Vitamin B12 trafficking and selectivity in gut bacteria

维生素 B12 在肠道细菌中的运输和选择性

基本信息

项目摘要

Project Summary The human gut microbiome is inhabited by trillions of bacteria that encode over 150-fold more genes than the human genome itself. The inter-individual differences in microbial composition can be significant, and the factors contributing to this diversity are not well understood. Metagenomic studies suggest that the microbiome might play an important role in determining an individual’s predisposition to disease and responses to treatments. The paucity of understanding how cofactors and other factors influence microbial composition limit strategies to rationally alter it for therapeutic purposes. Much of our current understanding of the factors that shape the gut microbial flora composition derives form studies on how bacteria generate energy, maintain redox balance and acquire carbon and nitrogen. The enzymatic reactions that support these metabolic processes often rely on cofactors that are in short supply. Vitamin B12 is an example of one such cofactor that is essential for many bacteria that are unable to biosynthesize it and lack parallel B12-independent metabolic pathways to circumvent its absence. So, one approach to the targeted manipulation of the gut microbiome is via altering the levels of available corrinoids. In this proposal, I seek to elucidate the corrinoid selectivity of transport systems to provide needed insights into how gut bacteria compete with each other and their hosts for a critical resource in a complex ecosystem. My studies will focus on Bacteroidetes thetaiotaomicron, a common gut bacterium, which lacks the genes required for de novo synthesis of vitamin B12 but encodes multiple B12-dependent enzymes. 5’-Deoxyadenosylcobalamin is the active cofactor form that is utilized by some B12 dependent enzymes and is synthesized by BtuR in B. thetaiotaomicron. The chaperone and catalytic activities are uncharacterized and will be addressed in Aim 1. It also encodes three copies of the outer membrane B12-transporter BtuB with each system displaying a different preference for corrinoid derivatives. The bacterium also possesses additional transport machinery that is not observed in E. coli, a model organism in which studies on B12 transport in gram-negative bacteria have been focused. Using a combination of biochemical and biophysical approaches, I propose to elucidate the mechanism of B12 transport by the B12-uptake (Btu) system in Aim 2. The kinetic and thermodynamic studies in Aims 1 and 2 will define the selectivity of the Btu proteins for cobamides and provide insights into protein-protein interactions. Combined with the structures determined in Aims 1 and 2, my studies will furnish mechanistic insights into how a precious and rare cofactor is relayed from the environment across two layers of bacterial membranes to support the metabolic needs of a common gut bacterium.
项目概要 人类肠道微生物群中栖息着数万亿个细菌,这些细菌编码的基因比人类肠道微生物多 150 倍。 人类基因组本身。微生物组成的个体差异可能很大,并且 造成这种多样性的因素尚不清楚。宏基因组研究表明 微生物组可能在确定个体的疾病易感性和 对治疗的反应。缺乏对辅助因子和其他因素如何影响微生物的了解 成分限制策略以合理地改变它以达到治疗目的。我们目前的大部分理解 影响肠道微生物菌群组成的因素来源于对细菌如何产生的研究 能量,维持氧化还原平衡并获取碳和氮。支持的酶促反应 这些代谢过程通常依赖于供应不足的辅助因子。维生素 B12 是一个例子 一种这样的辅助因子,对于许多无法生物合成它并且缺乏平行的细菌来说是必需的 独立于 B12 的代谢途径可避免其缺失。因此,一种实现目标的方法 肠道微生物群的操纵是通过改变可用类咕啉的水平来实现的。在这个提案中,我寻求 阐明转运系统的类咕啉选择性,为肠道细菌如何作用提供所需的见解 在复杂的生态系统中,彼此及其宿主争夺关键资源。我的学业将 重点关注 Bacteroidetes thetaiotaomicron,一种常见的肠道细菌,它缺乏 de 所需的基因 维生素 B12 的新合成,但编码多种 B12 依赖性酶。 5’-脱氧腺苷钴胺素 是一些 B12 依赖性酶利用的活性辅因子形式,由 BtuR 合成 B.thetaiotamicron。伴侣和催化活性尚未表征,将在 目标 1. 每个系统还编码外膜 B12 转运蛋白 BtuB 的三个副本 对类咕啉衍生物表现出不同的偏好。该细菌还具有额外的 在大肠杆菌中未观察到的转运机制,大肠杆菌是一种模式生物,其中对 B12 转运的研究 革兰氏阴性菌受到关注。结合使用生物化学和生物物理 方法,我建议阐明 Aim 中 B12 吸收 (Btu) 系统的 B12 运输机制 2. 目标 1 和 2 中的动力学和热力学研究将定义 Btu 蛋白的选择性 考巴酰胺并提供对蛋白质-蛋白质相互作用的见解。结合确定的结构 在目标 1 和 2 中,我的研究将为珍贵而稀有的辅助因子如何传递提供机制见解 从环境中穿过两层细菌膜来支持细菌的代谢需求 常见的肠道细菌。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Romila Nina Mascarenhas其他文献

Romila Nina Mascarenhas的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Romila Nina Mascarenhas', 18)}}的其他基金

Vitamin B12 trafficking and selectivity in gut bacteria
维生素 B12 在肠道细菌中的运输和选择性
  • 批准号:
    10660958
  • 财政年份:
    2022
  • 资助金额:
    $ 10万
  • 项目类别:

相似海外基金

Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
  • 批准号:
    23H01982
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
  • 批准号:
    23KJ0116
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
  • 批准号:
    10598276
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
  • 批准号:
    10682794
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
  • 批准号:
    2233343
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
    Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
  • 批准号:
    2233342
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
    Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
  • 批准号:
    479363
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
    Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
  • 批准号:
    10681989
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
  • 批准号:
    2237240
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
    Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
  • 批准号:
    2305592
  • 财政年份:
    2023
  • 资助金额:
    $ 10万
  • 项目类别:
    Continuing Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了