Discussion

Transfer RNAs (tRNAs) are extensively post-transcriptionally modified to increase their structural stability or fidelity maintenance. In particular, the modifications in the anti-codon loop, have a crucial role in accurate codon selection and translational frameshifting prevention. Queuosine (Q) is a hyper modified guanosine and may be found at the wobble position 34 of a 5’-GUN-3 anticodon sequence-containing tRNAs (His, Asp, Asn, Tyr). Though Q is present in nearly all forms of life, its exact physiological role remains unclear. In bacteria, queuosine is obtained by modifying GTP through five enzymatic steps; it is then added to the tRNA by a tRNA-guanine transglycosylase (TGT) activity. However, eukaryotes lack the enzymes required for de novo synthesis of queuosine and hence rely on their environment or gut microbiome to obtain queuine (free base of queuosine), which is recognised by eukaryotic TGT. In mice and humans, TGT exists as a mitochondrion-localised heterodimer with queuine tRNA ribotransferase 1 (QTRT1), and its splice variant queuine tRNA ribotransferase domain containing 1 (QTRTD1). The T. brucei genome encodes two TGT paralogs, TbTGT1 and TbTGT2.  TbTGT1 displays a nuclear localization in the procyclic form (insect gut) meanwhile in the bloodstream form (in mammalian host) the protein is extra-nuclear. Both TbTGT1 and TbTGT2 are involved in Q formation in tRNAs and TbTGT1 is essential for the growth of the bloodstream form of the parasite.  This essentiality has been observed exclusively in trypanosomes so far, as no noticeable phenotype has been observed in the downregulation of the protein in the mammals.  Consequently, TGT becomes an ideal target for drug development against diseases caused by trypanosomatid parasites.