Structure-Function Relationships in the Tautomerase Superfamily

互变酶超家族的结构-功能关系

• 批准号: 10202646
• 负责人: CHRISTIAN P. WHITMAN
• 金额: $ 29万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202646
• 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.

在基因组项目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 在人类和其他生物体中使用基因组数据在治疗疾病中。它仍然非常 困难的问题，但是使用功能多样的超家族的概念取得了真正的进步。这 这里提出的工作使用集成的计算/实验策略来增强当前方法 用于机械多样性互变异酶超家族（TSF）中的功能分配。剥削 TSF的关键特征（例如，生化表征的易于性）使其成为一个良好的模型系统 对于拟议的目的是将这些方法应用于所有其他超家族的基础。这会 导致我们在大规模使用结构功能关系的能力上持续提高 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，在TSF酶和其他超家族中的关系。它将移动 序列相似性网络（SSN）技术在识别和利用链接器，采矿领域的领域前进 元基因组序列和基因组上下文网络。这些方法可以应用于所有方法 超家族。它将表征TSF的巨噬细胞迁移抑制因子（MIF）亚组 与最直接的医学相关性的子组。 MIF的系统发育分布是5个中最宽的 TSF中的子组。哺乳动物MIF是促炎细胞因子，但对这些功能知之甚少 在细菌，真菌和其他生物中。这项工作将以三个特定的目标完成。这些目标是 至：（1）研究主动位点序列和结构如何分散以生成新功能； （2）探索 结构和活性演变中的序列长度和低聚物大小； （3）检查基因组环境 和TSF中的生物学功能。结果还将解决我们的长期目标，以获得 对酶催化的结构与功能之间的关系更全面地理解 反应以及这些功能如何变化以创建新活动。结果将提高我们的理解 细菌和寄生虫的功能及其与哺乳动物的关系 与多种炎症性疾病有关，并洞悉酶活性的演变， 对微生物耐药性的发展具有影响。

项目成果

Symmetry of 4-Oxalocrotonate Tautomerase Trimers Influences Unfolding and Fragmentation in the Gas Phase.

• DOI: 10.1021/jacs.2c03564
• 发表时间: 2022-07-13
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Sipe, Sarah N.;Lancaster, Emily B.;Butalewicz, Jamie P.;Whitman, Christian P.;Brodbelt, Jennifer S.
• 通讯作者: Brodbelt, Jennifer S.

The Birth of Genomic Enzymology: Discovery of the Mechanistically Diverse Enolase Superfamily.

• DOI: 10.1021/acs.biochem.1c00494
• 发表时间: 2021-11-23
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Allen, Karen N.;Whitman, Christian P.
• 通讯作者: Whitman, Christian P.

Kinetic and Structural Analysis of Two Linkers in the Tautomerase Superfamily: Analysis and Implications.

• DOI: 10.1021/acs.biochem.1c00220
• 发表时间: 2021-06-08
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Baas BJ;Medellin BP;LeVieux JA;Erwin K;Lancaster EB;Johnson WH Jr;Kaoud TS;Moreno RY;de Ruijter M;Babbitt PC;Zhang YJ;Whitman CP
• 通讯作者: Whitman CP

Kinetic, Inhibition, and Structural Characterization of a Malonate Semialdehyde Decarboxylase-like Protein from Calothrix sp. PCC 6303: A Gateway to the non-Pro1 Tautomerase Superfamily Members.

• DOI: 10.1021/acs.biochem.2c00101
• 发表时间: 2022-05-13
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Lancaster, Emily B.;Yang, Wanjie;Johnson, William H., Jr.;Baas, Bert-Jan;Zhang, Yan Jessie;Whitman, Christian P.
• 通讯作者: Whitman, Christian P.

A mutagenic analysis of NahE, a hydratase-aldolase in the naphthalene degradative pathway.

NahE（萘降解途径中的一种水合酶-醛缩酶）的诱变分析。

• DOI: 10.1016/j.abb.2022.109471
• 发表时间: 2023
• 期刊: Archives of biochemistry and biophysics
• 影响因子: 3.9
• 作者: Lancaster,EmilyB;JohnsonJr,WilliamH;LeVieux,JakeA;Hardtke,HaleyA;Zhang,YanJessie;Whitman,ChristianP
• 通讯作者: Whitman,ChristianP