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Chemical Society Reviews Oct 2005Adenosine 5'-triphosphate (ATP(4-)) and related nucleoside 5'-triphosphates (NTP(4-)) serve as substrates in the form of metal ion complexes in enzymic reactions taking... (Review)
Review
Adenosine 5'-triphosphate (ATP(4-)) and related nucleoside 5'-triphosphates (NTP(4-)) serve as substrates in the form of metal ion complexes in enzymic reactions taking part thus in central metabolic processes. With this in mind, the coordination chemistry of NTPs is critically reviewed and the conditions are defined for studies aiming to describe the properties of monomeric complexes because at higher concentrations (>1 mM) self-stacking may take place. The metal ion (M(2+)) complexes of purine-NTPs are more stable than those of pyrimidine-NTPs; this stability enhancement is attributed, in accord with NMR studies, to macrochelate formation of the phosphate-coordinated M(2+) with N7 of the purine residue and the formation degrees of the resulting isomeric complexes are listed. Furthermore, the formation of mixed-ligand complexes (including also those with buffer molecules), the effect of a reduced solvent polarity on complex stability and structure (giving rise to selectivity), the use of nucleotide analogues as antiviral agents, and the effect of metal ions on group transfer reactions are summarized.
Topics: Binding Sites; Crystallization; Dinucleoside Phosphates; Hydrogen-Ion Concentration; Ions; Metals; Nucleosides; Solutions
PubMed: 16172677
DOI: 10.1039/b505986k -
General Pharmacology Mar 19951. The actions of diadenosine polyphosphates, diadenosine tetraphosphate (Ap4A), diadenosine pentaphosphate (Ap5A) and diadenosine hexaphosphate (Ap6A) in the nervous... (Review)
Review
1. The actions of diadenosine polyphosphates, diadenosine tetraphosphate (Ap4A), diadenosine pentaphosphate (Ap5A) and diadenosine hexaphosphate (Ap6A) in the nervous system have been reviewed. 2. In the peripheral nervous system, diadenosine polyphosphates bind to P2-purinergic receptors such as the P2Y in chromaffin cells and Torpedo synaptosomes, P2X in vas deferens and urinary bladder and also Torpedo synaptosomes and P2U in endothelial chromaffin cells. 3. In the central nervous system ApnA compounds can act through P2X-purinoceptors opening cation channels in nodose ganglion neurones. Diadenosine polyphosphates bind to a P2d-purinergic receptor in rat brain synaptic terminals and hippocampus, linked to protein kinase C (PKC) activation. 4. P4-purinoceptors are specific receptors for diadenosine polyphosphates, coupled to the Ca2+ influx, in the central synapses. This purinoceptor is not activated by ATP and synthetic analogs. The P4-purinoceptor could act as a positive modulator of the synaptic transmission, giving even more importance to diadenosine polyphosphates as neurotransmitters.
Topics: Animals; Dinucleoside Phosphates; Male; Nervous System; Receptors, Purinergic P2
PubMed: 7590071
DOI: 10.1016/0306-3623(94)00182-m -
Nucleic Acids Research Apr 2021Nonenzymatic copying of RNA templates with activated nucleotides is a useful model for studying the emergence of heredity at the origin of life. Previous experiments...
Nonenzymatic copying of RNA templates with activated nucleotides is a useful model for studying the emergence of heredity at the origin of life. Previous experiments with defined-sequence templates have pointed to the poor fidelity of primer extension as a major problem. Here we examine the origin of mismatches during primer extension on random templates in the simultaneous presence of all four 2-aminoimidazole-activated nucleotides. Using a deep sequencing approach that reports on millions of individual template-product pairs, we are able to examine correct and incorrect polymerization as a function of sequence context. We have previously shown that the predominant pathway for primer extension involves reaction with imidazolium-bridged dinucleotides, which form spontaneously by the reaction of two mononucleotides with each other. We now show that the sequences of correctly paired products reveal patterns that are expected from the bridged dinucleotide mechanism, whereas those associated with mismatches are consistent with direct reaction of the primer with activated mononucleotides. Increasing the ratio of bridged dinucleotides to activated mononucleotides, either by using purified components or by using isocyanide-based activation chemistry, reduces the error frequency. Our results point to testable strategies for the accurate nonenzymatic copying of arbitrary RNA sequences.
