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7 Methylguanosine

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Kimitsuna Watanabe – One of the best experts on this subject based on the ideXlab platform.

Marzena Jankowska-anyszka – One of the best experts on this subject based on the ideXlab platform.

  • How to find the optimal partner–studies of snurportin 1 interactions with U snRNA 5′ TMG-cap analogues containing modified 2-amino group of 7Methylguanosine.
    Bioorganic & medicinal chemistry, 2015
    Co-Authors: Karolina Piecyk, Anna Niedzwiecka, Edward Darzynkiewicz, Aleksandra Ferenc-mrozek, Maciej Lukaszewicz, Marzena Jankowska-anyszka
    Abstract:

    Abstract Snurportin 1 is an adaptor protprotein that mediates the active nuclear import of uridine-rich small nuclear RNAs (U snRNA) by the importin-β receptor pathway. Its cellular activity influences the overall transport yield of small ribonucleoprotein complexes containing N 2 ,N 2 ,7-triMethylguanosine (TMG) capped U snRNA. So far little is still known about structural requirements related to molecular recognition of the triMethylguanosine moiety by snurportin in solution. Since these interactions are of a great biomedical importance, we synthesized a series of new 7Methylguanosine cap analogues with extended substituents at the exocyclic 2-amino group to gain a deeper insight into how the TMG-cap is adapted into the snurportin cap-binding pocket. Prepared chemical tools were applied in binding assays using emission spectroscopy. Surprisingly, our results revealed strict selectivity of snurportin towards the TMG-cap structure that relied mainly on its structural stiffness and compactness.

  • Synthesis of N2-modified 7Methylguanosine 5′-monophosphates as nematode translation inhibitors
    Bioorganic & medicinal chemistry, 2012
    Co-Authors: Karolina Piecyk, Richard E. Davis, Marzena Jankowska-anyszka
    Abstract:

    Abstract Preparative scale synthesis of 14 new N2-modified mononucleotide 5′ mRNA cap analogues was achieved. The key step involved use of an SNAr reaction with protected 2-fluoro inosine and various primary and secondary amines. The derivatives were tested in a parasitic nematode, Ascaris suum, cell-free system as translation inhibitors. The most effective compound with IC50 ∼0.9 μM was a N2-p-metoxybenzyl-7Methylguanosine-5′-monophosphate 35.

  • Diverse Role of Three Tyrosines in Binding of the RNA 5′ Cap to the Human Nuclear Cap Binding Complex
    Journal of molecular biology, 2008
    Co-Authors: Remigiusz Worch, Marzena Jankowska-anyszka, Anna Niedzwiecka, Janusz Stepinski, Catherine Mazza, Edward Darzynkiewicz, Stephen Cusack, Ryszard Stolarski
    Abstract:

    The heterodimeric nuclear cap-binding complex (CBC) specifically recognizes the monoMethylguanosine 5′ cap structure of the eukaryotic RNA polypolymerase/a> transcripts such as mRNA and U snRNA. The binding is essential for nuclear maturation of mRNA, for nuclear export of U snRNA in metazoans, and for nonsense-mediated decay of mRNA and the pioneer round of translation. We analysed the recognition of the cap by native human CBC and mutants in which each tyrosine that stacks with the 7Methylguanosine moiety was replaced by phenylalanine or alanine and both tyrosines were replaced by phenylalanines. The equilibrium association constants (Kas) for two selected cap analogues, P1-7Methylguanosine-5′ P3-guanosine-5′ triphosphate and 7Methylguanosine triphosphate, were determined by two independent methods, fluorescence titration and surface plasmon resonance. We could distinguish two tyrosines, Y43 and Y20, in stabilization of the cap inside the CBC-binding pocket. In particular, lack of Y20 in CBC leads to a greater affinity of the mono- than the dinucleotide cap analogue, in contrast to the wild-type protein. A crucial role of cation–π stacking in the mechanism of the specific cap recognition by CBC was postulated from the comparison of the experimentally derived Gibbs free binding energy (ΔG°) with the stacking energy (ΔE) of the 7Methylguanosine/Y binary and ternary complexes calculated by the Moller–Plesset second-order perturbation method. The resulting kinetic model of the association between the capped RNA and CBC, based on the experimental data and quantum calculations, is discussed with respect to the “CBC-to-eukaryotic initiation factor 4E handoff” of mRNA.

