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 brain function. At least 5 unique enzymes are involved in queuine utilisation in mammals, which have remained undefined. 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 neuronal differentiation. Our rationale is based on 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 uptake is dependent on unique transporters; (Aim 2) DUF proteins are required for queuine
salvage; (Aim 3) queuine sugarhypermodification is essential for intracellular retention; and (Aim 4) queuine affects the differentiation and metabolism of neuronal cells. At conclusion the project will
yield tangible resources to interrogate queuine’s role and supply new tools for therapeutic development. The work’s significance derives from the universality of queuine as a micronutrient with consequences for healthy aging of the brain.
The research is innovative because it, i. tackles an unaddressed fundamental 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.
