COLLABORATIVE CENTER FOR AN ENZYME FUNCTION INITIATIVE

酶功能倡议合作中心

• 批准号: 7901811
• 负责人: JOHN A GERLT
• 金额: $ 702.3万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901811
• 关键词: COLLABORATIVE; CENTER; ENZYME; FUNCTION; INITIATIVE

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)：酶功能倡议(EFI)将开发一种强大的基于序列/结构的策略，以促进发现基因组计划中发现的未知酶的体外酶功能和体内代谢/生理功能，这是基因组生物学中的一个关键限制。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：1)指导靶标选择以及根据序列关系和基因组背景设计功能分配策略；2)靶标的表达和纯化；3)靶标结构的实验确定；4)靶标结构的计算确定(同源建模)，以及通过重点文库筛选指导配基文库的电子对接，以指导体外功能的实验分配；以及5)体外分配功能的体内作用的微生物学和代谢组学表征。 这些功能预测将通过五个桥梁项目进行验证，这些项目侧重于功能多样化的氨基水解酶(AH)、烯醇化酶(EN)、谷胱甘肽转移酶(GST)、卤代烷酸脱卤酶(HAD)和类异戊二烯合成酶(IS)超家族。之所以选择这些超家族，是因为仅基于序列或结构相似性，不能通过转移先前的注释来完成功能分配：每个超家族内的反应共享保守的部分反应，但底物/产物的同一性不是保守的。 EFI将向科学界传播用于确定未知酶的体外和体内功能的智力、计算和实验工具、方案、材料和指南。为了实现这一目标，EFI将形成并使更大的研究人员联盟能够朝着实现基因组计划提供的大量序列数据的生物医学潜力的目标努力。