The human tRNA-guanine transglycosylase displays promiscuous nucleobase preference but strict tRNA specificity

Abstract Base-modification can occur throughout a transfer RNA molecule; however, elaboration is particularly prevalent at position 34 of the anticodon loop (the wobble position), where it functions to influence protein translation. Previously, we demonstrated that queuosine modification be substituted with an artificial analogue via queuine tRNA ribosyltransferase enzyme induce disease recovery in animal model multiple sclerosis. Here, demonstrate human recognize very broad range 7-deazaguanine derivatives for incorporation. By contrast, displays strict specificity species decoding dual synonymous NAU/C codons, determined using novel enzyme-RNA capture-release method. Our data highlight scope and therapeutic potential exploiting incorporation pathway intentionally engineer chemical diversity into anticodon.