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Ronald W. Trewyn - One of the best experts on this subject based on the ideXlab platform.
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2013Co-Authors: Jon R. Katze, Ronald W. Trewyn, Mark S. Elliott, Cancer Res, Contact The Aacr PublicationsAbstract:With normal human skin fibroblasts in culture, a transient decrease in Queuine modification of tRNA precedes a phorbol ester tumor promoter-induced 5- to 10-fold increase in saturation density. Subsequently, an increase in the Queuine content of cellular tRNA (to levels comparable to those in untreated cultures) precedes a decrease in saturation density. This reversal of the phorbol ester-induced alteration in tRNA modification occurs in the continued presence of the tumor promoter, and it parallels an increased ability of the cells to salvage Queuine from catabolized endogenous tRNA. Addition of exogenous Queuine concur rently with the tumor promoter at early passage significantly inhibits the increase in saturation density. The results suggest a role for the decrease in Queuine modification of tRNA in mediating the phenotypic change induced by the tumor promoter
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Defective Transfer RNA-Queuine Modification in C3H10T1/2 Murine Fibroblasts Transfected with Oncogenic ras
Cancer research, 1996Co-Authors: Claudia J. Morgan, Frank L. Merrill, Ronald W. TrewynAbstract:tRNA isoacceptors for aspartic acid, asparagine, histidine, and tyrosine are modified in the anticodon wobble position with the deazaguanine analogue Queuine. Queuine modification is defective in many tumors and transformed cell lines, and the extent of hypomodification correlates with staging and outcome in numerous human tumors. The molecular role of Queuine modification in normal cells and the mechanism of Queuine hypomodification in tumors are unknown. We have characterized nontransformed C3H10T1/2 murine fibroblasts (C3H) and their ras -transfected counterparts (RasC4) with respect to the causes and effects of Queuine hypomodification. RasC4 cells are hypomodified for Queuine compared with C3H cells, despite increased tRNA-guanine ribosyltransferase activity. Excess exogenous Queuine can cause repletion of tRNA Queuine levels in RasC4 cells. Queuine modification of both C3H and RasC4 cells can be decreased by treatment with 7-methylguanine. This treatment does not affect growth in monolayer culture but enhances anchorage-independent growth of RasC4 cells greatly. These cell lines may be useful systems for the study of Queuine function in normal cells and the causes and consequences of hypomodification for Queuine in tumors.
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defective transfer rna Queuine modification in c3h10t1 2 murine fibroblasts transfected with oncogenic ras
Cancer Research, 1996Co-Authors: Claudia J. Morgan, Frank L. Merrill, Ronald W. TrewynAbstract:tRNA isoacceptors for aspartic acid, asparagine, histidine, and tyrosine are modified in the anticodon wobble position with the deazaguanine analogue Queuine. Queuine modification is defective in many tumors and transformed cell lines, and the extent of hypomodification correlates with staging and outcome in numerous human tumors. The molecular role of Queuine modification in normal cells and the mechanism of Queuine hypomodification in tumors are unknown. We have characterized nontransformed C3H10T1/2 murine fibroblasts (C3H) and their ras -transfected counterparts (RasC4) with respect to the causes and effects of Queuine hypomodification. RasC4 cells are hypomodified for Queuine compared with C3H cells, despite increased tRNA-guanine ribosyltransferase activity. Excess exogenous Queuine can cause repletion of tRNA Queuine levels in RasC4 cells. Queuine modification of both C3H and RasC4 cells can be decreased by treatment with 7-methylguanine. This treatment does not affect growth in monolayer culture but enhances anchorage-independent growth of RasC4 cells greatly. These cell lines may be useful systems for the study of Queuine function in normal cells and the causes and consequences of hypomodification for Queuine in tumors.
