COLLABORATIVE CENTER FOR AN ENZYME FUNCTION INITIATIVE

酶功能倡议合作中心

• 批准号: 8665973
• 负责人: JOHN A GERLT
• 金额: $ 582.91万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-20 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8665973
• 关键词: Acids; Amidohydrolases; Bioinformatics; Biology; Communities; Computer Simulation; Data; Docking; Enzymatic Biochemistry; Enzymes; Genetic; Genome; Genomics; Glutathione S-Transferase; Goals; Guidelines; Health; Homology Modeling; Human; In Vitro; Intervention; Libraries; Ligands; Metabolic; Molecular; Physiological; Proteins; Protocols documentation; Reaction; Research Personnel; Role; Set protein; Structure; Substrate Specificity; Testing; Work; base; design; enolase; in vivo; isoprenoid; metabolomics; novel; novel therapeutic intervention; screening; small molecule; structural biology; tool

DESCRIPTION (provided by applicant): The Enzyme Function Initiative (EFI) will develop a robust sequence/structure-based strategy for facilitating discovery of in vitro enzymatic and in vivo metabolic/physiological functions of unknown enzymes discovered in genome projects, a crucial limitation in genomic biology. The EFI will accomplish this goal by integrating bioinformatics, structural biology, and computation with enzymology, genetics, and metabolomics. The EFI will establish five Scientific Cores for: 1) directing target selection as well as devising strategies for functional assignment based on sequence relationships and genome context; 2) expression and purification of targets; 3) experimental determination of structures of targets; 4) computational determination of structures of targets (homology modeling) and, also, in silico docking of ligand libraries to direct experimental assignment of in vitro functions by focused library screening; and 5) microbiological and metabolomic characterization of the in vivo roles of the in vitro assigned functions. The functional predictions will be tested by five Bridging Projects that focus on the functionally diverse amidohydrolase (AH), enolase (EN), glutathione transferase (GST), haloalkanoic acid dehalogenase (HAD), and isoprenoid synthase (IS) superfamilies. These superfamilies were selected because functional assignment cannot be accomplished by transfer of prior annotations based only on sequence or structural similarity: the reactions within each superfamily share conserved partial reactions but the identities of the substrates/products are not conserved. The EFI will disseminate to the scientific community the intellectual, computational, and experimental tools, protocols, materials, and guidelines for determining in vitro and in vivo functions of unknown enzymes. In achieving this goal, the EFI will nucleate and enable a larger consortium of investigators working toward the goal of realizing the biomedical potential of the vast amount of sequence data provided by genome projects.

描述（由申请人提供）：酶功能计划（EFI）将开发一种强大的基于序列/结构的策略，以促进基因组计划中发现的未知酶的体外酶促和体内代谢/生理功能的发现，这是基因组生物学的一个关键限制。 EFI 将通过将生物信息学、结构生物学和计算与酶学、遗传学和代谢组学相结合来实现这一目标。 EFI 将建立五个科学核心，用于：1）指导目标选择以及根据序列关系和基因组背景制定功能分配策略； 2) 靶标的表达和纯化； 3）靶标结构的实验测定； 4) 靶标结构的计算确定（同源建模），以及配体库的计算机对接，以通过重点库筛选指导体外功能的实验分配； 5) 体外指定功能的体内作用的微生物学和代谢组学表征。 功能预测将通过五个桥接项目进行测试，这些项目重点关注功能多样化的酰胺水解酶 (AH)、烯醇化酶 (EN)、谷胱甘肽转移酶 (GST)、卤代链烷酸脱卤酶 (HAD) 和类异戊二烯合酶 (IS) 超家族。选择这些超家族是因为功能分配不能通过仅基于序列或结构相似性的先前注释的转移来完成：每个超家族内的反应共享保守的部分反应，但底物/产物的身份不保守。 EFI 将向科学界传播用于确定未知酶的体外和体内功能的知识、计算和实验工具、方案、材料和指南。为了实现这一目标，EFI 将凝聚并支持更大的研究人员联盟，致力于实现基因组项目提供的大量序列数据的生物医学潜力。