Base pairing-induced shift in tautomeric equilibrium of a promutagenic analogue, N6-methoxyadenosine

AbstractThe nuclear magnetic resonance spectra of N6-methoxyadenosine and of uridine, both methylated in the 2′-,3′- and 5′-positions to obtain solution in deuterochloroform, reveal the formation of hetero-associates in which the amino—tautomeric equilibrium is shifted to the amino form. These results ar discussed in terms of the mutagenicity of O-methylhydroxylamine which converts adenosine to N6-methoxyadenosine

Halogen bonding at the ATP binding site of protein kinases: Preferred geometry and topology of ligand binding

ABSTRACT Halogenated ligands have been widely developed as potent, and frequently selective, inhibitors of protein kinases (PK). Herein, all structures of protein kinases complexed with a halogenated ligand, identified in the PDB, were analyzed in the context of eventual contribution of halogen bonding to protein-ligand interactions. Global inspection shows that two carbonyl groups of residues located in the hinge region are the most abundant halogen bond acceptors. In contrast to solution data, well-defined water molecules, located at sites conserved across most PK structures, are also involved in halogen bonding. Analysis of cumulative distributions of halogen-acceptor distances shows that structures displaying short contacts involving a halogen atom are overpopulated, contributing together to clearly defined maxima of 2.82, 2.91 and 2.94 Å for chlorine, bromine and iodine, respectively. The angular preference of a halogen bond favors ideal topology (180°, 120°) for iodine. For bromine the distribution is much more dispersed, and no such preference was found for chlorine

Halogen bonds involved in binding of halogenated ligands by protein kinases.

Analysis of 664 known structures of protein kinase complexes with halogenated ligands revealed 424 short contacts between a halogen atom and a potential protein X-bond acceptor, the topology and geometry of which were analyzed according to the type of a halogen atom (X = Cl, Br, I) and a putative protein X-bond acceptor. Among 236 identified halogen bonds, the most represented ones are directed to backbone carbonyls of the hinge region and may replace the pattern of ATP-like hydrogen bonds. Some halogen-π interactions with either aromatic residues or peptide bonds, that accompany the interaction with the hinge region, may possibly enhance ligand selectivity. Interestingly, many of these halogen-π interactions are bifurcated. Geometrical preferences identify iodine as the strongest X-bond donor, less so bromine, while virtually no such preferences were observed for chlorine; and a backbone carbonyl as the strongest X-bond acceptor. The presence of a halogen atom in a ligand additionally affects the properties of proximal hydrogen bonds, which according to geometrical parameters get strengthened, when a nitrogen of a halogenated ligand acts as the hydrogen bond donor

A rockfall-induced glacial lake outburst flood, Upper Barun Valley, Nepal

On April 20, 2017, a flood from the Barun River, Makalu-Barun National Park, eastern Nepal formed a 2&ndash;3-km-long lake at its confluence with the Arun River as a result of blockage by debris. Although the lake drained spontaneously the next day, it caused nationwide concern and triggered emergency responses. We identified the primary flood trigger as a massive rockfall from the northwest face of Saldim Peak (6388&nbsp;m) which fell approximately 570&nbsp;m down to the unnamed glacier above Langmale glacial lake, causing a massive dust cloud and hurricane-force winds. The impact also precipitated an avalanche, carrying blocks of rock and ice up to 5&nbsp;m in diameter that plummeted a further 630&nbsp;m down into Langmale glacial lake, triggering a glacial lake outburst flood (GLOF). The flood carved steep canyons, scoured the river&rsquo;s riparian zone free of vegetation, and deposited sediment, debris, and boulders throughout much of the river channel from the settlement of Langmale to the settlement of Yangle Kharka about 6.5&nbsp;km downstream. Peak discharge was estimated at 4400&thinsp;&plusmn;&thinsp;1800&nbsp;m3&nbsp;s&minus;1, and total flood volume was estimated at 1.3&thinsp;&times;&thinsp;106&nbsp;m3 of water. This study highlights the importance of conducting integrated field studies of recent catastrophic events as soon as possible after they occur, in order to best understand the complexity of their triggering mechanisms, resultant impacts, and risk reduction management options. </div

Lysozyme activity of the Ruminococcus champanellensis cellulosome

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135571/1/emi13501.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135571/2/emi13501_am.pd

Template properties of mutagenic cytosine analogues in reverse transcription

We have studied the mutagenic properties of ribonucleotide analogues by reverse transcription to understand their potential as antiretroviral agents by mutagenesis of the viral genome. The templating properties of nucleotide analogues including 6-(β-D-ribofuranosyl)-3,4-dihydro-8H-pyrimido[4,5-c](1,2)oxazin-7-one, N(4)-hydroxycytidine, N(4)-methoxycytidine, N(4)-methylcytidine and 4-semicarbazidocytidine, which have been reported to exhibit ambiguous base pairing properties, were examined. We have synthesized RNA templates using T3 RNA polymerase, and investigated the specificity of the incorporation of deoxyribonucleoside triphosphates opposite these cytidine analogues in RNA by HIV and AMV reverse transcriptases. Except for N(4)-methylcytidine, both enzymes incorporated both dAMP and dGMP opposite these analogues in RNA. This indicates that they would be highly mutagenic if present in viral RNA. To study the basis of the differences among the analogues in the incorporation ratios of dAMP to dGMP, we have carried out kinetic analysis of incorporation opposite the analogues at a defined position in RNA templates. In addition, we examined whether the triphosphates of these analogues were incorporated competitively into RNA by human RNA polymerase II. Our present data supports the view that these cytidine analogues are mutagenic when incorporated into RNA, and that they may therefore be considered as candidates for antiviral agents by causing mutations to the retroviral genome

Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

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