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

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Queuine is the only micronutrient that directly affects translation efficiency and accuracy in eukaryotes, with roles in metabolism and healthy-aging of the brain (Fig. 1). It is a precursor of the tRNA modification Queuosine (Q) and is exclusively retrieved from ingested food or provided by the gut microbiota1. The Q modification is found at the wobble base (position 34) of cytoplasmic and mitochondrial tRNAs for the amino acids Tyr, Asp, Asn and His. Absence of Q in tRNAs of mice or human HepG2 cells lowers biopterin (BH4) pools and leads to serious tyrosine metabolic defect and eventually death2, highlighting the importance of Q in mammalian physiology. Cognisant of the fact that tRNA of rapidly-proliferating cells is hypomodified with respect to Q, chemical analogues have been developed that induce complete remission of multiple sclerosis in an animal model3. The realization that tRNA modifications are associated with neurological and mitochondrial diseases4–6 has led to renewed interest and in the biosynthesis and function of Q1. A common goal of the Crécy and Kelly laboratories is to characterize the Q synthesis pathways and explore the functional importance of this modification in all kingdoms of life, leading to 15 publications and laying the groundwork for this proposal. The bacterial Q synthesis pathway and the human tRNA Q addition enzyme, tRNA-guanine transglycosylase (hTGT), are well characterized7,8.
However, many gaps in knowledge of eukaryotic Q metabolism remain1. These include unknown transporters, hydrolases and sugar transferases. The lead PIs have gathered a multidisciplinary team taking advantage of the US-Ireland R&D Partnership, where funds are provided by each jurisdiction for their investigations (see commitment letters), to identify the “missing” human players in Q biosynthesis and elucidate the biologicalrole of this overlooked micronutrient in metabolism and neuronal function.