Novel Biochemical Pathways for the Metabolism of Carbohydrates in the Human gut Micriobiome

人类肠道微生物组中碳水化合物代谢的新生化途径

基本信息

批准号：
10063528
负责人：
Frank M. Raushel
金额：
$ 30.97万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063528
关键词：
3-Dimensional Amino Acid Sequence Bacteria Bacterial Genome Benchmarking Biochemical Biochemical Pathway Bioinformatics Campylobacter jejuni Candidate Disease Gene Carbohydrate Metabolism Pathway Carbohydrates Cells Complex Computational Biology DNA Library DNA sequencing Development Enzymatic Biochemistry Enzymes Escherichia coli Evolution Gene Cluster Genes Genome Health Homologous Gene Human Human body In Vitro Intestines Investigation Libraries Maintenance Metabolic Metabolic Pathway Metabolism Methods Molecular Pathway interactions Physiology Property Proteins Protocols documentation Reaction Research Research Project Grants Research Proposals Resolution Salmonella enterica Structure Substrate Specificity Therapeutic Intervention Uncertainty base carbohydrate biosynthesis carbohydrate metabolism commensal bacteria gut microbiome human reference genome in vivo insight knockout gene metabolomics novel novel strategies pathogenic bacteria protein structure screening structural biology targeted treatment

项目摘要

The primary focus of this research proposal will be the identification, discovery, and elucidation of novel biochemical pathways for the metabolism of complex carbohydrates in the human gut microbiome. Currently, more than one thousand different bacterial species have been identified in the human intestinal tract and the total number of genes contained within these bacteria exceeds the number of human genes by more than two orders of magnitude. Moreover, it has been demonstrated that the composition of the human gut microbiome and the associated metabolic diversity contained within these bacteria contribute significantly to the maintenance of human health and physiology. Unfortunately, a significant fraction of the enzymes and corresponding metabolic pathways contained within the bacteria found in the human gut have an uncertain, unknown, or incorrect functional annotation. This uncertainty suggests that a substantial fraction of the metabolic potential contained within the human gut microbiome remains to be properly characterized. Our proposed experimental approach for the discovery and elucidation of novel metabolic pathways for the metabolism of complex carbohydrates will involve the concerted and synergistic utilization of bioinformatics, computational biology, three-dimensional protein structure determination, metabolomics and physical screening of focused compound libraries. The determination of the substrate and reaction diversity contained within the newly discovered enzyme-catalyzed reactions will provide unique insights into the molecular mechanisms for the evolution and development of novel enzymatic activities and will provide potential targets for therapeutic intervention.

本研究计划的主要重点是识别、发现和阐明人体复杂碳水化合物代谢的新生化途径肠道微生物组。目前，已鉴定出1000多种不同的细菌种类。人类肠道和这些细菌中包含的基因总数超过了人类基因的数量增加了两个数量级以上。此外，已经证明人类肠道微生物组的组成和相关的代谢多样性包含这些细菌对维持人类健康和生理机能做出了重大贡献。不幸的是，很大一部分酶和相应的代谢途径包含人类肠道中发现的细菌具有不确定、未知或不正确的功能注解。这种不确定性表明代谢潜力的很大一部分包含人类肠道微生物组内的微生物仍有待正确表征。我们提出的实验发现和阐明新代谢途径的方法复杂碳水化合物将涉及生物信息学的协调和协同利用，计算生物学、三维蛋白质结构测定、代谢组学和重点化合物库的物理筛选。底物和反应的测定新发现的酶催化反应中包含的多样性将提供独特的深入了解新型酶的进化和发展的分子机制活动并将为治疗干预提供潜在目标。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structural and Functional Characterization of YdjI, an Aldolase of Unknown Specificity in Escherichia coli K12.

YdjI（大肠杆菌 K12 中特异性未知的醛缩酶）的结构和功能表征。

DOI：
发表时间：
2019
期刊：
影响因子：
2.9
作者：
Huddleston, Jamison P;Thoden, James B;Dopkins, Brandon J;Narindoshvili, Tamari;Fose, Blair J;Holden, Hazel M;Raushel, Frank M
通讯作者：
Raushel, Frank M

Discovery of a Kojibiose Phosphorylase in Escherichia coli K-12.

在大肠杆菌 K-12 中发现曲二糖磷酸化酶。

DOI：
10.1021/acs.biochem.8b00392
发表时间：
2018-05-15
期刊：
Biochemistry
影响因子：
2.9
作者：
Mukherjee K;Narindoshvili T;Raushel FM
通讯作者：
Raushel FM

Biosynthesis of GDP-d-glycero-α-d-manno-heptose for the Capsular Polysaccharide of Campylobacter jejuni.

空肠弯曲杆菌荚膜多糖的 GDP-d-甘油-α-d-甘露庚糖的生物合成。

DOI：
发表时间：
2019
期刊：
影响因子：
2.9
作者：
Huddleston, Jamison P;Raushel, Frank M
通讯作者：
Raushel, Frank M

Structural Analysis of Cj1427, an Essential NAD-Dependent Dehydrogenase for the Biosynthesis of the Heptose Residues in the Capsular Polysaccharides of Campylobacter jejuni.

Cj1427 的结构分析，Cj1427 是空肠弯曲杆菌荚膜多糖中庚糖残基生物合成所必需的 NAD 依赖性脱氢酶。

DOI：
发表时间：
2020
期刊：
影响因子：
2.9
作者：
Huddleston, Jamison P;Anderson, Thomas K;Spencer, Keelan D;Thoden, James B;Raushel, Frank M;Holden, Hazel M
通讯作者：
Holden, Hazel M

Bifunctional Epimerase/Reductase Enzymes Facilitate the Modulation of 6-Deoxy-Heptoses Found in the Capsular Polysaccharides of Campylobacter jejuni.

双功能差向异构酶/还原酶促进空肠弯曲杆菌荚膜多糖中发现的 6-脱氧庚糖的调节。