags小鼠小鼠与野生型同意识的NAGS/CPSI水平。除了两年内完成的这些新目标外，该项目还将在长期的两个目的中增强，以研究精氨酸对NAG功能的影响以及自然存在突变对NAGS缺乏症患者的影响。在这个修订后的项目中，我们将开发，研究并向研究社区提供一种新颖的“可滴定的鼠标高度血症鼠标模型。这种敲除nags鼠标将被NCG救出，并将在撤回该辅助因子类似物后发展高氨血症。我们将确定Nitrogen平衡与Nags nags regument od-deprive ncipers od-deprive ncrive nc deprive ncrive nc deprive nc deprive ncrive nc deprive'age'age''agnage''的差异，自然受调节的窝点的窝点将使用基因表达和蛋白质曲线，并首次在体内“隔离”该项目的调节作用。通过使全国各地的OTHR调查人员可用的Kongas Mouse模型可以利用，从而增强了他们的研究并促进了新的工作创造。 公共卫生相关性：该项目致力于研究重要的基因和蛋白质（NAG），该基因和蛋白质（NAGS）确定了我们从身体中消除了多少氮。重要的是要知道这一点很重要，因为肝病的主要问题之一是无法消除可能毒害大脑的有毒氮（氨）。我们将研究一种工程的鼠标，该鼠标不具有na，以使我们能够更好地理解该系统及其如何调节。该项目的结果可以允许开发升高氨水的新疗法，以保护大脑免受其毒性作用的影响。