Queuine is a hypermodified nucleobase found in the first position of the anticodon of tRNAs specific for Asn, Asp, His, and Tyr, in most eukaryotes and prokaryotes. The nucleoside of queuine is queuosine. Queuine is not found in the tRNA of archaea; however, a related 7-deazaguanine derivative, the nucleoside of which is archaeosine, occurs in different tRNA position, the dihydrouridine loop, and in tRNAs with more specificities.
History and Naming
In 1967, it was discovered that the four above-mentioned tRNAs contained an as-yet unknown nucleoside, which was designated "Nucleoside Q". This name remained in use throughout much of the work to characterize the compound, after which it was proposed that its common name should be based on the sound of the letter Q—thus producing "queuine" by analogy to guanine and other nucleobases, and "queuosine" by analogy to guanosine and other nucleosides.
Biosynthesis and Function
Although queuosine is found in the tRNA of nearly all eukaryotic organisms, it is produced exclusively by bacteria; higher organisms must obtain queuine from the diet or salvage it from symbiotic microbes—a process for which dedicated enzymatic machinery exists. As such, queuine has been described as a vitamin. Because it can be generated from guanine by some species in the human microbiome, its status as a vitamin may be analogous to that of 4-Aminobenzoic acid, a "conditional" vitamin which is only essential in the diet if the microbiome does not produce sufficient quantities. As of 2019, human queuine requirements are not well understood, and the prevalence of queuine deficiency in humans is unknown. Once salvaged, queuine replaces a guanine base in the anticodon of certain tRNAs, where it appears to play a role in ensuring rapid and accurate recognition of the corresponding mRNAs' codons. In the absence of queuosine modification, translation at Q-decoded codons slows down to the point that many proteins cannot fold properly. This biomolecular "traffic jam" triggers the unfolded protein response, a hallmark of various neurodegenerative diseases.
Role in Biopterin Recycling and Neurotransmitter Biosynthesis
The effects of queuine deficiency have been studied in germ-free animals, which have no intestinal microbiota. After removal of all queuine from the diet, germ-free mice lose the ability to convert the dietary amino acidphenylalanine into tyrosine–a phenotype mimicking the human diseasephenylketonuria. Further investigation of this effect revealed it to be a consequence of impaired tetrahydrobiopterin regeneration. BH4 is a cofactor for the biopterin-dependent aromatic amino acid hydroxylase enzymes, which catalyze the conversion of phenylalanine to tyrosine, tyrosine to L-DOPA, and tryptophan to 5-HTP, oxidizing BH4 to dihydrobiopterin in the process. BH2 must then be converted back to BH4 by the enzyme dihydropteridine reductase before it can be used again. Queuine depletion appears to impair this "recycling" process, resulting in a deficit of BH4 and an excess of BH2, which in turn impairs the activity of the aromatic amino acid hydroxylase enzymes. Because these enzymes play a critical role in the biosynthesis of the neurotransmitters serotonin, melatonin, dopamine, norepinephrine, and epinephrine, problems with biopterin metabolism have long been considered a promising candidate to explain the origins of some psychiatric disorders characterized by imbalances in these neurotransmitters, including depression and schizophrenia. A number of studies suggest that these disorders are indeed associated with disrupted biopterin metabolism. As queuine appears to be essential for the maintenance of adequate BH4 levels, queuine deficiency—resulting from disruption to the microbiome by factors like antibiotics—has been proposed as a possible cause of mental illnesses related to imbalances of these neurotransmitters.
Role in Cancer
Although general queuine repletion status has not been studied in humans, studies of cancerous tissue have found a uniform trend of queuine deficiency in lung, ovarian, and lymphatic cancers. In one study of patients with lung cancer, a lack of queuosine in tumor tissue tRNA was associated with worse odds of survival four years post-biopsy. It has been postulated that this correlation is attributable to decreased activity of tRNA guanine transglycosylase, the enzyme which replaces guanine with queuine in tRNA.
