Structure-Function Relationships in the Tautomerase Superfamily

在基因组计划中发现的未知功能的蛋白质的注释是有效的关键目标 基因组数据在治疗人类和其他生物体疾病中的应用。它仍然是一个极端的 这是一个困难的问题，但使用功能多样化的超级家庭的概念已经取得了真正的进展。这个 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 用于机械多样化的互变消除酶超家族(TSF)的功能分配。开发利用 TSF的关键特征(如易于生化表征)使其成为一个很好的模型系统 因为提出的目标为将这些方法应用于所有其他超级家庭奠定了基础。这将是 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 函数预测。拟议的工作将解决关于结构-功能的基本问题 使用TSF作为模型系统的TSF酶和其他超家族中的关系。它会移动 序列相似性网络(SSN)技术在识别和利用连接子、挖掘 元基因组序列和基因组背景网络。这些方法可以应用于所有 超级家庭。它将表征TSF的巨噬细胞移动抑制因子(MIF)亚群，即 具有最直接医学关联的亚群。MIF的系统发育分布是5个中最广泛的 TSF中的子组。哺乳动物的MIF是促炎细胞因子，但人们对其功能知之甚少 在细菌、真菌和其他有机体中。这项工作将按三个具体目标完成。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的功能；(2)探索 序列长度和寡聚体大小在结构和活性进化中的作用；以及(3)检查基因组环境 以及TSF的生物学功能。结果也将解决我们的长期目标，即获得一个 更全面地理解酶催化的结构和功能之间的关系 反应，以及这些功能如何改变以创建新的活动。这一结果将增进我们的理解 细菌和寄生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，并提供了对酶活性演变的洞察，这些酶活性 对微生物中抗药性的发展具有重要意义。

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.