Bacterial Corrinoid Metabolism Across Scales: From Molecular Specificity to Community Dynamics

细菌跨尺度的类咕啉代谢：从分子特异性到群落动态

• 批准号: 10684534
• 负责人: Michiko E. Taga
• 金额: $ 8.35万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684534
• 关键词: Address; Amino Acids; Automobile Driving; Bacteria; Biochemical Pathway; Biochemistry; Bioinformatics; Cobalt; Coenzymes; Communities; Complex; Corrinoids; Development; Environment; Enzymes; Family; Foundations; Funding; Genes; Genetic; Genome; Goals; Health; Human; Human body; Metabolic; Metabolism; Methods; Microbiology; Modeling; Molecular; National Institute of General Medical Sciences; Outcome; Planet Earth; Reaction; Research; Sampling; Specificity; Structure; System; Testing; Vitamin B 12; Work; bioinformatics pipeline; cofactor; design; genetic approach; human model; microbial community; microorganism interaction; nucleobase; predictive signature; preference; programs

Project Summary/Abstract -- No Change Microbial communities inhabit nearly all environments on earth, including the human body, where they can influence health in myriad ways. These communities are often composed of hundreds or more species that form networks of metabolic interactions. Because metabolic interactions are complex and difficult to study at a molecular level, my research program focuses on interactions involving one family of metabolites – corrinoid cofactors – as a model to understand metabolic interactions among bacteria. Corrinoids are the vitamin B12 family of cobalt-containing metabolites that are used as enzyme cofactors for a variety of reactions. Corrinoids, like many amino acids, nucleobases, and other cofactors, are synthesized by only a fraction of bacteria that use them, and therefore are considered to be shared metabolites. Corrinoids are unique in their structural diversity, with over a dozen different forms discovered and up to eight of these forms found in microbial community samples, including the human gut. This structural diversity is a significant factor in microbial interactions because most bacteria are selective in the corrinoids they can use. The hypothesis driving this work is that structurally distinct corrinoids can be used as handles to manipulate microbial communities. Our previous NIGMS-funded research has laid the groundwork for the proposed research by establishing experimental methods; discovering and characterizing new genes; investigating corrinoid selectivity in enzymes, riboswitches, and bacteria; and creating a bioinformatic pipeline to predict corrinoid metabolism in bacteria. Our long-term vision is to build on this foundation to generate a newly detailed understanding of microbial community interactions through the study of corrinoids across scales, from molecular mechanisms to whole community perturbations. We will achieve this goal by (1) identifying genome sequence signatures predictive of bacterial corrinoid preferences in corrinoid-dependent enzymes and riboswitches, with an emphasis on evolutionary approaches and (2) investigating the molecular basis of corrinoid-dependent community dynamics by applying sequencing, culture-dependent, and genetic approaches to a model human gut-derived enrichment culture. As a test of our ability to understand and predict corrinoid-based metabolism and community dynamics, we will design and build bacterial strains with corrinoid-dependent metabolic networks, as well as consortia of bacteria with predictable dynamics. This research will be accomplished by using a combination of genetics, biochemistry, microbiology, and bioinformatics, building upon the past research of my group. Our work on corrinoids will not only serve as a model for microbial community interactions across systems, but may also lead to the development of new methods to alter microbial communities for beneficial outcomes.

项目摘要/摘要 - 没有更改 微生物群落继承了地球上几乎所有环境，包括人体 以多种方式影响健康。这些社区通常由数百个或更多的物种组成 形成代谢相互作用的网络。因为代谢相互作用很复杂且难以研究 在分子层面，我的研究计划着重于涉及一个代谢产物家族的相互作用 - Corrinoid Cofactors - 一种了解细菌之间代谢相互作用的模型。类cor依者是维生素 B12含钴的代谢产物家族，用作各种反应的酶辅因子。 像许多氨基酸，核苷酸酶和其他辅助因子一样 使用它们的细菌，因此被认为是共享代谢物。类corrinoids是独一无二的 结构多样性，发现了十几种不同的形式，最多八种形式发现 微生物社区样本，包括人类肠道。这种结构多样性是一个重要因素 微生物相互作用是因为大多数细菌在它们可以使用的类似石中都是选择性的。假设 推动这项工作的是，结构上不同的类似石可以用作操纵微生物的手柄 社区。我们以前由诺格姆斯资助的研究为拟议研究的基础奠定了基础 建立实验方法；发现和表征新基因；研究类corinoid 酶，核糖开关和细菌的选择性；并创建生物信息学的管道来预测类corinoid 细菌中的代谢。我们的长期愿景是建立在这个基础的基础上，以产生新的详细信息 通过研究跨尺度的类似类型，了解微生物群落的相互作用。 整个社区扰动的机制。我们将通过（1）识别基因组序列来实现这一目标 符号可预测类细菌依赖性酶和核糖开关中的细菌类似型偏好， 重点是进化方法，（2）研究了corrinoid依赖性的分子基础 通过将测序，依赖文化和遗传方法应用于人类的社区动态 肠道衍生的丰富文化。作为我们理解和预测基于影响代谢的能力的测试 和社区动态，我们将设计和建立与抗corrinoid代谢的细菌菌株 网络以及具有可预测动力学的细菌财团。这项研究将是 通过使用遗传学，生物化学，微生物学和生物信息学的组合来完成 基于我小组的过去研究。我们在类cor上的工作不仅将作为模型 微生物社区跨系统的互动，但也可能导致新方法的发展 改变微生物群落的有益结果。