Diet-dependent depletion of queuosine in tRNAs in Caenorhabditis elegans does not lead to a developmental block

Gaur, Rahul; Björk, Glenn R.; Tuck, Simon; Varshney, Umesh

doi:10.1007/s12038-007-0074-4

Cited by 13 publications

(13 citation statements)

References 37 publications

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“…This observation is in agreement with earlier studies on various other queuine-deprived eukaryotic species, including Dictyostelium (39), fly (26), and worm (27). It may be concluded that queuine or queuosine-modified (t)RNA does not impact on the development, growth, or reproduction of eukaryotic organisms under laboratory conditions.…”

Section: Discussionsupporting

confidence: 92%

“…3) showed that TGT deficiency does not influence viability or sex bias (supplemental Table 1). In addition, breeding of homozygous animals revealed that both males and females have normal fecundity (supplemental Table 2), concurring with the lack of an obvious phenotype in queuine-deficient fly (26), worm (27), and mouse (28).…”

Section: Queuine Deficiency In Hepg2 Cellsmentioning

confidence: 55%

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Queuosine Deficiency in Eukaryotes Compromises Tyrosine Production through Increased Tetrahydrobiopterin Oxidation

Rakovich

Boland

Bernstein

et al. 2011

Journal of Biological Chemistry

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Queuosine is a modified pyrrolopyrimidine nucleoside found in the anticodon loop of transfer RNA acceptors for the amino acids tyrosine, asparagine, aspartic acid, and histidine. Because it is exclusively synthesized by bacteria, higher eukaryotes must salvage queuosine or its nucleobase queuine from food and the gut microflora. Previously, animals made deficient in queuine died within 18 days of withdrawing tyrosine, a nonessential amino acid, from the diet (Marks, T., and Farkas, W. R. (1997) Biochem. Biophys. Res. Commun. 230, 233-237). Here, we show that human HepG2 cells deficient in queuine and mice made deficient in queuosine-modified transfer RNA, by disruption of the tRNA guanine transglycosylase enzyme, are compromised in their ability to produce tyrosine from phenylalanine. This has similarities to the disease phenylketonuria, which arises from mutation in the enzyme phenylalanine hydroxylase or from a decrease in the supply of its cofactor tetrahydrobiopterin (BH4). Immunoblot and kinetic analysis of liver from tRNA guanine transglycosylase-deficient animals indicates normal expression and activity of phenylalanine hydroxylase. By contrast, BH4 levels are significantly decreased in the plasma, and both plasma and urine show a clear elevation in dihydrobiopterin, an oxidation product of BH4, despite normal activity of the salvage enzyme dihydrofolate reductase. Our data suggest that queuosine modification limits BH4 oxidation in vivo and thereby potentially impacts on numerous physiological processes in eukaryotes.Bacteria and humans have co-evolved for millennia, and many examples exist of how various symbiotic and commensal partnerships contribute to human health and nutrition ranging from the metabolism of complex carbohydrates to the provision of vital micronutrients (1). Queuosine is an example of a micronutrient, synthesized exclusively by bacteria but which, for poorly defined reasons, is utilized by almost all eukaryotic species with the exception of the baker's yeast, Saccharomyces cerevisiae (2).Bacterial queuosine biosynthesis occurs in two stages. First, a series of five enzymatic steps convert guanosine triphosphate nucleoside (GTP) to the soluble 7-aminomethyl-7-deazaguanine molecule. Subsequently, 7-aminomethyl-7-deazaguanine is inserted into the wobble position of tRNA containing a GUN consensus sequence (Tyr, Asp, Asn, and His) by means of the single enzyme species, tRNA guanine transglycosylase (TGT), and is further remodeled in situ to queuosine (3). Eukaryotes must acquire queuosine or its free nucleobase, queuine, from food and the gut microflora. Curiously, both cytosolic and mitochondrial tRNA species are modified by queuosine (2). The eukaryotic enzyme that performs this reaction, queuine tRNA ribosyltransferase, has recently been identified as a heterodimeric complex, consisting of the eukaryotic homologue of the catalytic TGT subunit and a related protein called queuine tRNA ribosyltransferase domain containing 1 (QTRTD1), both of which localize to the mitochondria (4, 5).Stu...

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Section: Discussionsupporting

confidence: 92%

Section: Queuine Deficiency In Hepg2 Cellsmentioning

confidence: 55%

Queuosine Deficiency in Eukaryotes Compromises Tyrosine Production through Increased Tetrahydrobiopterin Oxidation

Rakovich

Boland

Bernstein

et al. 2011

Journal of Biological Chemistry

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“…A physiological role for Q has eluded discovery partly because of gaps in understanding of the biosynthetic pathway. De novo biosynthesis of Q occurs in bacteria whereas eukaryotes acquire the free base, queuine, from dietary sources (3)(4)(5). The bacterial pathway for biosynthesis of Q has been elucidated up to the penultimate intermediate, epoxyqueuosine (oQ) (6,7).…”

mentioning

confidence: 99%

Discovery of epoxyqueuosine (oQ) reductase reveals parallels between halorespiration and tRNA modification

