Resolving the Problem of Orphan Enzyme Activities

解决孤儿酶活性问题

• 批准号: 7808849
• 负责人: Jennifer L DuBois
• 金额: $ 32.59万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2012-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7808849
• 关键词: Accounting; Algorithms; Amino Acid Sequence; Animal Model; Biochemical; Bioinformatics; Biological Assay; Biology; Biomedical Research; Computer Analysis; DNA Sequence; Data; Databases; Development; Drug Delivery Systems; Ensure; Enzymatic Biochemistry; Enzymes; Face; Feeding Methods; Future; Genes; Genome; Genomics; Goals; Guidelines; Individual; International; Isoelectric Point; Laboratories; Literature; Maps; Medicine; Metabolism; Methods; Molecular Weight; Morphologic artifacts; Organism; Orphan; Output; Peptide Sequence Determination; Pharmaceutical Preparations; Phase; Process; Protein Databases; Protocols documentation; Reaction; Reporting; Research; Research Personnel; Resolution; Resources; Solutions; Source; Speed; Staging; System; Techniques; Time; Universities; Work; base; cost; enzyme activity; gene function; genome sequencing; high throughput screening; improved; interest; international center; literature survey; microbial genome; pathogen; public health relevance; success

DESCRIPTION (provided by applicant): The value of a newly sequenced genome is directly dependent on our ability to assign function to the genes within that genome. This is especially true in an era in which pathogen genomes may be fully sequenced shortly after a pathogen is isolated, and in which sequencing capacity has already outstripped the ability of experimentalists to examine a large number of genes within each individual organism in the lab. Unfortunately, the ability to assign gene functions has not kept pace with sequencing output, and a significant fraction of the genes in many new genomes remain unassigned. Our group and others have also identified another problem related to the inability to assign gene functions, that of previously characterized enzyme activities that have no assigned sequence data. In fact, over a third of activities with assigned E.C. numbers have neither gene nor protein sequence information associated with them. These "orphan enzyme activities" represent a significant problem and opportunity in biomedical research. Most notably, as long as these activities remain "orphan" and devoid of sequence, they will never be predicted as functions for any genes in newly sequenced genomes. It is our hypothesis that there is likely to be significant overlap between these orphan activities and many of the genes that currently have no assigned function. As a consequence, it is critically important for modern, genome-driven biology to find sequences for orphan activities. We propose to develop a systematic approach for resolving the problem of orphan activities by identifying a gene sequence associated with each such activity. We will carry out an initial literature evaluate stage that will confirm the orphan status of each activity, a phase that we expect will yield 200-300 artifactual orphans, immediately adding a large body of activities associated with sequence to public databases. This will be followed by laboratory work that will identify 21 major orphan activities and help lay the groundwork for future large- and small-scale orphan identifications, with the eventual goal of enabling the identification of at least one gene for each activity. PUBLIC HEALTH RELEVANCE: This project will generate a list of orphan activities with a demonstrated lack of sequence, capture literature and other key data related to those orphans, resolve hundreds of artifactual orphan activities, identify sequences for 21 major orphan activities, and provide guidelines for other investigators to identify additional orphans. The resolution of 200-300 artifactual orphan activities and 21 genuine orphan activities will help reduce wasteful duplicated efforts in enzymology and will enhance the quality of all future genome annotations.

描述（由申请人提供）：新测序基因组的价值直接取决于我们为该基因组中的基因分配功能的能力。在一个病原体分离后不久就可以对病原体基因组进行完全测序的时代尤其如此，在这个时代，测序能力已经超过了实验人员在实验室中检查每个个体生物体内大量基因的能力。不幸的是，分配基因功能的能力并没有跟上测序成果的步伐，许多新基因组中的很大一部分基因仍未分配。我们的团队和其他人还发现了另一个与无法指定基因功能相关的问题，即先前表征的酶活性没有指定的序列数据。事实上，超过三分之一具有指定E.C.号码的活动既没有与之相关的基因也没有与之相关的蛋白质序列信息。这些“孤儿酶活性”代表了生物医学研究中的重大问题和机遇。最值得注意的是，只要这些活动仍然是“孤儿”，缺乏序列，它们就永远不会被预测为新测序基因组中任何基因的功能。我们的假设是，在这些孤儿活动和许多目前没有指定功能的基因之间可能存在显著的重叠。因此，对于现代基因组驱动的生物学来说，寻找孤儿活动的序列是至关重要的。我们建议开发一种系统的方法来解决孤儿活动的问题，通过识别与每个此类活动相关的基因序列。我们将进行初步的文献评估阶段，以确认每个活动的孤儿状态，我们预计在这个阶段将产生200-300个人工孤儿，并立即将与序列相关的大量活动添加到公共数据库中。随后将进行实验室工作，确定21个主要的孤儿活动，并帮助为今后大规模和小规模的孤儿活动确定奠定基础，最终目标是能够为每项活动确定至少一个基因。公共卫生相关性：该项目将生成缺乏序列的孤儿活动列表，获取与这些孤儿相关的文献和其他关键数据，解析数百个人工孤儿活动，确定21个主要孤儿活动的序列，并为其他研究者确定其他孤儿提供指导。200-300个人工孤儿活动和21个真正的孤儿活动的分辨率将有助于减少酶学上浪费的重复工作，并将提高所有未来基因组注释的质量。

项目成果

Finding sequences for over 270 orphan enzymes.

查找超过270个孤儿酶的序列。

• DOI: 10.1371/journal.pone.0097250
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Shearer AG;Altman T;Rhee CD
• 通讯作者: Rhee CD

Dynamic Gut Microbiome Changes in Response to Low-Iron Challenge.

• DOI: 10.1128/aem.02307-20
• 发表时间: 2021-01-15
• 期刊: Applied and environmental microbiology
• 影响因子: 4.4
• 作者: Coe GL;Pinkham NV;Celis AI;Johnson C;DuBois JL;Walk ST
• 通讯作者: Walk ST