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Absence of tRNA-guanine transglycosylase in a human colon adenocarcinoma cell line
Biochimica et biophysica acta, 1992Co-Authors: Ufuk Gündüz, Ronald W. Trewyn, Mark S. Elliott, Patricia H. Seubert, Janet A. Houghton, Peter J. Houghton, Jon R. KatzeAbstract:Abstract Queuosine (Q), found exclusively in th first position of the anticodons of tRNAAsp, tRNAAsn, tRNAHis and tRNATyr, is synthesized in eucaryotes by a base-for-base exchange of Queuine, the base of Q, for guanine at tRNA position 34. This reaction is catalyzed by the enzyme tRNA-guaning transglucosylate (EC 2.4.2.29). We measured the specific release of Queuine from Q-5′-phsphate (Queuine salvage) and the extent of tRNA Q modification in 6 human tumors carried as xenografts in immune-deprived mice. Q-deficient tRNA was found in 3 of the tumors but it did not correlate with diminished Queuine salvage. The low tRNA Q content of one tumor, the HxGC3 colo adenocarcinoma, prompted us to examine a HxGC3-derived cell line, GC3/M. GC3/M completely lacks Q in its tRNA and measurable tRNA-guanine transglycosylase activity; the first example of a higher eucaryotic cell which lacks this enzyme. Exposure of GC3/M cells to 5-azacytidine induces the transient appearance of Q-positive tRNA. This result suggests that at least one allele of the transglycosylase gene in GC3/M cells may have been inactivated by DNA methylation. In clinical samples, we found Q-deficient tRNA in 10 of 46 solid tumors, including 2 of 13 colonic carcinomas.
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Queuine, a tRNA anticodon wobble base, maintains the proliferative and pluripotent potential of HL-60 cells in the presence of the differentiating agent 6-thioguanine.
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: Bernard T. French, D E Patrick, Michael R. Grever, Ronald W. TrewynAbstract:6-Thioguanine (6-TG)-induced differentiation of hypoxanthine phosphoribosyltransferase (IMP: pyrophosphate phosphoribosyltransferase, EC 2.4.2.8)-deficient HL-60 cells is characterized by 2 days of growth, after which morphological differentiation proceeds. Addition of the tRNA wobble base Queuine, in the presence of 6-TG, maintains the proliferative capability of the cells. The ability of 6-TG to induce differentiation correlates with c-myc mRNA down-regulation, but Queuine has no effect on this parameter. Treatment with 6-TG for 2-3 days commits HL-60 cells to granulocytic differentiation, and, once committed, these cells do not respond to the monocytic inducer phorbol 12-myristate 13-acetate. Nonetheless, when cells are treated with Queuine and 6-TG, they maintain the promyelocytic morphology and are capable of being induced down the monocytic pathway by phorbol 12-myristate 13-acetate as indicated by stabilization of c-fms mRNA and cell adherence. In the absence of Queuine, phorbol 12-myristate 13-acetate is incapable of inducing monocytic markers in the 6-TG-treated cells. The data presented indicate that 6-TG-induced differentiation of HL-60 cells is a tRNA-facilitated event and that the tRNA wobble base Queuine is capable of maintaining both the proliferative and pluripotent potential of the cells.
George A. Garcia - One of the best experts on this subject based on the ideXlab platform.
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A short, concise synthesis of Queuine
Tetrahedron Letters, 2010Co-Authors: Allen F. Brooks, George A. Garcia, H. D. Hollis ShowalterAbstract:A short, concise synthesis of Queuine was accomplished in a 36% overall yield through a convergent scheme utilizing a reductive amination as the penultimate step. The synthesis demonstrates the utility of silylation to facilitate reactions of various pyrrolo[2,3-d]pyrimidine intermediates, and offers the possibility of easily accessing related pyrrolo[2,3-d]pyrimidines as well as making additional analogues of Queuine.
