STRUCTURAL STUDIES OF METABOLIC ENZYMES

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。 本实验室主要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：蛋白质之间的相互作用，蛋白质功能的进化和药物设计。 PurP是生物合成肌苷5 '-单磷酸（IMP）的基本途径中的酶。嘌呤核苷酸是RNA和DNA的结构单元，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。晶体的分辨率相当高，浸泡将有助于更好地表征活性位点，并提供缺失的结构信息。 在拟南芥中，负责芳香族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，来自詹氏甲烷球菌的两种蛋白质产物Mj 0400和Mj 1249已被报道为DHQ形成的非邻苯二甲酸催化剂。 Mj 400的晶体结构将进一步帮助识别底物，并阐明其催化机制。晶体已经被浸泡在努力结合小分子在活性位点，以帮助提供这一信息。 尿苷磷酸化酶（UP）是嘧啶补救途径中的关键酶。催化尿苷可逆磷酸解为尿嘧啶和1-磷酸核糖。UP在人体中的抑制增加血液尿苷水平，并产生针对化疗剂5-氟尿嘧啶的毒性的保护作用，而不降低其抗肿瘤活性。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和新的抑制剂的设计。新的浸泡将有助于表征活性部位。 该实验室已经发表了7篇关于嘌呤生物合成途径中的酶的论文和2篇关于其他生物尿苷磷酸化酶的论文。芳香族氨基酸的生物合成是该小组感兴趣的一个新领域。

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.