Interaction and association of bases and nucleosides in aqueous solutions.  V.  Studies of the association of purine nucleosides by vapor pressure osmometry and by proton magnetic resonance

Broom, Arthur D.; Schweizer, Martin; Ts’o, Paul O. P.

doi:10.1021/ja00990a047

Cited by 240 publications

(138 citation statements)

References 32 publications

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“…ATP is a more efficient substrate than UTP when tested with the mutant enzymes, in agreement with the expectation that a purine base will form stronger -interactions than a pyrimidine base (27). Introduction of a methyl group on the aromatic base of either ATP or UTP increased the catalytic efficiency of the reaction by the mutant enzymes, and methylation has been shown to enhance -interactions (3,27). Finally, reduction of a double bond in UTP to form dihydro-UTP preferentially reduced the catalytic efficiency of the mutant enzymes, in agreement with the loss of aromatic structure resulting from this modification, which would disfavor -interactions.…”

Section: Vol 46 2002 Notes 1541supporting

confidence: 80%

Effects of Specific Zidovudine Resistance Mutations and Substrate Structure on Nucleotide-Dependent Primer Unblocking by Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Meyer¹,

Matsuura²,

Tolun³

et al. 2002

Antimicrob Agents Chemother

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Nucleotide-dependent unblocking of chain-terminated DNA by human immunodeficiency virus type 1 reverse transcriptase (RT) is enhanced by the presence of mutations associated with 3-azido-3-deoxythymidine (AZT) resistance. The increase in unblocking activity was greater for mutant combinations associated with higher levels of in vivo AZT resistance. The difference between mutant and wild-type activity was further enhanced by introduction of a methyl group into the nucleotide substrate and was decreased for a nonaromatic substrate, suggesting that -interactions between RT and an aromatic structure may be facilitated by these mutations.Many nucleoside analogues, including 3Ј-azido-3Ј-deoxythymidine (AZT), inhibit human immunodeficiency virus type 1 (HIV-1) replication. The phosphorylated forms of these compounds are incorporated during DNA synthesis by the HIV-1 reverse transcriptase (RT), resulting in chain termination and inhibition of viral replication (7,9,12,22,31,32). Mutations at codons 41, 67, 70, 210, 215, and 219 in the HIV-1 RT gene result in resistance of HIV-1 to AZT in cell culture assays (29). Substitutions of phenylalanine and tyrosine for threonine at position 215 (T215F and T215Y) are the predominant mutations observed in vivo and are considered the most important for the resistance phenotype (16,17,25).The inhibitory effect of incorporating a chain-terminating nucleotide analogue can be partially relieved by a reaction catalyzed by RT in which the terminating nucleotide is removed from the 3Ј end of a DNA chain by transfer to a nucleotide di-or triphosphate, producing an unblocked DNA chain and dinucleoside polyphosphate with the chain terminator linked to the nucleotide acceptor through a tri-or tetraphosphate chain (19,21). HIV-1 RT can also transfer the chain-terminating residue to pyrophosphate (PP i ), regenerating the triphosphate form of the chain terminator (1, 5, 10, 23). These observations have suggested that enhanced removal of 3Ј-azido-3Ј-deoxythymidine-5Ј-monophosphate (AZTMP) is a possible mechanism for AZT resistance, and an increase in the removal reaction has been reported for RT containing various AZT resistance mutations (1,2,18,19). The biochemical contribution of each of these mutations in the removal reaction remains unclear. Boyer et al. (2) have modeled the amino acid substitutions associated with AZT resistance, as well as ATP or PP i , into the three-dimensional structure of HIV-1 RT and concluded that several of these amino acid substitutions could affect the binding of ATP but are unlikely to affect binding of PP i .In this report we describe further investigation into the contributions made by specific mutations in HIV-1 RT to its removal activity and the effects of changes in the structure of the nucleotide substrate on the wild-type (WT) and mutant activities. The mutations associated with AZT resistance identify a region of HIV-1 RT that may interact with the nucleoside moiety of a transition intermediate to facilitate the formation of the dinucleoside tetraphospha...

