Study of queuosine salvage and function in eukaryotes; a forgotten micronutrient

真核生物中奎乌苷的挽救和功能研究；

基本信息

批准号：
10080744
负责人：
Juan D Alfonzo
金额：
$ 38.29万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080744
关键词：
Adult Affect Aging Amino Acids Anabolism Animals Awareness Behavioral Biochemical Biochemistry Biogenic Amine Neurotransmitters Bioinformatics Biological Biopterin Brain Cell Proliferation Cells Chemicals Chemistry Communities Comparative Genomic Analysis Complement Complex Crystallography Cytoplasm Defect Development Disease remission Enzymes Eukaryota Family Fission Yeast Food Funding Galactose Genes Genetic Genetic Transcription Goals Health HepG2 Homologous Gene Human Human body Hydrolase Ingestion Investigation Ireland Knowledge Laboratories Lead Letters Life Literature Liver Mammalian Cell Mammals Mannose Metabolic Metabolism Methods Micronutrients Mitochondria Modification Molecular Multiple Sclerosis Mus Neurodegenerative Disorders Neurologic Neuronal Differentiation Neurons Nucleoside Q Nucleosides Nucleotides Pathway interactions Physiological Physiology Play Positioning Attribute Process Production Proliferating Protein Family Publications Purines Rattus Research Resources Ribonucleosides Ribosomes Role Specificity Sterility Structural Models Structure Symbiosis Testing Therapeutic Transfer RNA Transferase Translations Trypanosoma brucei brucei Tyrosine Weight Gain Work age related aged aging brain analog base brain cell enzyme activity experimental study feeding glycosylation gut-brain axis healthy aging in silico innovation interest knockout gene metabolomics multidisciplinary nerve stem cell neuronal metabolism novel nucleobase nutrition protein function queuine tRNA-ribosyltransferase receptor relating to nervous system research and development small molecule sugar tRNA Precursor tetrahydrobiopterin therapeutic development three dimensional structure tool uptake

项目摘要

Queuine is a largely forgotten bacterial-derived micronutrient that is obtained exclusively from the gut; a preeminent small-molecule of the gut-brain axis. Our contention is that queuine is important in metabolism and development—mammals are born sterile and queuine free—and induces long-lasting effects into adulthood, particularly in the brain. At least 5 unique enzyme activities are involved in queuine utilisation in mammals, 4 of which remained undefined. Our long-term goals are to clarify how queuine contributes to human health, raise scientific and public awareness about its importance and exploit the newly defined pathways for therapeutic purposes. The specific objectives of this study are to identify and characterise the unknown queuine mechanistic enzymes and to define how queuine deficiency affects neuronal metabolism and differentiation. Our central hypothesis is that the near universal conservation of queuine emanates from an essential (albeit subtle) role in metabolism—through affecting ribosomal translation—that influences differentiation and that in animals protects against age-related neurological decline. Our rationale is based on numerous observations from the early literature, and recent bioinformatic, biochemical, and gene-knockout studies from the Crécy and Kelly laboratories. Our specific aims will demonstrate that; (Aim 1) queuine transport is dependent on unique uptake receptors; (Aim 2) DUF2419 family proteins are required for queuine salvage; (Aim 3) queuine hypermodification with mannose and galactose is required for intracellular retention; and (Aim 4) neuronal function is compromised in the absence of queuine. At conclusion the project will have furnished the scientific community with tangible resources to interrogate queuine’s physiological role and supply new tools for therapeutic development. The significance of the work derives from the universality of queuine as a micronutrient for eukaryotic life with consequences for healthy aging. The research is innovative because it, i. tackles an unaddressed fundamental unknown of life, ii. is relevant to age-related neurological decline (a major present-day concern) and iii. merges team expertise in bioinformatics, genetics, chemistry, biochemistry, crystallography and metabolomics.

Queuine是一种在很大程度上被遗忘的细菌衍生的微量营养素，仅从肠；肠脑轴的巨大小分子。我们的论点是队列是在新陈代谢和发展中重要 - 妈妈天生无菌和无奎因 - 诱导成年后的长期影响，尤其是在大脑中。至少5种独特的酶哺乳动物中的皇后利用涉及活动，其中4种仍然不确定。我们的长期目标是阐明Queuine如何为人类健康贡献，提高科学和公众意识到其重要性并利用新定义的途径用于治疗目的。这项研究的具体目标是识别和表征未知队列机械酶并定义了女王缺乏症如何影响神经元代谢和分化。我们的中心假设是队列的几乎普遍保护从代谢中的基本作用（尽管微妙）发出 - 通过影响核糖体翻译 - 影响差异化，而动物在动物中可以防止与年龄有关神经系统衰落。我们的理由是基于早期文献的众多观察以及最近来自Crécy和Kelly的生物信息学，生化和基因敲除研究实验室。我们的具体目标将证明这一点；（AIM 1）Queuine运输取决于独特的吸收接收器；（AIM 2）DUF2419族蛋白需要列出的蛋白质；（目的 3）细胞内保留需要用甘露糖和半乳糖过度修饰；（AIM 4）在没有队列的情况下，神经元功能被损害。结论项目将为科学界提供切实的资源来审问 Queuine的身体角色并为治疗开发提供新的工具。意义作品源自皇后区的宇宙，作为真核生活的微量营养素健康衰老的后果。这项研究具有创新性，因为它，我。解决一个未解决的基本未知生活，ii。与年龄相关的神经系统下降有关（a 当今的主要关注点）和iii。合并团队在生物信息学，遗传学，化学，化学方面的专业知识生物化学，晶体学和代谢组学。