Disease relevance of nucleoside Q

• Isogenic pairs of Escherichia coli, containing or lacking the tRNA-transglycosylase (JE 7335, tgt+ lacZ+ and JE 7337, tgt- lacZ+; JE 7334, tgt+ lacZ- and JE 7336, tgt- lacZ-), have been employed to study the function of queuosine in tRNA [1].
• Genetic analysis of ykvJKLM mutants in Acinetobacter confirmed that each was essential for queuosine biosynthesis, and the genes were renamed queCDEF [2].
• These results, taken together with other previous studies, suggest that a decreased queuosine content of tRNA may be a general feature of neoplasms and may be useful for grading malignancy and perhaps also for the prediction of survival in human lung cancer [3].
• Specific lack of the hypermodified nucleoside, queuosine, in hepatoma mitochondrial aspartate transfer RNA and its possible biological significance [4].
• Full expression of the virulence genes of Shigella flexneri requires the presence of two modified nucleosides in the tRNA [queuosine, Q34, present in the wobble position (position 34) and 2-methylthio-N6-isopentenyladenosine (ms2i6A37, adjacent to and 3' of the anticodon)] [5].

High impact information on nucleoside Q

• The hyper-modified nucleoside Q (queuosine) is exclusively located in the wobbling position of anticodons of tRNATyr tRNAHis, tRNAAsn and tRNAAsp that recognise codons NAUC (ref. 1). Queuosine and its hexose-containing derivatives are widely distributed in microorganisms, animals and plants [6].
• Queuosine modification of the wobble base in tRNAHis influences 'in vivo' decoding properties [7].
• Queuosine modification in tRNA and expression of genes of electron transport chains [8].
• Bacterial tRNA-guanine transglycosylase (TGT) replaces the G in position 34 of tRNA with preQ(1), the precursor to the modified nucleoside queuosine [9].
• The enzyme S-adenosylmethionine:tRNA ribosyltransferase-isomerase catalyzes the penultimate step in the biosynthesis of the hypermodified tRNA nucleoside queuosine (Q), an unprecedented ribosyl transfer from the cofactor S-adenosylmethionine (AdoMet) to a modified-tRNA precursor to generate epoxyqueuosine (oQ) [10].

Chemical compound and disease context of nucleoside Q

• A Q nucleoside containing mannose (manQ) was synthesized by a cell-free system from rat liver, using purified E. coli tRNAAsp as an acceptor and GDP-mannose as a donor molecule [11].
• Under-modified E. coli tRNATyr that contains 7-(aminomethyl)-7-deazaguanosine in place of Q nucleoside can be chemically modified by dansyl chloride under neutral conditions [12].
• Thus, the actual substrate for tRNA-guanine transglycosylase in queuosine biosynthesis in vivo in rat liver may not be 7-(aminomethyl)-7-deazaguanine, which is thought to be an actual substrate guanine, the E. coli system [13].
• New function of vitamin B12: cobamide-dependent reduction of epoxyqueuosine to queuosine in tRNAs of Escherichia coli and Salmonella typhimurium [14].
• Administration of queuine to mice relieves modified nucleoside queuosine deficiency in Ehrlich ascites tumor tRNA [15].

Biological context of nucleoside Q

• Nucleotide sequence analysis showed that tRNAAsn contains three derivatives of the Q nucleoside, possibly Q precursors, in addition to guanosine in the first position of the anticodon [16].
• The N-terminal catalytic domain folds into an (alpha/beta)(8) barrel with a characteristic zinc-binding site, showing structural similarity with that of the bacterial queuosine TGT (QueTGT), which is involved in queuosine (7-[[(4,5-cis-dihydroxy-2-cyclopenten-1-yl)-amino]methyl]-7-deazaguanosine) biosynthesis and targets the tRNA anticodon [17].
• Colicin E5 specifically cleaves four tRNAs in Escherichia coli that contain the modified nucleotide queuosine (Q) at the wobble position, thereby preventing protein synthesis and ultimately resulting in cell death [18].
• Plasmids containing the ORF encoding the 39-kDa protein (ORF 39) complemented a mutation in Q biosynthesis after the Tgt step [19].
• Queuosine (Q), one of the most complex modifications occurring at the wobble position of tRNAs with GUN anticodons, is implicated in a number of biological activities, including accuracy of decoding, virulence, and cellular differentiation [20].

Anatomical context of nucleoside Q

• We designate this the queuine salvage activity because it apparently is responsible for the ability of intact Vero cells to salvage queuosine base from tRNA degraded during the normal turnover process [21].
• In addition, because of the 7-substituent, Q nucleoside also is hypothesized to bind as the syn conformer and, therefore, to be a potential B-lymphocyte activator [22].
• Therefore, it was shown by direct measurements that the HxGC(3) cell line is completely lacking in queuosine-modified tRNA due to loss of functional TGRase, while the MCF-7 cell line has an inefficient queuine salvage mechanism resulting in a significant deficiency of queuosine-modified tRNA [23].
• These results were compared with data obtained from normal human fibroblast (HFF) cultures which maintain 100% queuosine-modified tRNA populations [23].
• These techniques can be applied to any cultured cell types to determine specific lesions of the queuosine modification system, which have been suggested to be associated with neoplastic progression [23].

Associations of nucleoside Q with other chemical compounds

• The new nucleoside has been characterized as an epoxy derivative of queuosine: 7-(5-[(2,3-epoxy-4,5-dihydroxycyclopent-1-yl)amino]methyl)-7-de azaguanosine, oQ, based on data from directly combined liquid chromatography/mass spectrometry, high resolution mass spectrometry, and proton NMR spectroscopy [24].
• The eukaryotic tRNA:guanine transglycosylase (TGT) catalyses the base-for-base exchange of guanine for queuine (the q-base)--a nutrition factor for eukaryotes--at position 34 of the anticodon of tRNAsGUN (where 'N' represents one of the four canonical tRNA nucleosides), yielding the modified tRNA nucleoside queuosine (Q) [25].
• Biochemical approaches and mass spectrometry investigations revealed that YadB transfers the activated glutamate on the cyclopenthene-diol ring of the modified nucleoside queuosine posttranscriptionally inserted at the wobble position of the anticodon-loop to form glutamyl-queuosine [26].
• This positions the dihydroxycyclopentenediol ring of queuosine in proper orientation for hydrogen bonding with the backbone of the neighboring uridine 33 residue [27].
• In addition to the Q nucleoside, these tRNAs appear to differ by the presence (tRNATyr1delta) or absence (tRNATyr1gamma) of 5-methylcytidine [28].

Gene context of nucleoside Q

• Genetic analysis identifies a function for the queC (ybaX) gene product at an initial step in the queuosine biosynthetic pathway in Escherichia coli [20].
• Isolation and characterization of an Escherichia coli mutant lacking tRNA-guanine transglycosylase. Function and biosynthesis of queuosine in tRNA [29].
• In eubacteria, the tRNA transglycosylase (Tgt) in specific tRNAs exchanges a guanine in the anticodon for 7-aminomethyl-7-deazaguanine, which is finally converted to queuosine [30].
• The enzyme tRNA-guanine transglycosylase, which is a key enzyme in biosynthesis of queuosine in tRNA (inserting Q base into tRNA by a transglycosylase reaction), is active in both tumor cells and normal cells [31].

Analytical, diagnostic and therapeutic context of nucleoside Q

• High pressure liquid chromatography analysis showed the Q nucleoside was absent from the tRNAs of each of four deletion strains [32].

References