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Role of Aspartate 143 in Escherichia coli tRNA-Guanine Transglycosylase: Alteration of Heterocyclic Substrate Specificity†
Biochemistry, 2006Co-Authors: Katherine Abold Todorov, George A. GarciaAbstract:There are approximately 100 modified nucleosides that occur in RNA, with the vast majority of them occurring in tRNAs (1). The tRNA anticodon is one “hot spot” for hypermodification (e.g., the incorporation of elaborately modified nucleosides). Queuine (Figure 1) is one example of a hypermodified base that occurs in the wobble position of the anticodon of tRNAs Asp, Asn, His and Tyr. Queuine is incorporated into tRNA via a base exchange reaction (replacing guanine) catalyzed by tRNA-guanine transglycosylase (TGT). In eukaryotes, Queuine is directly exchanged into tRNA while in eubacteria, a Queuine precursor (preQ1, Figure 1) is incorporated and ultimately modified to Queuine (2). Queuine, guanine and preQ1 all share the same 2-amino-pyrimidin-4-one moiety that is involved in the Watson-Crick type base pairing between the tRNA anticodon and the mRNA codon during translation. In order to accurately maintain this interaction, and hence the identity of the tRNAs and the fidelity of translation, TGT must exercise precise and specific recognition of its heterocyclic substrate. Fig. 1 Physiological and Potential Alternative Heterocyclic Substrates for TGT. The X-ray crystal structure of the Zymomonas mobilis TGT bound to preQ1 revealed that aspartate 143 (D143, E. coli TGT numbering) appears to make two hydrogen bonds to the amino pyrimidone portion of preQ1 (3). In order to experimentally probe the role of D143 in heterocyclic substrate recognition, we carried out a thorough biochemical and computational characterization of wild-type and D143 mutant TGTs. Their interactions with guanine confirmed that D143 does play a vital role in heterocyclic substrate recognition (4). Computational simulations of guanine binding to wild-type and D143 mutant TGTs provided insight as to which interactions assisted in binding guanine (4). Since D143 was ascertained to be the determinant for guanine specificity, it follows that mutating this residue may allow for alternate substrate recognition. Not only is there precedence for altering substrate specificity with guanine binding proteins using hypoxanthine and xanthine (Figure 1) (5–7), but these purines are readily available in vivo and therefore provide an interesting and physiologically-relevant study of substrate specificity. We herein report biochemical studies to probe the recognition between wild-type and D143 mutant TGTs and the alternate purine heterocycles, hypoxanthine and xanthine.
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tRNA‐guanine transglycosylase from Escherichia coli: recognition of full‐length ‘Queuine‐cognate' tRNAs
FEBS letters, 1998Co-Authors: Fan-lu Kung, George A. GarciaAbstract:Abstract A key enzyme involved in the incorporation of the modified base Queuine into tRNA (position 34) is tRNA-guanine transglycosylase (TGT). Studies of the recognition of truncated tRNAs by the Escherichia coli TGT have established a minimal recognition motif involving a minihelix with a 7 base loop containing a U- G -U sequence (where G is replaced with Queuine) [Curnow, A.W. and Garcia, G.A. (1995) J. Biol. Chem. 270, 17264–17267; Nakanishi, S. et al. (1994) J. Biol. Chem. 269, 32221–32225]. Still, a clearer understanding of the recognition of full-length `Queuine-cognate' tRNAs by TGT remains lacking. In this paper, we report the in vitro transcription and enzymological characterization (Km and kcat) of all four `Queuine-cognate' tRNAs from E. coli and from Saccharomyces cerevisiae with the TGT from E. coli. No primary or secondary structures emerge as important recognition elements from this study. The modest differences in substrate specificity (relative kcat/Km values vary from 0.5 to 8.4) seen among these `Queuine-cognate' tRNAs most likely result from the accumulated effects of many subtle factors. Interestingly, the yeast tRNAs are essentially equivalent to the E. coli tRNAs as substrates for TGT, indicating that there is nothing intrinsic to the yeast tRNAs that accounts for the absence of Queuine in yeast.
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trna guanine transglycosylase from escherichia coli recognition of full length Queuine cognate trnas
FEBS Letters, 1998Co-Authors: Fan-lu Kung, George A. GarciaAbstract:Abstract A key enzyme involved in the incorporation of the modified base Queuine into tRNA (position 34) is tRNA-guanine transglycosylase (TGT). Studies of the recognition of truncated tRNAs by the Escherichia coli TGT have established a minimal recognition motif involving a minihelix with a 7 base loop containing a U- G -U sequence (where G is replaced with Queuine) [Curnow, A.W. and Garcia, G.A. (1995) J. Biol. Chem. 270, 17264–17267; Nakanishi, S. et al. (1994) J. Biol. Chem. 269, 32221–32225]. Still, a clearer understanding of the recognition of full-length `Queuine-cognate' tRNAs by TGT remains lacking. In this paper, we report the in vitro transcription and enzymological characterization (Km and kcat) of all four `Queuine-cognate' tRNAs from E. coli and from Saccharomyces cerevisiae with the TGT from E. coli. No primary or secondary structures emerge as important recognition elements from this study. The modest differences in substrate specificity (relative kcat/Km values vary from 0.5 to 8.4) seen among these `Queuine-cognate' tRNAs most likely result from the accumulated effects of many subtle factors. Interestingly, the yeast tRNAs are essentially equivalent to the E. coli tRNAs as substrates for TGT, indicating that there is nothing intrinsic to the yeast tRNAs that accounts for the absence of Queuine in yeast.
