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-无变化 微生物群落几乎栖息在地球上的所有环境中，包括人体，在那里它们可以 以各种方式影响健康。这些群落通常由数百种或更多的物种组成， 形成代谢相互作用的网络。因为代谢的相互作用是复杂的，很难研究 在分子水平上，我的研究项目集中在涉及一个代谢物家族的相互作用上， corrinoid辅因子-作为了解细菌之间代谢相互作用的模型。类可丽素是维生素 B12家族含钴代谢物，用作各种反应的酶辅因子。 像许多氨基酸、核碱基和其他辅因子一样，类皮质激素仅由一小部分合成。 使用它们的细菌，因此被认为是共享的代谢产物。Corrinoids是独一无二的， 结构多样性，发现了十几种不同的形式，其中多达八种形式被发现， 微生物群落样本，包括人类肠道。这种结构多样性是一个重要因素， 微生物的相互作用，因为大多数细菌在它们可以使用的类可丽素中是有选择性的。的假设 推动这项工作的是结构上不同的类可丽素可以用作操纵微生物的手柄 社区.我们以前的NIGMS资助的研究为拟议的研究奠定了基础， 建立实验方法;发现和鉴定新基因;研究corrinoid 酶，核糖开关和细菌的选择性;并创建生物信息学管道来预测corrinoid 细菌的新陈代谢。我们的长期愿景是在此基础上， 通过对各种规模的corrinoids的研究，从分子水平， 整个社会的动荡。我们将通过（1）识别基因组序列 在类咕啉依赖性酶和核糖开关中预测细菌类咕啉偏好的特征， 强调进化的方法和（2）调查的分子基础的corrinoid依赖 社区动态通过应用测序，文化依赖，和遗传方法，以一个模型人 肠源性富集培养物。作为对我们理解和预测类可丽素代谢能力的测试 和社区动态，我们将设计和建立细菌菌株与corrinoid依赖的代谢 网络以及具有可预测动态的细菌财团。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， 建立在我小组过去的研究基础上。我们对类可啉的研究不仅可以作为一个模型， 微生物群落在系统中的相互作用，但也可能导致新方法的开发 改变微生物群落以获得有益的结果。