LAYING THE FOUNDATION FOR GENOMIC ENZYMOLOGY

为基因组酶学奠定基础

• 批准号: 6636387
• 负责人: PATRICIA CLEMENT BABBITT
• 金额: $ 24.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6636387
• 关键词: Internet; chemical information system; classification; computer assisted sequence analysis; computer program /software; computer system design /evaluation; data collection methodology /evaluation; enzyme mechanism; enzyme model; enzyme structure; molecular biology information system; open reading frames; protein structure function

The goal of this research is to lay the foundations for what we call Genomic Enzymology, the extension of our understanding of enzyme chemistry to include the structural context. To accomplish this, we propose to investigate how nature re-engineers protein structures for new functions by studying enzyme superfamilies whose members have diverged to perform substantially different overall chemical reactions. We focus on enzymes because the relationships between protein structure and function can be more easily identified than in other classes of proteins. This is because the individual steps of the chemical reactions can be mapped explicitly to specific elements of their associated structures. To accomplish this goal, we propose 1) to cluster the known enzyme sequences into their respective superfamilies at divergence distances that are not currently available; 2) to examine the reactions of the enzymes in these superfamilies to distinguish the fundamental steps of their mechanisms that can be associated with the common elements of the superfamily architecture; 3) to use this information to generate a correlated structure/function "fingerprint" for each superfamily that can be used to infer important overall and sub-group properties of the member enzymes, and 4) to organize the results into an internet-accessible database that can be used and further developed by the scientific community. For enzyme superfamilies that we have previously investigated, this work has led to the correct prediction for unknown reading frames, identification of new functions for previously characterized enzymes and insight into the fundamental aspects of enzyme mechanism for proteins that had been only poorly characterized. As proposed in this work, we expect that a systematic investigation of the universe of enzyme superfamilies will provide a conceptual framework for prediction of enzyme function for the many unknown reading frames that have been generated by the genome projects. Our proposal for identification of sequence elements associated with specific sub-groups within an enzyme superfamily will be useful for refining the assignments of function generated by automated annotation of genomic data. Finally, by providing a better understanding into the functional opportunities and constraints nature has engineered into a particularly superfamily scaffold, we expect that this research will provide information useful for reengineering of proteins in the laboratory and for rational drug design.

这项研究的目的是为我们称为基因组酶学的基础，扩展我们对酶化学的理解，以包括结构背景。为了实现这一目标，我们建议通过研究成员已经差异以执行实质不同的整体化学反应的酶差异来研究自然重新设计新功能的蛋白质结构。我们专注于酶，因为与其他类别的蛋白质相比，蛋白质结构和功能之间的关系更容易鉴定。这是因为可以将化学反应的各个步骤明确映射到其相关结构的特定元素上。为了实现这一目标，我们建议1）将已知的酶序列聚集到当前尚不可用的差异距离的各自的超家族中； 2）检查酶在这些超家族中的反应，以区分其机制的基本步骤，这些步骤可能与超家族建筑的共同元素相关联； 3）使用此信息为每个超家族生成相关的结构/功能“指纹”，可用于推断成员酶的重要整体和子组属性，以及4）将结果组织到可访问的数据库中科学界可以使用并进一步发展。对于我们以前已经研究的酶超家族，这项工作导致了对未知读取框架的正确预测，鉴定了先前表征的酶的新功能以及对蛋白质机制的基本方面的洞察力，这些蛋白质的基本方面仅表征不佳。正如这项工作所提出的那样，我们期望对酶超家族宇宙进行系统研究，将为基因组项目生成的许多未知的阅读框架预测酶功能的概念框架。我们确定与酶超家族中特定子组相关的序列元素的建议将有助于完善通过基因组数据自动注释产生的功能分配。最后，通过更好地了解自然界的功能机会和限制，已设计为特别的超家族脚手架，我们希望这项研究将为重新设计实验室和理性药物设计的蛋白质提供有用的信息。