Manjula Vinayak - One of the best experts on this subject based on the ideXlab platform.
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Queuosine modification of tRNA: its divergent role in cellular machinery.
Bioscience reports, 2009Co-Authors: Manjula Vinayak, Chandramani PathakAbstract:tRNAs possess a high content of modified nucleosides, which display an incredible structural variety. These modified nucleosides are conserved in their sequence and have important roles in tRNA functions. Most often, hypermodified nucleosides are found in the wobble position of tRNAs, which play a direct role in maintaining translational efficiency and fidelity, codon recognition, etc. One of such hypermodified base is Queuine, which is a base analogue of guanine, found in the first anticodon position of specific tRNAs (tyrosine, histidine, aspartate and asparagine tRNAs). These tRNAs of the 'Q-family' originally contain guanine in the first position of anticodon, which is post-transcriptionally modified with Queuine by an irreversible insertion during maturation. Queuine is ubiquitously present throughout the living system from prokaryotes to eukaryotes, including plants. Prokaryotes can synthesize Queuine de novo by a complex biosynthetic pathway, whereas eukaryotes are unable to synthesize either the precursor or Queuine. They utilize salvage system and acquire Queuine as a nutrient factor from their diet or from intestinal microflora. The tRNAs of the Q-family are completely modified in terminally differentiated somatic cells. However, hypomodification of Q-tRNA (queuosine-modified tRNA) is closely associated with cell proliferation and malignancy. The precise mechanisms of Queuine- and Q-tRNA-mediated action are still a mystery. Direct or indirect evidence suggests that Queuine or Q-tRNA participates in many cellular functions, such as inhibition of cell proliferation, control of aerobic and anaerobic metabolism, bacterial virulence, etc. The role of Q-tRNA modification in cellular machinery and the signalling pathways involved therein is the focus of this review.
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Queuine mediated inhibition in phosphorylation of tyrosine phosphoproteins in cancer
Molecular Biology Reports, 2008Co-Authors: Chandramani Pathak, Yogesh K. Jaiswal, Manjula VinayakAbstract:Protein phosphorylation or dephosphorylation is the most important regulatory switch of signal transduction contributing to control of cell proliferation. The reversibility of phosphorylation and dephosphorylation is due to the activities of kinases and phosphatase, which determine protein phosphorylation level of cell under different physiological and pathological conditions. Receptor tyrosine kinase (RTK) mediated cellular signaling is precisely coordinated and tightly controlled in normal cells which ensures regulated mitosis. Deregulation of RTK signaling resulting in aberrant activation in RTKs leads to malignant transformation. Queuine is one of the modified base of tRNA which participates in down regulation of tyrosine kinase activity. The guanine analogue Queuine is a nutrient factor to eukaryotes and occurs as free base or modified nucleoside queuosine into the first anticodon position of specific tRNAs. The tRNAs are often Queuine deficient in cancer and fast proliferating tissues. The present study is aimed to investigate Queuine mediated inhibition in phosphorylation of tyrosine phosphorylated proteins in lymphoma bearing mouse. The result shows high level of cytosolic and membrane associated tyrosine phosphoprotein in DLAT cancerous mouse liver compared to normal. Queuine treatments down regulate the level of tyrosine phosphoproteins, which suggests that Queuine is involved in regulation of mitotic signaling pathways.
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Queuine promotes antioxidant defence system by activating cellular antioxidant enzyme activities in cancer.