Takuya Ueda – One of the best experts on this subject based on the ideXlab platform.

  • 7 Methylguanosine at the anticodon wobble position of squid mitochondrial trnasergcu molecular basis for assignment of aga agg codons as serine in invertebrate mitochondria
    Biochimica et Biophysica Acta, 1998
    Co-Authors: Kozo Tomita, Takuya Ueda, Kimitsuna Watanabe
    Abstract:

    Abstract In mitochondria of the squid, Loligo bleekeri , both the AGA and AGG codons are considered to correspond to serine instead of arginine as in the universal genetic code, and its genome encodes a single tRNA Ser gene with the anticodon GCT. Therefore, this gene product, tRNA Ser GCU, should be able to translate all four AGN (N; U, C, A, and G) codons as serine. To elucidate this recognition mechanism, the tRNA Ser GCU was isolated from squid liver and its complete nucleotide sequence determined. The tRNA Ser GCU was found to possess 7Methylguanosine (m 7 G) at the wobble position of the anticodon. This suggests that in the squid mitochondrial system, tRNA Ser GCU with the anticodon m 7 GCU can recognize not only the usual serine codons AGU and AGC, but also the unusual serine codons AGA and AGG, as in the case of starfish mitochondria (Matsuyama et al., J. Biol. Chem. 273 (1988) 3363–3368).

  • 7Methylguanosine at the anticodon wobble position of squid mitochondrial tRNASerGCU: molecular basis for assignment of AGA/AGG codons as serine in invertebrate mitochondria
    Biochimica et biophysica acta, 1998
    Co-Authors: Kozo Tomita, Takuya Ueda, Kimitsuna Watanabe
    Abstract:

    Abstract In mitochondria of the squid, Loligo bleekeri , both the AGA and AGG codons are considered to correspond to serine instead of arginine as in the universal genetic code, and its genome encodes a single tRNA Ser gene with the anticodon GCT. Therefore, this gene product, tRNA Ser GCU, should be able to translate all four AGN (N; U, C, A, and G) codons as serine. To elucidate this recognition mechanism, the tRNA Ser GCU was isolated from squid liver and its complete nucleotide sequence determined. The tRNA Ser GCU was found to possess 7Methylguanosine (m 7 G) at the wobble position of the anticodon. This suggests that in the squid mitochondrial system, tRNA Ser GCU with the anticodon m 7 GCU can recognize not only the usual serine codons AGU and AGC, but also the unusual serine codons AGA and AGG, as in the case of starfish mitochondria (Matsuyama et al., J. Biol. Chem. 273 (1988) 3363–3368).

  • A novel wobble rule found in starfish mitochondria. Presence of 7Methylguanosine at the anticodon wobble position expands decoding capability of tRNA.
    The Journal of biological chemistry, 1998
    Co-Authors: Satoshi Matsuyama, Takuya Ueda, Pamela F. Crain, James A. Mccloskey, Kimitsuna Watanabe
    Abstract:

    Abstract In the starfish mitochondrial (mt) genome, codons AGA and AGG (in addition to AGU and AGC) have been considered to be translated as serine. There is, however, only a single candidate mt tRNA gene responsible for translating these codons and it has a GCT anticodon sequence, but guanosine at the first position of the anticodon should base pair only with pyrimidines according to the conventional wobble rule. To solve this enigma, the mt tRNAGCU ser was purified, and sequence determination in combination with electrospray liquid chromatography/mass spectrometry revealed that 7Methylguanosine is located at the first position of the anticodon. This is the first case in which a tRNA has been found to have 7Methylguanosine at the wobble position. It is suggested that methylation at N-7 of wobbling guanosine endows the tRNA with the capability of forming base pairs with all four nucleotides, A, U, G, and C, and expands the repertoire of codon-anticodon interaction. This finding indicates that a nonuniversal genetic code in starfish has been generated by base modification in the tRNA anticodon.

