STRUCTURAL STUDIES OF METABOLIC ENZYMES

代谢酶的结构研究

• 批准号: 7955549
• 负责人: STEVEN E EALICK
• 金额: $ 1.34万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955549
• 关键词: 3-dehydroquinate; Active Sites; Anabolism; Antiviral Agents; Archaea; Area; Aromatic Amino Acids; Binding; Blood; Cattle; Computer Retrieval of Information on Scientific Projects Database; DNA; Drug Design; Enzymes; Evolution; Fluorouracil; Funding; Genes; Grant; Human; Individual; Inosine; Institution; Interest Group; Laboratory Study; Metabolic; Organism; Paper; Pathway interactions; Proteins; Publishing; Purine Nucleotides; Purines; Pyrimidine; Pyrimidines; RNA; Reporting; Research; Research Personnel; Resolution; Resources; Source; Structure; Toxic effect; United States National Institutes of Health; Uracil; Uridine; Uridine Phosphorylase; aminoacid biosynthesis; antimicrobial drug; catalyst; chemotherapeutic agent; design; drug discovery; inhibitor/antagonist; interest; metabolic abnormality assessment; protective effect; protein function; protein protein interaction; purine; ribose 1-phosphate; small molecule

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. Our laboratory studies the structures and functions of metabolic enzymes. We are interested in the catalytic mechanisms of individual enzymes, protein:protein interactions between enzymes within a pathway, evolution of protein function, and drug design. PurP is an enzyme in the basic pathway for the biosynthesis of inosine 5`-monophosphate (IMP). Purine nucleotides are the building blocks of RNA and DNA and enzymes of the purine biosynthetic pathway are targets for anticancer, antiviral and antimicrobial drug discovery. The crystals diffract to reasonably high resolution and soaks will help better characterize the active site and provide missing structural information. In Archaea, genes responsible for the first two steps of the aromatic amino acid biosynthesis leading to 3-dehydroquinate (DHQ) are missing. Recently, two protein products from Methanocaldococcus jannaschii, Mj0400 and Mj1249, have been reported as the nonorthologous catalysts of the DHQ formation. The crystal structures of Mj400 will further assist the identification of the substrates, and the elucidation of their catalytic mechanisms. Crystals have been soaked in effort to bind small molecules at the active site to help provide this information. Uridine Phosphorylase (UP) is a key enzyme in the pyrimidine salvage pathway. It catalyses the reversible phosphorolysis of uridine to uracil and ribose-1-phosphate. The inhibition of UP in human increases blood uridine levels and produces a protective effect against the toxicity of the chemotherapeutic agent 5-fluorouracil without reducing its antitumor activity. Present studies are focused on structural characterization and mechanistic understanding of bovine uridine phosphorylase and the design of new inhibitors. New soaks will help characterize the active site. The lab has published seven papers on enzymes in the purine biosynthetic pathway and two papers on uridine phosphosphorylase from other organisms. Aromatic amino acid biosynthesis is a new area of interest for the group.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们的实验室研究代谢酶的结构和功能。我们感兴趣的是单个酶的催化机制，蛋白质：途径中酶之间的蛋白质相互作用，蛋白质功能的进化，以及药物设计。 PURP是肌苷5‘-单磷酸(IMP)生物合成基本途径中的一种酶。嘌呤核苷酸是RNA和DNA的基础，嘌呤生物合成途径的酶是抗癌、抗病毒和抗微生物药物发现的靶标。晶体衍射到相当高的分辨率，浸泡将有助于更好地表征活性中心，并提供缺失的结构信息。 在古生代，负责芳香氨基酸生物合成的前两步导致3-脱氢奎尼酸(DHQ)的基因缺失。最近，简氏甲烷球菌的两种蛋白产物Mj0400和Mj1249被报道为DHQ形成的非同源催化剂。Mj400的晶体结构将进一步有助于底物的鉴定和催化机理的阐明。晶体已经被浸泡，以努力结合活性部位的小分子，以帮助提供这一信息。 尿苷磷酸化酶(UP)是嘧啶抢救途径中的关键酶。它催化尿苷的可逆磷酸化为尿嘧啶和核糖-1-磷酸。在人体内抑制UP会增加血尿苷水平，并在不降低5-FU抗肿瘤活性的情况下对化疗药物5-FU的毒性产生保护作用。目前的研究主要集中在牛尿苷磷酸化酶的结构表征和机理的理解，以及新型抑制剂的设计。新的浸泡将有助于确定活性部位的特征。 该实验室已经发表了七篇关于嘌呤生物合成途径中的酶的论文，以及两篇关于其他生物的尿苷磷酸化酶的论文。芳香氨基酸的生物合成是该小组感兴趣的一个新领域。