Bioscience reports, 2008Co-Authors: Chandramani Pathak, Yogesh K. Jaiswal, Manjula VinayakAbstract:Constant generation of Reactive oxygen species (ROS) during normal cellular metabolism of an organism is generally balanced by similar rate of consumption by antioxidants. Imbalance between ROS production and antioxidant defense results in increased level of ROS causing oxidative stress which leads to promotion of malignancy. Queuine is a hyper modified base analogue of guanine, found at first anti-codon position of Q- family of tRNAs. These tRNAs are completely modified with respect to queuosine in terminally differentiated somatic cells, however hypomodification of Q-tRNAs is close association with cell proliferation. Q-tRNA modification is essential for normal development, differentiation and cellular functions. Queuine is a nutrient factor to eukaryotes. It is found to promote cellular antioxidant defense system and inhibit tumorigenesis. The activities of antioxidant enzymes like catalase, SOD, glutathione peroxidase and glutathione reductase are found to be low in Dalton's lymphoma ascites transplanted (DLAT) mouse liver compared to normal. However, exogenous administration of Queuine to DLAT mouse improves the activities of antioxidant enzymes. The results suggest that Queuine promotes antioxidant defense system by increasing antioxidant enzyme activities and in turn inhibits oxidative stress and tumorigenesis.
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Modulation in the activity of lactate dehydrogenase and level of c-Myc and c-Fos by modified base Queuine in cancer.
Cancer biology & therapy, 2007Co-Authors: Chandramani Pathak, Yogesh K. Jaiswal, Manjula VinayakAbstract:Cancer is characterized by uncontrolled cell growth, which results from unlimited proliferation and disturbs various cellular activities. Queuine is a highly modified base analogue of guanine found at first anti-codon position of specific tRNAs i.e. tRNA(Tyr), tRNA(His), tRNA(Asp) and tRNA(Asn). These tRNAs are known as Q-family of tRNA. The tRNAs of Q-family are completely modified to Q-tRNAs in terminally differentiated somatic cells, however hypomodification of Q-tRNA is closely associated with cell proliferation and malignancy. Queuosine modification of tRNAs may be essential for normal development, differentiation and cellular functions. Physiological role of Queuine remains ill defined but direct or indirect evidences suggest that Queuine or Q-tRNA participates in many cellular functions such as regulation of cell proliferation, control of glycolytic metabolism, alteration in expression of proto-oncogenes, modulation of signal transduction pathways but the mechanism is not well known. Increase in LDH-A expression regulated by c-myc is well documented in a variety of tumor cells. Overexpression of proto-oncogenes cause deregulated cellular responses which may lead to development of cancer. The cellular proto-oncogenes like c-myc and c-fos have important role in cell growth, proliferation and differentiation. The present study is aimed to investigate Queuine mediated modulation in the activity of lactate dehydrogenase and expression of proto-oncogenes like c-myc and c-fos in T-cell lymphoma (DLAT) induced cancerous mouse. The results indicate that elevated lactate dehydrogenase activity is brought down by Queuine treatments and the elevated levels of c-Myc and c-Fos in DLAT cancerous mouse are down-regulated, suggesting that Queuine inhibits anaerobic metabolism and cell proliferation.
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Possible involvement of Queuine in regulation of cell proliferation.
BioFactors (Oxford England), 2007Co-Authors: Chandramani Pathak, Yogesh K. Jaiswal, Manjula VinayakAbstract:An increase in cell number is one of the most prominent characteristics of cancer cells. This may be caused by an increase in cell proliferation or decrease in cell death. Queuine is one of the modified base which is found at first anticodon position of specific tRNAs. It is ubiquitously present throughout the living system except mycoplasma and yeast. The tRNAs of Q-family are completely modified to Q-tRNAs in terminally differentiated somatic cells, however hypomodification of Q-tRNA is closely associated with cell proliferation and malignancy. Queuine participates at various cellular functions such as regulation of cell proliferation, cell signaling and alteration in the expression of growth associated proto-oncogenes. Like other proto-oncogenes bcl2 is known to involve in cell survival by inhibiting apoptosis. Queuine or Q-tRNA is suggested to inhibit cell proliferation but the mechanism of regulation of cell proliferation by Queuine or Q-tRNA is not well understood. Therefore, in the present study regulation in cell proliferation by Queuine in vivo and in vitro as well as the expression of cell death regulatory protein Bcl2 are investigated. For this DLAT cancerous mouse, U87 cell line and HepG2 cell line are treated with different concentrations of Queuine and the effect of Queuine on cell proliferation and apoptosis are studied. The results indicate that Queuine down regulates cell proliferation and expression of Bcl2 protein, suggesting that Queuine promotes cell death and participates in the regulation of cell proliferation.
