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Bioconjugate Chemistry Sep 2021Adenosine receptors (ARs) play many important roles in physiology and have been recognized as potential targets for pain relief. Here, we introduce three photoswitchable...
Adenosine receptors (ARs) play many important roles in physiology and have been recognized as potential targets for pain relief. Here, we introduce three photoswitchable adenosine derivatives that function as light-dependent agonists for ARs and confer optical control to these G protein-coupled receptors. One of our compounds, AzoAdenosine-3, was evaluated in the classical formalin model of pain. The molecule, active in the dark, was not metabolized by adenosine deaminase and effectively reduced pain perception in a light-dependent manner. These antinociceptive effects suggested a major role for AR and AR in peripheral-mediated pain sensitization, whereas an average adenosine-mediated antinociceptive effect will be facilitated by AR and AR. Our results demonstrate that a photoswitchable adenosine derivative can be used to map the contribution of ARs mediating analgesia .
Topics: Adenosine; Receptor, Adenosine A1
PubMed: 34448572
DOI: 10.1021/acs.bioconjchem.1c00387 -
Journal of the American Society For... Aug 2019The 2'-substituent is the primary distinguishing feature between DNA and RNA nucleosides. Modifications to this critical position, both naturally occurring and...
The 2'-substituent is the primary distinguishing feature between DNA and RNA nucleosides. Modifications to this critical position, both naturally occurring and synthetic, can produce biologically valuable nucleoside analogues. The unique properties of fluorine make it particularly interesting and medically useful as a synthetic nucleoside modification. In this work, the effects of 2'-fluoro modification on the protonated gas-phase purine nucleosides are examined using complementary tandem mass spectrometry and computational methods. Direct comparisons are made with previous studies on related nucleosides. Infrared multiple photon dissociation action spectroscopy performed in both the fingerprint and hydrogen-stretching regions allows for the determination of the experimentally populated conformations. The populated conformers of protonated 2'-fluoro-2'-deoxyadenosine, [Adofl+H], and 2'-fluoro-2'-deoxyguanosine, [Guofl+H], are highly parallel to their respective canonical DNA and RNA counterparts. Both N3 and N1 protonation sites are accessed by [Adofl+H], stabilizing syn and anti nucleobase orientations, respectively. N7 protonation and anti nucleobase orientation dominates in [Guofl+H]. Spectroscopically observable intramolecular hydrogen-bonding interactions with fluorine allow more definitive sugar puckering determinations than possible for the canonical systems. [Adofl+H] adopts C2'-endo sugar puckering, whereas [Guofl+H] adopts both C2'-endo and C3'-endo sugar puckering. Energy-resolved collision-induced dissociation experiments with survival yield analyses provide relative glycosidic bond stabilities. The N-glycosidic bond stabilities of the protonated 2'-fluoro-substituted purine nucleosides are found to exceed those of their canonical analogues. Further, the N-glycosidic bond stability is found to increase with increasing electronegativity of the 2'-substituent, i.e., H < OH < F. The N-glycosidic bond stability is also greater for the adenine nucleoside analogues than the guanine nucleoside analogues.
Topics: Deoxyadenosines; Dideoxynucleosides; Halogenation; Hydrogen Bonding; Models, Molecular; Molecular Conformation; Protons; Purine Nucleosides; Spectrophotometry, Infrared
PubMed: 31111413
DOI: 10.1007/s13361-019-02222-6 -
The Journal of Antibiotics Dec 2019Nucleoside antibiotics possess various biological activities such as antibacterial, antifungal, anticancer, and herbicidal activities. RIKEN scientists contributed to... (Review)
Review
Nucleoside antibiotics possess various biological activities such as antibacterial, antifungal, anticancer, and herbicidal activities. RIKEN scientists contributed to this area of research with two representative antifungal nucleoside antibiotics, blasticidin S and polyoxin. Blasticidin S was the first antibiotic exploited in agriculture worldwide. Meanwhile, the polyoxins discovered by Isono and Suzuki are still used globally as an agricultural antibiotic. In this review article, the research on nucleoside antibiotics mainly done by Isono and his collaborators is summarized from the discovery of polyoxin to subsequent investigations.
Topics: Adenosine; Aminoglycosides; Anti-Bacterial Agents; Azepines; Cell Wall; Drug Discovery; Fungicides, Industrial; Guanine; Nucleosides; Protein Kinase Inhibitors; Purine Nucleotides; Pyrimidine Nucleosides; Ribonucleosides; Uridine
PubMed: 31554959
DOI: 10.1038/s41429-019-0237-1 -
Physical Chemistry Chemical Physics :... Mar 2022Photostability is thought to be an inherent property of nucleobases required to survive the extreme ultraviolet radiation conditions of the prebiotic era. Previous...