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Section: Vol 46 2002 Notes 1541supporting

confidence: 80%

Effects of Specific Zidovudine Resistance Mutations and Substrate Structure on Nucleotide-Dependent Primer Unblocking by Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Meyer¹,

Matsuura²,

Tolun³

et al. 2002

Antimicrob Agents Chemother

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“…þ as estimated by Steenken. 58 Furthermore, it is also well known that in an aqueous medium, dAdo tends to dimerize in the stacked conformation at ambient temperatures [170][171][172][173] . þ is quite stable with a calculated pK a of the dimer of 7 and that of the monomer of À0.3 (described below).…”

Section: Nature Of Hole Delocalization In Adenine Stacks: the Dimer Rmentioning

confidence: 99%

Theoretical Modeling of Radiation‐Induced DNA Damage

Kumar

Sevilla

2009

Radical and Radical Ion Reactivity in Nucleic Acid Chemistry

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“…The amino protons of these two mononucleotides show concentration-dependent upfield shifts comparable to those of ring protons. It has been demonstrated for adenosine that if the amino group is methylated, the methyl-amino protons exhibit concentrationdependent PMR shifts similar to those of the aromatic protons (20). However, for GMP, it is possible that the amino group is additionally involved in hydrogen bonding selfassociation, as judged by its relatively smaller upfield shift when the GMP concentration is increased.…”

Section: Self-association Of Mononucleotides In Watermentioning

confidence: 99%

Association by Hydrogen Bonding of Mononucleotides in Aqueous Solution

Raszka

Kaplan

1972

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

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Evidence for hydrogen bonding between 5'-ribonucleotides in water has been obtained from a 220-MHz proton magnetic resonance study of nitrogenous protons. The amino groups of GMP, AMP, and CMP exhibit proton resonance lines which are somewhat broadened by proton exchange with the solvent at 00; their downfield shifts in mixtures of mononucleotides provide the basis for the following order of base-pairing tendencies: GMP CMP > AMP. UMP. Hydrogen bonding is also observed in other pairs of mononucleotides, notably GMP UMP, AMP-CMP, and CMP-UMP, to a lesser extent in GMP-IMP, CMPS XMP, and possibly in CMP-IMP. In agreement with previous reports, hydrophobic interactions of mononucleotides have also been observed; base pairing occurs in addition to vertical stacking of these bases, their hydrogen bonding to water, or self-association. Only CMP shows clear evidence of self-association via hydrogen bonding in water; the evidence for GMP is less direct, and that for AMP is negative. This lack of observable self-association may occur as a result of competition from strong stacking interactions.Only CMP shows restricted rotation of the amino group at 00 and neutral pH. As expected, higher temperatures increase the rate of rotation of the amino group for CMP, as well as accelerate the rate of proton exchange between water and the amino protons of mononucleotides. High-resolution proton magnetic resonance spectroscopy could prove to be a valuable tool in mapping out the specificities conferred by hydrogen bonding between biomolecules in aqueous solution.Hydrogen bonding between the monomers of nucleic acids has been the object of numerous investigations. The initial success of infrared spectroscopy in demonstrating hydrogen bonding between A and U derivatives in deuterochloroform (1) was quickly followed by more extensive infrared studies (2, 3), as well as by two proton magnetic resonance (PMR) reports (4, 5) that showed the remarkable Watson-Crick specificity of G * C, and the much weaker A * U interaction in organic solvents. Other possible combinations of bases showed little or no association, as analyzed by infrared and PMR spectroscopy.Although interactions occurring in aqueous solvents are more applicable to biological systems, little work has been done on hydrogen bonding of nucleotide bases in water. Several workers (6-8) have interpreted their results in terms of base pairing, but these chromatographic and solubility studies, as well as an extensive osmometric study (9), were incapable of distinguishing between hydrogen bonding and stacking interactions. Raman spectroscopy studies of complementary mononucleotides failed to detect any spectral changes (10), whereas PMR spectroscopy studies generally revealed upfield shifts of nondissociable ring protons; this result is consistent with the view that stacking of mononucleotides is predominant in D20 (11-13).We believe that we have PMR evidence of hydrogen bonding between mononucleotides in aqueous solution. This evidence is based on the detection and measurem...

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Interaction and association of bases and nucleosides in aqueous solutions. V. Studies of the association of purine nucleosides by vapor pressure osmometry and by proton magnetic resonance

Cited by 240 publications

References 32 publications

Effects of Specific Zidovudine Resistance Mutations and Substrate Structure on Nucleotide-Dependent Primer Unblocking by Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Effects of Specific Zidovudine Resistance Mutations and Substrate Structure on Nucleotide-Dependent Primer Unblocking by Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Theoretical Modeling of Radiation‐Induced DNA Damage

Association by Hydrogen Bonding of Mononucleotides in Aqueous Solution

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