Vincent P. Kelly - One of the best experts on this subject based on the ideXlab platform.
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Queuine Micronutrient Deficiency Promotes Warburg Metabolism and Reversal of the Mitochondrial ATP Synthase in Hela Cells.
Nutrients, 2020Co-Authors: Patti Hayes, Claire Fergus, Magda Ghanim, Cansu Cirzi, Lyubomyr Burtnyak, Callum J. Mcgrenaghan, Francesca Tuorto, Derek P. Nolan, Vincent P. KellyAbstract:Queuine is a eukaryotic micronutrient, derived exclusively from eubacteria. It is incorporated into both cytosolic and mitochondrial transfer RNA to generate a queuosine nucleotide at position 34 of the anticodon loop. The transfer RNA of primary tumors has been shown to be hypomodified with respect to queuosine, with decreased levels correlating with disease progression and poor patient survival. Here, we assess the impact of Queuine deficiency on mitochondrial bioenergetics and substrate metabolism in HeLa cells. Queuine depletion is shown to promote a Warburg type metabolism, characterized by increased aerobic glycolysis and glutaminolysis, concomitant with increased ammonia and lactate production and elevated levels of lactate dehydrogenase activity but in the absence of significant changes to proliferation. In intact cells, Queuine deficiency caused an increased rate of mitochondrial proton leak and a decreased rate of ATP synthesis, correlating with an observed reduction in cellular ATP levels. Data from permeabilized cells demonstrated that the activity of individual complexes of the mitochondrial electron transport chain were not affected by the micronutrient. Notably, in Queuine free cells that had been adapted to grow in galactose medium, the re-introduction of glucose permitted the mitochondrial F1FO-ATP synthase to operate in the reverse direction, acting to hyperpolarize the mitochondrial membrane potential; a commonly observed but poorly understood cancer trait. Together, our data suggest that queuosine hypomodification is a deliberate and advantageous adaptation of cancer cells to facilitate the metabolic switch between oxidative phosphorylation and aerobic glycolysis.
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The eukaryotic tRNA-guanine transglycosylase enzyme inserts Queuine into tRNA via a sequential bi-bi mechanism.
Chemical communications (Cambridge England), 2020Co-Authors: Mashael A. Alqasem, Claire Fergus, J. Mike Southern, Stephen J. Connon, Vincent P. KellyAbstract:Eukaryotic tRNA-guanine transglycosylase (TGT) – an enzyme recently recognised to be of potential therapeutic importance – catalyses base-exchange of guanine for Queuine at the wobble position of tRNAs associated with 4 amino acids via a distinct mechanism to that reported for its eubacterial homologue. The presence of Queuine is unequivocally required as a trigger for reaction between the enzyme and tRNA and exhibits cooperativity not seen using guanine as a substrate.
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The Queuine micronutrient: Charting a course from microbe to man
Nutrients, 2015Co-Authors: Claire Fergus, Dominic Barnes, Mashael A. Alqasem, Vincent P. KellyAbstract:Micronutrients from the diet and gut microbiota are essential to human health and wellbeing. Arguably, among the most intriguing and enigmatic of these micronutrients is Queuine, an elaborate 7-deazaguanine derivative made exclusively by eubacteria and salvaged by animal, plant and fungal species. In eubacteria and eukaryotes, Queuine is found as the sugar nucleotide queuosine within the anticodon loop of transfer RNA isoacceptors for the amino acids tyrosine, asparagine, aspartic acid and histidine. The physiological requirement for the ancient Queuine molecule and queuosine modified transfer RNA has been the subject of varied scientific interrogations for over four decades, establishing relationships to development, proliferation, metabolism, cancer, and tyrosine biosynthesis in eukaryotes and to invasion and proliferation in pathogenic bacteria, in addition to ribosomal frameshifting in viruses. These varied effects may be rationalized by an important, if ill-defined, contribution to protein translation or may manifest from other presently unidentified mechanisms. This article will examine the current understanding of Queuine uptake, tRNA incorporation and salvage by eukaryotic organisms and consider some of the physiological consequence arising from deficiency in this elusive and lesser-recognized micronutrient.