Photostability is thought to be an inherent property of nucleobases required to survive the extreme ultraviolet radiation conditions of the prebiotic era. Previous studies have shown that absorption of ultraviolet radiation by the canonical nucleosides results in ultrafast internal conversion to the ground state, demonstrating that these nucleosides efficiently dissipate the excess electronic energy to the environment. In recent years, studies on the photophysical and photochemical properties of nucleobase derivatives have revealed that chemical substitution influences the electronic relaxation pathways of purine and pyrimidine nucleobases. It has been suggested that amino or carbonyl substitution at the C6 position could increase the photostability of the purine derivatives more than the substitution at the C2 position. This investigation aims to elucidate the excited state dynamics of 2'-deoxyisoguanosine (dIsoGuo) and isoguanosine (IsoGuo) in aqueous solution at pH 7.4 and 1.4, which contain an amino group at the C6 position and a carbonyl group at the C2 position of the purine chromophore. The study of these derivatives is performed using absorption and emission spectroscopies, broadband transient absorption spectroscopy, and density functional and time-dependent density functional levels of theory. It is shown that the primary relaxation mechanism of dIsoGuo and IsoGuo involves nonradiative decay pathways, where the population decays from the S(ππ*) state through internal conversion to the ground state two relaxation pathways with lifetimes of hundreds of femtoseconds and less than 2 ps, making these purine nucleosides photostable in aqueous solution.
Topics: Adenosine; Guanosine; Ultraviolet Rays; Water
PubMed: 35244114
DOI: 10.1039/d1cp05795b -
Current Opinion in Chemical Biology Aug 2021The messenger RNA (mRNA) methylations in mammalian cells have been found to contain N-methyladenosine (mA), N-2'-O-dimethyladenosine (mAm), 7-methylguanosine (mG),... (Review)
Review
The messenger RNA (mRNA) methylations in mammalian cells have been found to contain N-methyladenosine (mA), N-2'-O-dimethyladenosine (mAm), 7-methylguanosine (mG), 1-methyladenosine (mA), 5-methylcytosine (mC), and 2'-O-methylation (2'-OMe). Their regulatory functions in control of mRNA fate and gene expression are being increasingly uncovered. To unambiguously understand the critical roles of mRNA methylations in physiological and pathological processes, mapping these methylations at single base resolution is highly required. Here, we will review the progresses made in methylation sequencing methodologies developed mainly in recent two years, with an emphasis on chemical labeling-assisted single base resolution methods, and discuss the problems and prospects as well.
Topics: Adenosine; Aldehydes; Amines; Base Sequence; Cell Line; Epigenesis, Genetic; Gene Expression Regulation; Guanosine; Humans; Methylation; RNA Processing, Post-Transcriptional; RNA, Messenger; Single Molecule Imaging; Staining and Labeling
PubMed: 33684855
DOI: 10.1016/j.cbpa.2021.02.001 -
Molecules (Basel, Switzerland) Mar 2022Reactive oxygen species (ROS) are continuously produced in living cells due to metabolic and biochemical reactions and due to exposure to physical, chemical and... (Review)
Review
Reactive oxygen species (ROS) are continuously produced in living cells due to metabolic and biochemical reactions and due to exposure to physical, chemical and biological agents. Excessive ROS cause oxidative stress and lead to oxidative DNA damage. Within ROS-mediated DNA lesions, 8-oxoguanine (8-oxoG) and its nucleotide 8-oxo-2'-deoxyguanosine (8-oxodG)-the guanine and deoxyguanosine oxidation products, respectively, are regarded as the most significant biomarkers for oxidative DNA damage. The quantification of 8-oxoG and 8-oxodG in urine, blood, tissue and saliva is essential, being employed to determine the overall effects of oxidative stress and to assess the risk, diagnose, and evaluate the treatment of autoimmune, inflammatory, neurodegenerative and cardiovascular diseases, diabetes, cancer and other age-related diseases. High-performance liquid chromatography with electrochemical detection (HPLC-ECD) is largely employed for 8-oxoG and 8-oxodG determination in biological samples due to its high selectivity and sensitivity, down to the femtomolar range. This review seeks to provide an exhaustive analysis of the most recent reports on the HPLC-ECD determination of 8-oxoG and 8-oxodG in cellular DNA and body fluids, which is relevant for health research.
Topics: 8-Hydroxy-2'-Deoxyguanosine
PubMed: 35268721
DOI: 10.3390/molecules27051620 -
Quantitation of Purine in Urine by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry.Methods in Molecular Biology (Clifton,... 2022Inborn errors of purine metabolism, either deficiencies of synthesis or catabolism pathways, lead to a wide spectrum of clinical presentations: urolithiasis (adenine...
Inborn errors of purine metabolism, either deficiencies of synthesis or catabolism pathways, lead to a wide spectrum of clinical presentations: urolithiasis (adenine phosphoribosyltransferase), primary immune deficiency (adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency), severe intellectual disability, and other neurological symptoms (Lesch-Nyhan disease, adenylosuccinase deficiency, and molybdenum cofactor deficiency). A rapid quantitative purine assay was developed using UPLC-MS/MS to determine purine nucleoside and base concentrations in urine. Taking advantages of ultra-performance liquid chromatography, we achieved satisfactory analyte separation and recovery with a polar T3 column in a short run time with no requirement of time-consuming sample preparation or derivatization. This targeted assay is intended for diagnosis and management of purine diseases, newborn screening follow-up of SCID, and evaluation of autism spectrum disorders.