Kozo Tomita – One of the best experts on this subject based on the ideXlab platform.

  • 7Methylguanosine at the anticodon wobble position of squid mitochondrial tRNASerGCU: molecular basis for assignment of AGA/AGG codons as serine in invertebrate mitochondria
    Biochimica et biophysica acta, 1998
    Co-Authors: Kozo Tomita, Takuya Ueda, Kimitsuna Watanabe
    Abstract:

    Abstract In mitochondria of the squid, Loligo bleekeri , both the AGA and AGG codons are considered to correspond to serine instead of arginine as in the universal genetic code, and its genome encodes a single tRNA Ser gene with the anticodon GCT. Therefore, this gene product, tRNA Ser GCU, should be able to translate all four AGN (N; U, C, A, and G) codons as serine. To elucidate this recognition mechanism, the tRNA Ser GCU was isolated from squid liver and its complete nucleotide sequence determined. The tRNA Ser GCU was found to possess 7Methylguanosine (m 7 G) at the wobble position of the anticodon. This suggests that in the squid mitochondrial system, tRNA Ser GCU with the anticodon m 7 GCU can recognize not only the usual serine codons AGU and AGC, but also the unusual serine codons AGA and AGG, as in the case of starfish mitochondria (Matsuyama et al., J. Biol. Chem. 273 (1988) 3363–3368).

  • 7 Methylguanosine at the anticodon wobble position of squid mitochondrial trnasergcu molecular basis for assignment of aga agg codons as serine in invertebrate mitochondria
    Biochimica et Biophysica Acta, 1998
    Co-Authors: Kozo Tomita, Takuya Ueda, Kimitsuna Watanabe
    Abstract:

    Abstract In mitochondria of the squid, Loligo bleekeri , both the AGA and AGG codons are considered to correspond to serine instead of arginine as in the universal genetic code, and its genome encodes a single tRNA Ser gene with the anticodon GCT. Therefore, this gene product, tRNA Ser GCU, should be able to translate all four AGN (N; U, C, A, and G) codons as serine. To elucidate this recognition mechanism, the tRNA Ser GCU was isolated from squid liver and its complete nucleotide sequence determined. The tRNA Ser GCU was found to possess 7Methylguanosine (m 7 G) at the wobble position of the anticodon. This suggests that in the squid mitochondrial system, tRNA Ser GCU with the anticodon m 7 GCU can recognize not only the usual serine codons AGU and AGC, but also the unusual serine codons AGA and AGG, as in the case of starfish mitochondria (Matsuyama et al., J. Biol. Chem. 273 (1988) 3363–3368).

Edward Darzynkiewicz – One of the best experts on this subject based on the ideXlab platform.

  • How to find the optimal partner–studies of snurportin 1 interactions with U snRNA 5′ TMG-cap analogues containing modified 2-amino group of 7Methylguanosine.
    Bioorganic & medicinal chemistry, 2015
    Co-Authors: Karolina Piecyk, Anna Niedzwiecka, Edward Darzynkiewicz, Aleksandra Ferenc-mrozek, Maciej Lukaszewicz, Marzena Jankowska-anyszka
    Abstract:

    Abstract Snurportin 1 is an adaptor protein that mediates the active nuclear import of uridine-rich small nuclear RNAs (U snRNA) by the importin-β receptor pathway. Its cellular activity influences the overall transport yield of small ribonucleoprotein complexes containing N 2 ,N 2 ,7-triMethylguanosine (TMG) capped U snRNA. So far little is still known about structural requirements related to molecular recognition of the triMethylguanosine moiety by snurportin in solution. Since these interactions are of a great biomedical importance, we synthesized a series of new 7Methylguanosine cap analogues with extended substituents at the exocyclic 2-amino group to gain a deeper insight into how the TMG-cap is adapted into the snurportin cap-binding pocket. Prepared chemical tools were applied in binding assays using emission spectroscopy. Surprisingly, our results revealed strict selectivity of snurportin towards the TMG-cap structure that relied mainly on its structural stiffness and compactness.

