Prequeuosine

Prequeuosine is a bicyclic guanine derivative that serves as an intermediate in the biosynthesis of queuosine, a hypermodified nucleoside found at the wobble position (position 34) of certain tRNAs, notably those that recognize codons for four amino acids—Isoleucine, Threonine, Asparagine, and Tyrosine. Queuosine enhances translational accuracy and efficiency, and its presence is conserved among many bacteria, archaea, and eukaryotes that recycle or acquire queuine from the environment.

The prequeuosine biosynthetic pathway begins with the conversion of guanine to prequeuosine 0 (preQ₀) by a series of enzymes: GTP cyclohydrolase I, QueD, QueE, and QueF. PreQ₀ is a 7‑azaguanine analogue that contains a fused imidazole ring system. In bacteria, preQ₀ is transported into the cell and subsequently exchanged by a tRNA‑guanine transglycosylase (TGT) enzyme with guanine in the wobble position of the target tRNA, forming preQ₁. PreQ₁ is then reduced and hydroxylated to yield the mature queuosine base.

In archaeal systems, the pathway diverges: prequeuosine 0 is converted to prequeuosine 1 by the enzyme QueC, and further modifications produce archaeal queuosine variants. Some organisms can salvage exogenous queuine, incorporating it directly into tRNA via a dedicated transglycosylase, bypassing the de novo synthesis route.

Functionally, queuosine and its precursors modulate codon-anticodon interactions, potentially reducing frameshifts and misincorporations, and may influence the response to oxidative stress and other environmental stimuli. Deficiencies in queuosine synthesis are linked to altered gene expression profiles and reduced cellular fitness in bacteria, while in eukaryotes, queuine deficiency is associated with neurodevelopmental disorders and cancer progression.

Prequeuosine compounds are of interest in biotechnology and medicine as potential targets for antimicrobial agents, given their essential role in the translation machinery of pathogens, and as biomarkers for metabolic conditions in humans.