Formation of new base pairs between inosine and 5-methyl-2-thiocytidine derivatives

Ohkubo, Akihiro; Nishino, Yudai; Yu, I.; Tsunoda, Hirosuke; Seio, Kohji; Sekine, Mitsuo

doi:10.1039/c2ob06641f

Cited by 11 publications

(4 citation statements)

References 13 publications

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“…The stereoelectronic character of the nucleobase can tune the sugar pucker confirmation of a nucleotide ( 20 ), and 2-thiolated pyrimidines (2-thioU, sU; 2-thio-C, sC) have been shown to have an increased preference for the C3′-endo configuration ( 21 ). Furthermore, the sU:A base pair is stronger than the U:A base pair ( 22 ), while the sC:I (inosine) base pair ( 23 ) is weaker than the C:G base pair because it has 2 instead of 3 hydrogen bonds per base pair. To examine the conformations, affinities and rates of the corresponding imidazolium-bridged dinucleotides, we synthesized the 2-thio-uridine homodimer (sU*sU) and the 2-thio-cytidine homodimer (sC*sC).…”

Section: Resultsmentioning

confidence: 99%

Kinetic explanations for the sequence biases observed in the nonenzymatic copying of RNA templates

Ding

Zhou

Giurgiu

et al. 2021

Nucleic Acids Research

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The identification of nonenzymatic pathways for nucleic acid replication is a key challenge in understanding the origin of life. We have previously shown that nonenzymatic RNA primer extension using 2-aminoimidazole (2AI) activated nucleotides occurs primarily through an imidazolium-bridged dinucleotide intermediate. The reactive nature and preorganized structure of the intermediate increase the efficiency of primer extension but remain insufficient to drive extensive copying of RNA templates containing all four canonical nucleotides. To understand the factors that limit RNA copying, we synthesized all ten 2AI-bridged dinucleotide intermediates and measured the kinetics of primer extension in a model system. The affinities of the ten dinucleotides for the primer/template/helper complexes vary by over 7,000-fold, consistent with nearest neighbor energetic predictions. Surprisingly, the reaction rates at saturating intermediate concentrations still vary by over 15-fold, with the most weakly binding dinucleotides exhibiting a lower maximal reaction rate. Certain noncanonical nucleotides can decrease sequence dependent differences in affinity and primer extension rate, while monomers bridged to short oligonucleotides exhibit enhanced binding and reaction rates. We suggest that more uniform binding and reactivity of imidazolium-bridged intermediates may lead to the ability to copy arbitrary template sequences under prebiotically plausible conditions.

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Section: Resultsmentioning

confidence: 99%

Kinetic explanations for the sequence biases observed in the nonenzymatic copying of RNA templates

Ding

Zhou

Giurgiu

et al. 2021

Nucleic Acids Research

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“…Scheme 1 shows the synthesis of 2’-OMe g C s phosphoramidite unit 2 . 2’-OMe s T phosphoramidite unit was converted to compound 6 by using phosphoryl chloride and then 1, 2, 4-triazole and introduction of a 2-aminoethylamino group into the 4-position of the pyrimidine ( 19 , 24 ) was carried out to obtain compound 7 . 2’-OMe g C s phosphoramidite unit 2 was synthesized by treating compound 7 with S -methylthiourea derivative 8 in 68% isolated yield from compound 5 (3 steps, Scheme 1 ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and triplex-forming properties of oligonucleotides capable of recognizing corresponding DNA duplexes containing four base pairs