  • 7Methylguanosine Diphosphate (m7GDP) Is Not Hydrolyzed but Strongly Bound by Decapping Scavenger (DcpS) Enzymes and Potently Inhibits Their Activity
    Biochemistry, 2012
    Co-Authors: Anna Wypijewska, Janusz Stepinski, Richard E. Davis, Maciej Lukaszewicz, Elzbieta Bojarska, Jacek Jemielity, Edward Darzynkiewicz
    Abstract:

    Decapping scavenger (DcpS) enzymes catalyze the cleavage of a residual cap structure following 3′ → 5′ mRNA decay. Some previous studies suggested that both m(7)GpppG and m(7)GDP were substrates for DcpS hydrolysis. Herein, we show that mononucleoside diphosphates, m(7)GDP (7Methylguanosine diphosphate) and m(3)(2,2,7)GDP (2,2,7-triMethylguanosine diphosphate), resulting from mRNA decapping by the Dcp1/2 complex in the 5′ → 3′ mRNA decay, are not degraded by recombinant DcpS proteins (human, nematode, and yeast). Furthermore, whereas mononucleoside diphosphates (m(7)GDP and m(3)(2,2,7)GDP) are not hydrolyzed by DcpS, mononucleoside triphosphates (m(7)GTP and m(3)(2,2,7)GTP) are, demonstrating the importance of a triphosphate chain for DcpS hydrolytic activity. m(7)GTP and m(3)(2,2,7)GTP are cleaved at a slower rate than their corresponding dinucleotides (m(7)GpppG and m(3)(2,2,7)GpppG, respectively), indicating an involvement of the second nucleoside for efficient DcpS-mediated digestion. Although DcpS enzymes cannot hydrolyze m(7)GDP, they have a high binding affinity for m(7)GDP and m(7)GDP potently inhibits DcpS hydrolysis of m(7)GpppG, suggesting that m(7)GDP may function as an efficient DcpS inhibitor. Our data have important implications for the regulatory role of m(7)GDP in mRNA metabolic pathways due to its possible interactions with different cap-binding protproteins, such as DcpS or eIF4E.

  • Diverse Role of Three Tyrosines in Binding of the RNA 5′ Cap to the Human Nuclear Cap Binding Complex
    Journal of molecular biology, 2008
    Co-Authors: Remigiusz Worch, Marzena Jankowska-anyszka, Anna Niedzwiecka, Janusz Stepinski, Catherine Mazza, Edward Darzynkiewicz, Stephen Cusack, Ryszard Stolarski
    Abstract:

    The heterodimeric nuclear cap-binding complex (CBC) specifically recognizes the monoMethylguanosine 5′ cap structure of the eukaryotic RNA polymerase II transcripts such as mRNA and U snRNA. The binding is essential for nuclear maturation of mRNA, for nuclear export of U snRNA in metazoans, and for nonsense-mediated decay of mRNA and the pioneer round of translation. We analysed the recognition of the cap by native human CBC and mutants in which each tyrosine that stacks with the 7Methylguanosine moiety was replaced by phenylalanine or alanine and both tyrosines were replaced by phenylalanines. The equilibrium association constants (Kas) for two selected cap analogues, P1-7Methylguanosine-5′ P3-guanosine-5′ triphosphate and 7Methylguanosine triphosphate, were determined by two independent methods, fluorescence titration and surface plasmon resonance. We could distinguish two tyrosines, Y43 and Y20, in stabilization of the cap inside the CBC-binding pocket. In particular, lack of Y20 in CBC leads to a greater affinity of the mono- than the dinucleotide cap analogue, in contrast to the wild-type protein. A crucial role of cation–π stacking in the mechanism of the specific cap recognition by CBC was postulated from the comparison of the experimentally derived Gibbs free binding energy (ΔG°) with the stacking energy (ΔE) of the 7Methylguanosine/Y binary and ternary complexes calculated by the Moller–Plesset second-order perturbation method. The resulting kinetic model of the association between the capped RNA and CBC, based on the experimental data and quantum calculations, is discussed with respect to the “CBC-to-eukaryotic initiation factor 4E handoff” of mRNA.