Chandramani Pathak - One of the best experts on this subject based on the ideXlab platform.
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Queuosine modification of tRNA: its divergent role in cellular machinery.
Bioscience reports, 2009Co-Authors: Manjula Vinayak, Chandramani PathakAbstract:tRNAs possess a high content of modified nucleosides, which display an incredible structural variety. These modified nucleosides are conserved in their sequence and have important roles in tRNA functions. Most often, hypermodified nucleosides are found in the wobble position of tRNAs, which play a direct role in maintaining translational efficiency and fidelity, codon recognition, etc. One of such hypermodified base is Queuine, which is a base analogue of guanine, found in the first anticodon position of specific tRNAs (tyrosine, histidine, aspartate and asparagine tRNAs). These tRNAs of the 'Q-family' originally contain guanine in the first position of anticodon, which is post-transcriptionally modified with Queuine by an irreversible insertion during maturation. Queuine is ubiquitously present throughout the living system from prokaryotes to eukaryotes, including plants. Prokaryotes can synthesize Queuine de novo by a complex biosynthetic pathway, whereas eukaryotes are unable to synthesize either the precursor or Queuine. They utilize salvage system and acquire Queuine as a nutrient factor from their diet or from intestinal microflora. The tRNAs of the Q-family are completely modified in terminally differentiated somatic cells. However, hypomodification of Q-tRNA (queuosine-modified tRNA) is closely associated with cell proliferation and malignancy. The precise mechanisms of Queuine- and Q-tRNA-mediated action are still a mystery. Direct or indirect evidence suggests that Queuine or Q-tRNA participates in many cellular functions, such as inhibition of cell proliferation, control of aerobic and anaerobic metabolism, bacterial virulence, etc. The role of Q-tRNA modification in cellular machinery and the signalling pathways involved therein is the focus of this review.
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Queuine mediated inhibition in phosphorylation of tyrosine phosphoproteins in cancer
Molecular Biology Reports, 2008Co-Authors: Chandramani Pathak, Yogesh K. Jaiswal, Manjula VinayakAbstract:Protein phosphorylation or dephosphorylation is the most important regulatory switch of signal transduction contributing to control of cell proliferation. The reversibility of phosphorylation and dephosphorylation is due to the activities of kinases and phosphatase, which determine protein phosphorylation level of cell under different physiological and pathological conditions. Receptor tyrosine kinase (RTK) mediated cellular signaling is precisely coordinated and tightly controlled in normal cells which ensures regulated mitosis. Deregulation of RTK signaling resulting in aberrant activation in RTKs leads to malignant transformation. Queuine is one of the modified base of tRNA which participates in down regulation of tyrosine kinase activity. The guanine analogue Queuine is a nutrient factor to eukaryotes and occurs as free base or modified nucleoside queuosine into the first anticodon position of specific tRNAs. The tRNAs are often Queuine deficient in cancer and fast proliferating tissues. The present study is aimed to investigate Queuine mediated inhibition in phosphorylation of tyrosine phosphorylated proteins in lymphoma bearing mouse. The result shows high level of cytosolic and membrane associated tyrosine phosphoprotein in DLAT cancerous mouse liver compared to normal. Queuine treatments down regulate the level of tyrosine phosphoproteins, which suggests that Queuine is involved in regulation of mitotic signaling pathways.
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Queuine promotes antioxidant defence system by activating cellular antioxidant enzyme activities in cancer.