Topics: Dinucleoside Phosphates; Genetic Techniques; Kinetics; Polymerization; RNA; Templates, Genetic
PubMed: 33744957
DOI: 10.1093/nar/gkab173 -
RNA (New York, N.Y.) Oct 2015Simple nucleotide templating activities are of interest as potential primordial reactions. Here we describe the acceleration of 5'-5' AppA synthesis by 3'-5' poly(U)...
Simple nucleotide templating activities are of interest as potential primordial reactions. Here we describe the acceleration of 5'-5' AppA synthesis by 3'-5' poly(U) under normal solution conditions. This reaction is apparently templated via complementary U:A base-pairing, despite the involvement of two different RNA backbones, because poly(U), unlike other polymers, significantly stimulates AppA synthesis. These interactions occur in moderate (K(+)) and (Mg(2+)) and are temperature sensitive, being more efficient at 10°C than at 4°C, but absent at 20°C. The reaction is only slightly pH sensitive, despite potentially relevant substrate pKa's. Kinetic data explicitly support production of AppA by interaction of stacked 2MeImpA and pA nucleotides paired with a single molecule of U template. At a lower rate, AppA can also be produced by a chemical reaction between 2MeImpA and pA, without participation of poly(U). Molecular modeling suggests that 5'-5' joining between stacked or concurrently paired A's can occur without major departures from normal U-A helical coordinates. So, coenzyme-like 5'-5' purine dinucleotides might be readily synthesized from 3'-5' RNAs with complementary sequences.
Topics: Dinucleoside Phosphates; Poly U; RNA
PubMed: 26272215
DOI: 10.1261/rna.052696.115 -
ACS Chemical Biology Oct 2017The intracellular concentration of diadenosine tetraphospate (ApA) increases upon exposure to stress conditions. Despite being discovered over 50 years ago, the cellular...
The intracellular concentration of diadenosine tetraphospate (ApA) increases upon exposure to stress conditions. Despite being discovered over 50 years ago, the cellular functions of ApA are still enigmatic. If and how the varied ApA is a signal and involved in the signaling pathways leading to an appropriate cellular response remain to be discovered. Because the turnover of ApA by ApA cleaving enzymes is rapid, small molecule inhibitors for these enzymes would provide tools for the more detailed study of the role of ApA. Here, we describe the development of a high-throughput screening assay based on a fluorogenic ApA substrate for the identification and optimization of small molecule inhibitors for ApA cleaving enzymes. As proof-of-concept we screened a library of over 42 000 compounds toward their inhibitory activity against the ApA phosphorylase (Rv2613c) of Mycobacterium tuberculosis (Mtb). A sulfanylacrylonitril derivative with an IC of 260 ± 50 nM in vitro was identified. Multiple derivatives were synthesized to further optimize their properties with respect to their in vitro IC values and their cytotoxicity against human cells (HeLa). In addition, we selected two hits to study their antimycobacterial activity against virulent Mtb to show that they might be candidates for further development of antimycobacterial agents against multidrug-resistant Mtb.
Topics: Cell Survival; Dinucleoside Phosphates; Enzyme Inhibitors; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Enzymologic; HeLa Cells; High-Throughput Screening Assays; Humans; Inhibitory Concentration 50; Mycobacterium tuberculosis; Nucleotidyltransferases; Protein Binding
PubMed: 28892605
DOI: 10.1021/acschembio.7b00653 -
Enzyme & Protein 1993In our search for potential inhibitors of casein kinase II (CKII) in Artemia, we have shown that dinucleoside polyphosphates are a novel class of effectors for this... (Comparative Study)
Comparative Study
In our search for potential inhibitors of casein kinase II (CKII) in Artemia, we have shown that dinucleoside polyphosphates are a novel class of effectors for this ubiquitous protein kinase. P1,P4-di(guanosine-5')-tetraphosphate (Gp4G) is a better CKII inhibitor than P1,P4-di(adenosine-5')-tetraphosphate (Ap4A). The inhibition by both effectors is more potent when GTP is used as phosphate donor instead of ATP. The inhibition of CKII increases with the number of phosphates linking the guanosine/adenosine moieties (for n = 2-6). Ap4A does not compete with the protein substrate and causes an increase in the apparent KmATP and a decrease in the apparent VmATP, indicating a mixed type of inhibition with respect to ATP.
