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: 10348118
• 负责人: Michiko E. Taga
• 金额: $ 39.06万
• 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/10348118
• 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; Lead; Metabolic; Metabolism; Methods; Microbiology; Modeling; Molecular; National Institute of General Medical Sciences; Outcome; Planet Earth; Reaction; Research; Sampling; Specificity; Structure; System; Testing; Vision; Vitamin B 12; Work; base; bioinformatics pipeline; cofactor; design; genetic approach; human model; microbial community; microorganism interaction; molecular scale; nucleobase; predictive signature; preference; programs

Project Summary/Abstract 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.

项目总结/摘要 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个或更多的物种组成， 代谢相互作用的网络。由于代谢相互作用很复杂，很难进行全面研究， 在分子水平上，我的研究项目集中在涉及一个代谢产物家族的相互作用- corrinoid 辅助因子-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。类皮质激素 许多氨基酸，核碱基和其他辅因子，仅由一小部分细菌合成， 它们，因此被认为是共享代谢物。类咕啉在其结构多样性方面是独特的， 发现了十几种不同的形式，其中多达八种在微生物群落中发现 包括人类的内脏。这种结构多样性是微生物相互作用的重要因素， 大多数细菌对它们可以使用的类可丽素具有选择性。推动这项工作的假设是， 不同的类咕啉可用作操纵微生物群落的柄。我们以前的NIGMS资助 研究通过建立实验方法为拟议的研究奠定了基础;发现 并表征新基因;研究在酶，核糖开关和细菌中的corrinoid选择性; 创建一个生物信息学管道来预测细菌中的corrinoid代谢。我们的长远目标是 这一基础通过研究产生了对微生物群落相互作用的新的详细了解 从分子机制到整个群落的扰动。我们将实现这一目标 目标是通过（1）鉴定预测细菌在类可啉中的类可啉偏好的基因组序列特征， 依赖的酶和核糖开关，重点是进化的方法和（2）调查 通过应用测序、培养依赖性和 基因方法来建立人肠道来源的富集培养模型。作为对我们理解能力的测试， 预测基于类科里醇的代谢和群落动态，我们将设计和构建细菌菌株， 依赖于类可丽素的代谢网络，以及具有可预测动力学的细菌聚生体。这 研究将通过使用遗传学、生物化学、微生物学和 生物信息学，建立在我的团队过去的研究基础上。我们对类可啉的研究不仅可以作为 模型的微生物群落相互作用的系统，但也可能导致新的发展 改变微生物群落以获得有益结果的方法。