Structure-Function Relationships in the Tautomerase Superfamily

互变酶超家族的结构-功能关系

• 批准号: 9767833
• 负责人: CHRISTIAN P. WHITMAN
• 金额: $ 30.92万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767833
• 关键词: Active Sites; Address; Amino Acids; Area; Autoimmune Diseases; Bacteria; Biochemical; Biological; Biological Models; Biological Process; Carboxy-Lyases; Disease; Drug resistance; Enzymes; Evolution; Family; Genome; Genomics; Goals; Health; Human; Infection; Inflammatory; Length; Malignant Neoplasms; Malonates; Medical; Metagenomics; Methodology; Methods; Migration Inhibitory Factor; Mining; Organism; Phylogenetic Analysis; Proline; Property; Proteins; Reaction; Research; Sepsis; Structure; Structure-Activity Relationship; Subgroup; Technology; Work; cis-3-chloroacrylic acid dehalogenase; cytokine; drug development; drug resistant microorganism; enzyme activity; fungus; genomic data; human migration; insight; member; microorganism; oxalocrotonate

The annotation of proteins with unknown functions discovered in genome projects is a key goal for the effective use of genomic data in the treatment of disease in humans and in other organisms. It remains an extremely difficult problem, but real progress has been made using the concept of functionally diverse superfamilies. The work proposed here uses an integrated computational/experimental strategy to enhance current approaches for the assignment of function in the mechanistically diverse tautomerase superfamily (TSF). Exploitation of key features of the TSF (such as the ease of biochemical characterization) that make it a good model system for the proposed aims lays the groundwork for application of these methods to all other superfamilies. This will lead to a sustained improvement in our ability to use structure-function relationships on a large scale to inform function prediction. The proposed work will address fundamental questions about structure-function relationships in TSF enzymes and in other superfamilies using the TSF as a model system. It will move sequence similarity network (SSN) technology forward in the areas of identifying and exploiting linkers, mining metagenomic sequences, and genome context networks. These methodologies can be applied to all superfamilies. It will characterize the macrophage migration inhibitory factor (MIF) subgroup of the TSF, the subgroup with the most direct medical relevance. The phylogenetic distribution of MIF is the broadest of the 5 subgroups in the TSF. Mammalian MIFs are proinflammatory cytokines, but little is known about the functions in bacteria, fungi, and other organisms. The work will be accomplished in three specific aims. These aims are to: (1) investigate how active site sequences and structures diverge to generate new functions; (2) explore sequence length and oligomer size in the evolution of structure and activity; and (3) examine genomic context and biological function in the TSF. The results will also address our long-term goals, which are to obtain a more comprehensive understanding of the relationship between structure and function in enzyme-catalyzed reactions, and how these features change to create new activities. The results will advance our understanding of the functions of bacterial and parasitic MIFs and their relationships to the mammalian ones, which are implicated in multiple inflammatory disorders, and provide insight into the evolution of enzyme activities, which has implications for the development of drug resistance in microorganisms.

在基因组计划中发现的具有未知功能的蛋白质的注释是有效的关键目标 使用基因组数据治疗人类和其他生物体的疾病。它仍然是一个极其 这是一个难题，但利用功能多样化超家族的概念已经取得了真正的进展。这 这里提出的工作使用集成的计算/实验策略来增强当前的方法 用于机械多样性互变异构酶超家族 (TSF) 中的功能分配。剥削 TSF 的关键特征（例如易于生化表征）使其成为一个良好的模型系统 拟议的目标为将这些方法应用于所有其他总科奠定了基础。这将 导致我们大规模使用结构-功能关系来提供信息的能力持续提高 功能预测。拟议的工作将解决有关结构功能的基本问题 使用 TSF 作为模型系统，研究 TSF 酶和其他超家族中的关系。它会移动 序列相似性网络（SSN）技术在识别和利用链接器、挖掘等领域取得进展 宏基因组序列和基因组背景网络。这些方法可以应用于所有 超家族。它将表征 TSF 的巨噬细胞迁移抑制因子 (MIF) 亚组， 具有最直接医学相关性的亚组。 MIF 的系统发育分布是 5 种中最广泛的 TSF 中的子组。哺乳动物 MIF 是促炎细胞因子，但对其功能知之甚少 存在于细菌、真菌和其他生物体中。这项工作将实现三个具体目标。这些目标是 目的：（1）研究活性位点序列和结构如何分化以产生新功能； (2)探索 结构和活性演化中的序列长度和寡聚体大小； (3) 检查基因组背景 和 TSF 中的生物学功能。结果还将解决我们的长期目标，即获得 更全面地了解酶催化结构与功能的关系 反应，以及这些特征如何变化以创建新的活动。结果将增进我们的理解 细菌和寄生虫 MIF 的功能及其与哺乳动物 MIF 的关系， 与多种炎症性疾病有关，并提供对酶活性演变的深入了解， 对微生物耐药性的发展具有影响。