Topics: Amino Acid Sequence; Animals; Artemia; Casein Kinase II; Dinucleoside Phosphates; Kinetics; Molecular Sequence Data; Oligopeptides; Protein Serine-Threonine Kinases; Structure-Activity Relationship; Substrate Specificity
PubMed: 8012498
DOI: 10.1159/000468651 -
Organic Letters May 2006[reaction: see text] We report a one-flask route for the synthesis of dinucleoside tetra- and pentaphosphates, in isolated yields of 50-85%. This route relies on a...
[reaction: see text] We report a one-flask route for the synthesis of dinucleoside tetra- and pentaphosphates, in isolated yields of 50-85%. This route relies on a mixture of P(III) and P(V) chemistries, using phosphitylation of a protected nucleoside with 2-chloro-4H-l,3,2-benzo-dioxaphosphorin-4-one (salicylchlorophosphite), followed by sequential reaction with inorganic pyrophosphate and a nucleoside 5' mono- or diphosphate.
Topics: Catalysis; Dinucleoside Phosphates; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular
PubMed: 16671785
DOI: 10.1021/ol060491d -
Postepy Biochemii 2001
Review
Topics: Animals; Bacterial Proteins; Cardiovascular System; Dinucleoside Phosphates; Escherichia coli Proteins; Humans; Neurotransmitter Agents; Phosphoric Monoester Hydrolases; Proteins; Pyrophosphatases; Stress, Physiological; Nudix Hydrolases
PubMed: 11503434
DOI: No ID Found -
Current Topics in Microbiology and... 1992
Review
Topics: DNA; DNA Replication; Dinucleoside Phosphates; Genes, Immunoglobulin; Humans; Methylation; Receptors, Antigen, T-Cell; Transcription, Genetic
PubMed: 1490346
DOI: 10.1007/978-3-642-77633-5_15 -
Nucleic Acids Research Dec 2020A set of modified 2'-deoxyribonucleoside triphosphates (dNTPs) bearing a linear or branched alkane, indole or phenyl group linked through ethynyl or alkyl spacer were...
A set of modified 2'-deoxyribonucleoside triphosphates (dNTPs) bearing a linear or branched alkane, indole or phenyl group linked through ethynyl or alkyl spacer were synthesized and used as substrates for polymerase synthesis of hypermodified DNA by primer extension (PEX). Using the alkyl-linked dNTPs, the polymerase synthesized up to 22-mer fully modified oligonucleotide (ON), whereas using the ethynyl-linked dNTPs, the enzyme was able to synthesize even long sequences of >100 modified nucleotides in a row. In PCR, the combinations of all four modified dNTPs showed only linear amplification. Asymmetric PCR or PEX with separation or digestion of the template strand can be used for synthesis of hypermodified single-stranded ONs, which are monodispersed polymers displaying four different substituents on DNA backbone in sequence-specific manner. The fully modified ONs hybridized with complementary strands and modified DNA duplexes were found to exist in B-type conformation (B- or C-DNA) according to CD spectral analysis. The modified DNA can be replicated with high fidelity to natural DNA through PCR and sequenced. Therefore, this approach has a promising potential in generation and selection of hypermodified aptamers and other functional polymers.
Topics: Adenine; Aptamers, Nucleotide; Base Pairing; Base Sequence; Cytosine; DNA; DNA Replication; DNA-Directed DNA Polymerase; Deoxyribonucleosides; Dinucleoside Phosphates; Guanine; Hydrophobic and Hydrophilic Interactions; Polymerase Chain Reaction; Polymers; Uracil
PubMed: 33152081
DOI: 10.1093/nar/gkaa999