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

甜菜碱是一种很大程度上被遗忘的细菌来源的微量营养素， 肠;肠-脑轴的一个杰出的小分子。我们的论点是， 在新陈代谢和发育中很重要--哺乳动物出生时是不育的， 会对成年期产生长期影响，特别是在大脑中。至少5种独特的酶 在哺乳动物中，活性参与了马槟榔碱的利用，其中4种尚未确定。我们 长期目标是阐明甜菜碱如何有助于人类健康，提高科学和公众 认识到其重要性，并利用新定义的途径用于治疗目的。 本研究的具体目的是鉴定和鉴定未知的野罂粟碱 机制酶，并确定精氨酸缺乏如何影响神经元代谢， 分化我们的中心假设是，几乎普遍的保守性， 通过影响核糖体， 抑制-影响分化，在动物中保护免受年龄相关的 神经功能衰退我们的理论基础是早期文献中的大量观察， 以及Crécy和Kelly最近的生物信息学，生物化学和基因敲除研究 laboratories.我们的具体目标将证明：（目标1）药物运输依赖于 独特的摄取受体;（Aim 2）DUF 2419家族蛋白质是精氨酸补救所必需的;（Aim 3)用甘露糖和半乳糖对精氨酸进行过度修饰是细胞内滞留所必需的; 和（目的4）在没有胡萝卜碱的情况下，神经元功能受损。最后， 该项目将为科学界提供切实的资源， 探讨了苦参碱的生理作用，为药物开发提供了新的工具。意义 这项工作的基础来自于甜菜碱作为真核生物微量营养素的普遍性， 健康老龄化的后果。该研究具有创新性，因为它，我。铲球， 未解决的基本未知的生活，二。与年龄相关的神经功能衰退（a 当前的主要问题）和iii.融合了生物信息学、遗传学、化学 生物化学、晶体学和代谢组学。

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.