Bioscience reports, 2008Co-Authors: Chandramani Pathak, Yogesh K. Jaiswal, Manjula VinayakAbstract:Constant generation of Reactive oxygen species (ROS) during normal cellular metabolism of an organism is generally balanced by similar rate of consumption by antioxidants. Imbalance between ROS production and antioxidant defense results in increased level of ROS causing oxidative stress which leads to promotion of malignancy. Queuine is a hyper modified base analogue of guanine, found at first anti-codon position of Q- family of tRNAs. These tRNAs are completely modified with respect to queuosine in terminally differentiated somatic cells, however hypomodification of Q-tRNAs is close association with cell proliferation. Q-tRNA modification is essential for normal development, differentiation and cellular functions. Queuine is a nutrient factor to eukaryotes. It is found to promote cellular antioxidant defense system and inhibit tumorigenesis. The activities of antioxidant enzymes like catalase, SOD, glutathione peroxidase and glutathione reductase are found to be low in Dalton's lymphoma ascites transplanted (DLAT) mouse liver compared to normal. However, exogenous administration of Queuine to DLAT mouse improves the activities of antioxidant enzymes. The results suggest that Queuine promotes antioxidant defense system by increasing antioxidant enzyme activities and in turn inhibits oxidative stress and tumorigenesis.
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Modulation in the activity of lactate dehydrogenase and level of c-Myc and c-Fos by modified base Queuine in cancer.
Cancer biology & therapy, 2007Co-Authors: Chandramani Pathak, Yogesh K. Jaiswal, Manjula VinayakAbstract:Cancer is characterized by uncontrolled cell growth, which results from unlimited proliferation and disturbs various cellular activities. Queuine is a highly modified base analogue of guanine found at first anti-codon position of specific tRNAs i.e. tRNA(Tyr), tRNA(His), tRNA(Asp) and tRNA(Asn). These tRNAs are known as Q-family of tRNA. The tRNAs of Q-family are completely modified to Q-tRNAs in terminally differentiated somatic cells, however hypomodification of Q-tRNA is closely associated with cell proliferation and malignancy. Queuosine modification of tRNAs may be essential for normal development, differentiation and cellular functions. Physiological role of Queuine remains ill defined but direct or indirect evidences suggest that Queuine or Q-tRNA participates in many cellular functions such as regulation of cell proliferation, control of glycolytic metabolism, alteration in expression of proto-oncogenes, modulation of signal transduction pathways but the mechanism is not well known. Increase in LDH-A expression regulated by c-myc is well documented in a variety of tumor cells. Overexpression of proto-oncogenes cause deregulated cellular responses which may lead to development of cancer. The cellular proto-oncogenes like c-myc and c-fos have important role in cell growth, proliferation and differentiation. The present study is aimed to investigate Queuine mediated modulation in the activity of lactate dehydrogenase and expression of proto-oncogenes like c-myc and c-fos in T-cell lymphoma (DLAT) induced cancerous mouse. The results indicate that elevated lactate dehydrogenase activity is brought down by Queuine treatments and the elevated levels of c-Myc and c-Fos in DLAT cancerous mouse are down-regulated, suggesting that Queuine inhibits anaerobic metabolism and cell proliferation.
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Possible involvement of Queuine in regulation of cell proliferation.
BioFactors (Oxford England), 2007Co-Authors: Chandramani Pathak, Yogesh K. Jaiswal, Manjula VinayakAbstract:An increase in cell number is one of the most prominent characteristics of cancer cells. This may be caused by an increase in cell proliferation or decrease in cell death. Queuine is one of the modified base which is found at first anticodon position of specific tRNAs. It is ubiquitously present throughout the living system except mycoplasma and yeast. The tRNAs of Q-family are completely modified to Q-tRNAs in terminally differentiated somatic cells, however hypomodification of Q-tRNA is closely associated with cell proliferation and malignancy. Queuine participates at various cellular functions such as regulation of cell proliferation, cell signaling and alteration in the expression of growth associated proto-oncogenes. Like other proto-oncogenes bcl2 is known to involve in cell survival by inhibiting apoptosis. Queuine or Q-tRNA is suggested to inhibit cell proliferation but the mechanism of regulation of cell proliferation by Queuine or Q-tRNA is not well understood. Therefore, in the present study regulation in cell proliferation by Queuine in vivo and in vitro as well as the expression of cell death regulatory protein Bcl2 are investigated. For this DLAT cancerous mouse, U87 cell line and HepG2 cell line are treated with different concentrations of Queuine and the effect of Queuine on cell proliferation and apoptosis are studied. The results indicate that Queuine down regulates cell proliferation and expression of Bcl2 protein, suggesting that Queuine promotes cell death and participates in the regulation of cell proliferation.