Ohkubo

Yamada

et al. 2015

Nucleic Acids Res

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A triplex-forming oligonucleotide (TFO) could be a useful molecular tool for gene therapy and specific gene modification. However, unmodified TFOs have two serious drawbacks: low binding affinities and high sequence-dependencies. In this paper, we propose a new strategy that uses a new set of modified nucleobases for four-base recognition of TFOs, and thereby overcome these two drawbacks. TFOs containing a 2’-deoxy-4N-(2-guanidoethyl)-5-methylcytidine (dgC) residue for a C-G base pair have higher binding and base recognition abilities than those containing 2’-OMe-4N-(2-guanidoethyl)-5-methylcytidine (2’-OMegC), 2’-OMe-4N-(2-guanidoethyl)-5-methyl-2-thiocytidine (2’-OMegCs), dgC and 4S-(2-guanidoethyl)-4-thiothymidine (gsT). Further, we observed that N-acetyl-2,7-diamino-1,8-naphtyridine (DANac) has a higher binding and base recognition abilities for a T-A base pair compared with that of dG and the other DNA derivatives. On the basis of this knowledge, we successfully synthesized a fully modified TFO containing DANac, dgC, 2’-OMe-2-thiothymidine (2’-OMesT) and 2’-OMe-8-thioxoadenosine (2’-OMesA) with high binding and base recognition abilities. To the best of our knowledge, this is the first report in which a fully modified TFO accurately recognizes a complementary DNA duplex having a mixed sequence under neutral conditions.

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“…The stereoelectronic character of the nucleobase can tune the sugar pucker confirmation of a nucleotide, (20) and 2-thiolated pyrimidines (2-thioU, sU; 2-thio-C, sC) have been shown to have an increased preference for the C3ʹ-endo configuration. ( 21) Furthermore, the sU:A base pair is stronger than U:A base pair, (22) while the sC:I (inosine) base pair (23) is weaker than the C:G base pair because it has 2 instead of 3 hydrogen bonds per base pair. To examine the conformations, affinities and rates of the corresponding imidazolium-bridged dinucleotides, we synthesized the 2-thio-uridine homodimer (sU*sU) and the 2-thiocytidine homodimer (sC*sC).…”

Section: Potential Solutions To the Weak Binding And Poor Reactivity Of Specific Dinucleotide Intermediatesmentioning

confidence: 99%

Kinetic Explanations for the Sequence Biases Observed in the Nonenzymatic Copying of RNA Templates

Ding

Zhou

Giurgiu

et al. 2021

Preprint

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The identification of nonenzymatic pathways for nucleic acid replication is a key challenge in understanding the origin of life. We have previously shown that nonenzymatic RNA primer extension using 2-aminoimidazole (2AI) activated nucleotides occurs primarily through an imidazolium-bridged dinucleotide intermediate. The reactive nature and preorganized structure of the intermediate increase the efficiency of primer extension but remain insufficient to drive extensive copying of RNA templates containing all four canonical nucleotides. To understand the factors that limit RNA copying, we synthesized all ten 2AI-bridged dinucleotide intermediates and measured the kinetics of primer extension in a model. The affinities of the ten dinucleotides for the primer/template/helper complexes vary by over 7,000-fold, consistent with nearest neighbor energetic predictions. Surprisingly, the reaction rates at saturating intermediate concentrations still vary by over 15-fold, with the most weakly binding dinucleotides exhibiting a lower maximal reaction rate. Certain noncanonical nucleotides can decrease sequence dependent differences in affinity and primer extension rate, while monomers bridged to short oligonucleotides exhibit enhanced binding and reaction rates. We suggest that more uniform binding and reactivity of imidazolium-bridged intermediates may lead to the ability to copy arbitrary template sequences under prebiotically plausible conditions.

show abstract

Formation of new base pairs between inosine and 5-methyl-2-thiocytidine derivatives

Cited by 11 publications

References 13 publications

Kinetic explanations for the sequence biases observed in the nonenzymatic copying of RNA templates

Kinetic explanations for the sequence biases observed in the nonenzymatic copying of RNA templates

Synthesis and triplex-forming properties of oligonucleotides capable of recognizing corresponding DNA duplexes containing four base pairs

Kinetic Explanations for the Sequence Biases Observed in the Nonenzymatic Copying of RNA Templates

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