Topics: Adenine Phosphoribosyltransferase; Chromatography, Liquid; Humans; Infant, Newborn; Purine Nucleosides; Purine-Pyrimidine Metabolism, Inborn Errors; Tandem Mass Spectrometry
PubMed: 36127609
DOI: 10.1007/978-1-0716-2565-1_37 -
Biological & Pharmaceutical Bulletin 2023Cancer treatment with natural killer (NK) cell immunotherapy is promising. NK cells can recognize and kill cancer cells without sensitization, making them a potential...
Cancer treatment with natural killer (NK) cell immunotherapy is promising. NK cells can recognize and kill cancer cells without sensitization, making them a potential cancer treatment alternative. To improve clinical efficacy and safety, more research is needed. Enhancing NK cell function improves therapeutic efficacy. Due to its potent apoptosis induction, Cordycepin, a bioactive compound from Cordyceps spp., inhibits cancer cell growth. Cordycepin has immunoregulatory properties, making it a promising candidate for combination therapy with NK cell-based immunotherapy. Cordycepin may enhance NK cell function and have clinical applications, but more research is needed. In this study, cordycepin treatment of NK-92 MI cells increased THP-1 and U-251 cell cytotoxicity. Cordycepin also significantly increased the mRNA expression of cytokine-encoding genes, including tumour necrosis factor (TNF), interferon gamma (IFNG), and interleukin 2 (IL2). NK-92 MI cells notably secreted more IFNG and granzyme B. Cordycepin also decreased CD27 and increased CD11b, CD16, and NKG2D in NK-92 MI cells, which improved its anti-cancer ability. In conclusion, cordycepin could enhance NK cell cytotoxicity against cancerous cells for the first time, supporting its use as an alternative immunoactivity agent against cancer cells. Further studies are needed to investigate its efficacy and safety in clinical settings.
Topics: Humans; Killer Cells, Natural; Interferon-gamma; Deoxyadenosines; Tumor Necrosis Factor-alpha
PubMed: 37661405
DOI: 10.1248/bpb.b23-00221 -
Nucleosides, Nucleotides & Nucleic Acids 2020Although most lactic acid bacteria do not directly incorporate purine nucleotides, the strain PA-3 was found to incorporate purine mononucleotides. To determine whether...
Although most lactic acid bacteria do not directly incorporate purine nucleotides, the strain PA-3 was found to incorporate purine mononucleotides. To determine whether the direct uptake of purine mononucleotides is dependent on the species or strain of lactic acid bacteria, incorporation of purine mononucleotides was assessed in , sbsp. and other species of lactic acid bacteria. Each bacterial strain was incubated with P-AMP or C-adenosine and the incorporation of each purine was evaluated by measuring their radioactivity. All investigated strains of incorporated P-AMP, whereas strains of and most strains of did not. Incorporation of P-AMP into strains of was dependent on the strain or species of that genus of bacteria. All investigated strains, except for one strain of , incorporated C-adenosine, with , and generally displaying greater incorporation of C-adenosine than . Although most lactic acid bacteria such as and do not incorporate purine mononucleotides, some species such as directly incorporate purine mononucleotides. These findings indicate that the preferential incorporation of purine mononucleotides or nucleosides by lactic acid bacteria is dependent on the species or strain.
Topics: Adenosine; Adenosine Monophosphate; Bacteria; Biological Transport; Lactic Acid; Species Specificity
PubMed: 32397874
DOI: 10.1080/15257770.2020.1733604 -
Molecules (Basel, Switzerland) Mar 2020The bi-enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, ara-A), catalyzed by uridine phosphorylase from (UP) and a purine nucleoside...
The bi-enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, ara-A), catalyzed by uridine phosphorylase from (UP) and a purine nucleoside phosphorylase from (PNP), was re-designed under continuous-flow conditions. Glyoxyl-agarose and EziG1 (Opal) were used as immobilization carriers for carrying out this preparative biotransformation. Upon setting-up reaction parameters (substrate concentration and molar ratio, temperature, pressure, residence time), 1 g of vidarabine was obtained in 55% isolated yield and >99% purity by simply running the flow reactor for 1 week and then collecting (by filtration) the nucleoside precipitated out of the exiting flow. Taking into account the substrate specificity of UP and PNP, the results obtained pave the way to the use of the UP/PNP-based bioreactor for the preparation of other purine nucleosides.
Topics: Aeromonas hydrophila; Antiviral Agents; Biocatalysis; Bioreactors; Biotransformation; Clostridium perfringens; Enzymes, Immobilized; Glyoxylates; Humans; Protein Engineering; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Sepharose; Substrate Specificity; Vidarabine
PubMed: 32182773
DOI: 10.3390/molecules25051223