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

奎因是一种很大程度上被遗忘的细菌衍生微量营养素，它只从 肠道；肠道-脑轴的一种卓越的小分子。我们的论点是排队是 在新陈代谢和发育中很重要-哺乳动物出生时不育，没有排队-和 在成年后会产生持久的影响，特别是对大脑。至少5种独特的酶 活动涉及哺乳动物的排队利用，其中4个活动仍未确定。我们的 长期目标是阐明排队对人类健康的贡献，提高科学和公众 认识到它的重要性，并利用新定义的治疗途径。 这项研究的具体目标是识别和描述未知排队的特征 并定义队列缺陷如何影响神经元代谢和 差异化。我们的中心假设是排队的近乎普遍的守恒 通过影响核糖体，在新陈代谢中发挥重要(虽然微妙)的作用。 翻译--影响分化，动物体内的翻译保护免受年龄相关的影响 神经功能衰退。我们的理论基础是基于早期文献中的大量观察， 以及CréCy和Kelly最近的生物信息学、生化和基因敲除研究 实验室。我们的具体目标将证明；(目标1)排队运输依赖于 独特的摄取受体；(目标2)排队抢救需要DUF2419家族蛋白；(目标2) 3)细胞内滞留需要甘露糖和半乳糖的超修饰； 以及(目标4)在没有排队的情况下，神经元功能受到损害。在结束时， 该项目将为科学界提供可供审问的有形资源 Queuine的生理作用，为治疗发展提供了新的工具。它的意义 工作的一部分源于队列作为真核生命的微量营养素的普遍性 对健康衰老的影响。这项研究具有创新性，因为它解决了一个问题。 未解决的生命的基本未知，2。与年龄相关的神经功能衰退(a 目前主要关注的问题)和3.融合了生物信息学、遗传学、化学、 生物化学、结晶学和代谢组学。

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.