Miles

McCarty

Molnár

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

104

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Transfer RNA is one of the most richly modified biological molecules. Biosynthetic pathways that introduce these modifications are underexplored, largely because their absence does not lead to obvious phenotypes under normal growth conditions. Queuosine (Q) is a hypermodified base found in the wobble positions of tRNA Asp, Asn, His, and Tyr from bacteria to mankind. Using liquid chromatography MS methods, we have screened 1,755 single gene knockouts of Escherichia coli and have identified the key final step in the biosynthesis of Q. The protein is homologous to B 12 -dependent iron-sulfur proteins involved in halorespiration. The recombinant Bacillus subtilis epoxyqueuosine (oQ) reductase catalyzes the conversion of oQ to Q in a synthetic substrate, as well as undermodified RNA isolated from an oQ reductase knockout strain. The activity requires inclusion of a reductant and a redox mediator. Finally, exogenously supplied cobalamin stimulates the activity. This work provides the framework for studies of the biosynthesis of other modified RNA components, where lack of accessible phenotype or obvious gene clustering has impeded discovery. Moreover, discovery of the elusive oQ reductase protein completes the biosynthetic pathway of Q.biochemistry | queuosine | reductive dehalogenation N early 100 modifications have been identified in RNA, many of which are found in tRNA and are common to eukaryotes, bacteria, and archaea (1). Most of these modifications are likely not essential under normal laboratory conditions, making discovery of biosynthetic pathways by phenotypic methods impossible. Queuosine (Q), a hypermodified RNA base containing a 7-deazapurine core, is among the more complex RNA modifications described to date. Q replaces the guanine in the wobble positions of the subset of tRNA molecules with a 5′-GUN-3′ sequence in their anticodon loops (His, Asp, Asn, and Tyr). Conservation of Q in RNA of organisms in nearly all kingdoms of life (2) suggests that the modification may be of cardinal importance. A physiological role for Q has eluded discovery partly because of gaps in understanding of the biosynthetic pathway. De novo biosynthesis of Q occurs in bacteria whereas eukaryotes acquire the free base, queuine, from dietary sources (3-5). The bacterial pathway for biosynthesis of Q has been elucidated up to the penultimate intermediate, epoxyqueuosine (oQ) (6, 7). However, the enzyme that catalyzes the final step in the pathway, conversion of oQ to Q, had yet to be identified. Because no selectable phenotypes have been demonstrated for the modification, discovery of the final step in the pathway required a different approach that melded modern analytical methods and emerging tools in bacterial genetics. This methodology has led to successful identification of the final step and can be generalized to other RNA modifications where lack of phenotype has hindered discovery of the biosynthetic pathway.Structural parallels between the 7-deazapurine core of queuosine and 7-deazapurine-containing antibiotic toyocamycin ...

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“…However, contrary to bacteria, eukaryotes lack the enzymatic pathway for queuosine synthesis. Instead, they acquire queuine and queuosine from external sources like nutrition and from the gut microbiota [21,22,23,24] (Figure 1). Q-containing tRNAs from these sources as well as endogenous tRNAs are digested, resulting in queuosine nucleoside, queuosine-3′-monophosphate and free queuine base, which circulates e.g., in blood (serum) and other body fluids (milk, amniotic fluid) and is taken up by the cells [13].…”

Section: Queuosine Modification On Trnasmentioning

confidence: 99%

Cross-Talk between Dnmt2-Dependent tRNA Methylation and Queuosine Modification

Ehrenhofer‐Murray

2017

Biomolecules

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Enzymes of the Dnmt2 family of methyltransferases have yielded a number of unexpected discoveries. The first surprise came more than ten years ago when it was realized that, rather than being DNA methyltransferases, Dnmt2 enzymes actually are transfer RNA (tRNA) methyltransferases for cytosine-5 methylation, foremost C38 (m5C38) of tRNAAsp. The second unanticipated finding was our recent discovery of a nutritional regulation of Dnmt2 in the fission yeast Schizosaccharomyces pombe. Significantly, the presence of the nucleotide queuosine in tRNAAsp strongly stimulates Dnmt2 activity both in vivo and in vitro in S. pombe. Queuine, the respective base, is a hypermodified guanine analog that is synthesized from guanosine-5’-triphosphate (GTP) by bacteria. Interestingly, most eukaryotes have queuosine in their tRNA. However, they cannot synthesize it themselves, but rather salvage it from food or from gut microbes. The queuine obtained from these sources comes from the breakdown of tRNAs, where the queuine ultimately was synthesized by bacteria. Queuine thus has been termed a micronutrient. This review summarizes the current knowledge of Dnmt2 methylation and queuosine modification with respect to translation as well as the organismal consequences of the absence of these modifications. Models for the functional cooperation between these modifications and its wider implications are discussed.

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Diet-dependent depletion of queuosine in tRNAs in Caenorhabditis elegans does not lead to a developmental block

Cited by 13 publications

References 37 publications

Queuosine Deficiency in Eukaryotes Compromises Tyrosine Production through Increased Tetrahydrobiopterin Oxidation

Queuosine Deficiency in Eukaryotes Compromises Tyrosine Production through Increased Tetrahydrobiopterin Oxidation

Discovery of epoxyqueuosine (oQ) reductase reveals parallels between halorespiration and tRNA modification

Cross-Talk between Dnmt2-Dependent tRNA Methylation and Queuosine Modification

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