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：
9904725
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/9904725
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 是一种基本上被遗忘的细菌来源的微量营养素，仅从肠道；肠脑轴的一个重要小分子。对新陈代谢和发育很重要——哺乳动物生来就不育且没有队列——并且对成年期尤其是至少 5 种独特的酶产生持久影响。活动涉及哺乳动物的队列利用，其中 4 个活动尚未定义。长期目标是阐明奎因如何为人类健康做出贡献，提高科学和公众意识认识其重要性并利用新定义的途径达到治疗目的。本研究的具体目标是识别和表征未知的队列机械酶并定义奎因缺乏如何影响神经元代谢和我们的中心假设是队列的近乎普遍守恒。源自新陈代谢中的重要（尽管微妙）作用——通过影响核糖体翻译——影响分化，并且在动物中可以防止与年龄相关的我们的理由是基于早期文献的大量观察，以及克雷西和凯利最近的生物信息、生物化学和基因敲除研究我们的具体目标将证明：（目标 1）队列传输取决于；独特的摄取受体；（目标 2）DUF2419 家族蛋白是队列挽救所必需的（目标； 3) 细胞内保留需要甘露糖和半乳糖的队列超修饰；（目标 4）在缺乏队列的情况下，神经功能会受到损害。项目将为科学界提供有形资源来质疑队列的生理作用并为治疗开发提供新工具。这项工作的重点源于奎因作为真核生物微量营养素的普遍性这项研究具有创新性，因为它解决了一个问题。未解决的生命基本未知，ii. 当前主要关注的问题）和 iii 合并了生物信息学、遗传学、化学、生物化学、晶体学和代谢组学。