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The Journal of Physical Chemistry. B Oct 2018The chemical difference between DNA and RNA nucleosides is their 2'-hydrogen versus 2'-hydroxyl substituents. Modification of the ribosyl moiety at the 2'-position and...
The chemical difference between DNA and RNA nucleosides is their 2'-hydrogen versus 2'-hydroxyl substituents. Modification of the ribosyl moiety at the 2'-position and 2'-O-methylation in particular, is common among natural post-transcriptional modifications of RNA. 2'-Modification may alter the electronic properties and hydrogen-bonding characteristics of the nucleoside and thus may lead to enhanced stabilization or malfunction. The structures and relative glycosidic bond stabilities of the protonated forms of the 2'-O-methylated purine nucleosides, 2'-O-methyladenosine (Adom) and 2'-O-methylguanosine (Guom), were examined using two complementary tandem mass spectrometry approaches, infrared multiple photon dissociation action spectroscopy and energy-resolved collision-induced dissociation. Theoretical calculations were also performed to predict the structures and relative stabilities of stable low-energy conformations of the protonated forms of the 2'-O-methylated purine nucleosides and their infrared spectra in the gas phase. Low-energy conformations highly parallel to those found for the protonated forms of the canonical DNA and RNA purine nucleosides are also found for the protonated 2'-O-methylated purine nucleosides. Importantly, the preferred site of protonation, nucleobase orientation, and sugar puckering are preserved among the DNA, RNA, and 2'-O-methylated variants of the protonated purine nucleosides. The 2'-substituent does however influence hydrogen-bond stabilization as the 2'-O-methyl and 2'-hydroxyl substituents enable a hydrogen-bonding interaction between the 2'- and 3'-substituents, whereas a 2'-hydrogen atom does not. Further, 2'-O-methylation reduces the number of stable low-energy hydrogen-bonded conformations possible and importantly inverts the preferred polarity of this interaction versus that of the RNA analogues. Trends in the CID values extracted from survival yield analyses of the 2'-O-methylated and canonical DNA and RNA forms of the protonated purine nucleosides are employed to elucidate their relative glycosidic bond stabilities. The glycosidic bond stability of Adom is found to exceed that of its DNA and RNA analogues. The glycosidic bond stability of Guom is also found to exceed that of its DNA analogue; however, this modification weakens this bond relative to its RNA counterpart. The glycosidic bond stability of the protonated purine nucleosides appears to be correlated with the hydrogen-bond stabilization of the sugar moiety.
Topics: Adenosine; Guanosine; Methylation; Models, Molecular; Molecular Conformation; Ribose; Tandem Mass Spectrometry; Thermodynamics
PubMed: 30203656
DOI: 10.1021/acs.jpcb.8b07687 -
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 -
Expert Opinion on Investigational Drugs Jun 2017Cutaneous T-cell lymphoma (CTCL) is characterized by the accumulation of neoplastic CD4+ T lymphocytes in the skin. Given the lack of curative treatments for CTCL, there... (Review)
Review
Cutaneous T-cell lymphoma (CTCL) is characterized by the accumulation of neoplastic CD4+ T lymphocytes in the skin. Given the lack of curative treatments for CTCL, there is a significant need for new, superior therapies. Forodesine is a transition-state analogue that inhibits purine nucleoside phosphorylase. Because it selectively targets T lymphocytes, it represents a drug of interest for the treatment of CTCL. Areas covered: Phase I/II dose-ranging studies of intravenous (IV) and oral forodesine demonstrated its activity, safety, and tolerability for refractory CTCL. Response rates were 31% and 27%, respectively. No dose-limiting toxicities were observed. These studies were followed by a phase II trial of oral forodesine 200 mg daily. This oral formulation showed only partial activity, with a response rate of 11%, likely attributable to underdosing. Common adverse events in these trials included infection, fatigue, peripheral edema, nausea, pruritus, headache, and insomnia. Expert opinion: IV and oral formulations of forodesine have demonstrated partial activity and an acceptable safety profile in patients with refractory CTCL. A higher oral dose, or sequential therapy consisting of IV forodesine followed by maintenance oral forodesine, may be more effective. With proper dosing, forodesine may emerge as a safe and effective treatment for refractory CTCL.
Topics: Administration, Intravenous; Administration, Oral; Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Humans; Lymphoma, T-Cell, Cutaneous; Purine Nucleosides; Pyrimidinones; Skin Neoplasms
PubMed: 28447489
DOI: 10.1080/13543784.2017.1324569 -
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 -
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 -
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 -
Critical Reviews in Biotechnology Aug 2018Mushrooms have become increasingly important as a reliable food source. They have also been recognized as an important source of bioactive compounds of high nutritional... (Review)
Review
Mushrooms have become increasingly important as a reliable food source. They have also been recognized as an important source of bioactive compounds of high nutritional and medicinal values. The nucleobases, nucleosides and nucleotides found in mushrooms play important roles in the regulation of various physiological processes in the human body via the purinergic and/or pyrimidine receptors. Cordycepin, a 3'-deoxyadenosine found in Cordyceps sinensis has received much attention as it possesses many medicinal values including anticancer properties. In this review, we provide a broad overview of the distribution of purine nucleobases (adenine and guanine); pyrimidine nucleobases (cytosine, uracil, and thymine); nucleosides (uridine, guanosine, adenosine and cytidine); as well as novel nucleosides/tides in edible and nonedible mushrooms. This review also discusses the latest research focusing on the successes, challenges, and future perspectives of the analytical methods used to determine nucleic acid constituents in mushrooms. Besides, the exotic taste and flavor of edible mushrooms are attributed to several nonvolatile and water-soluble substances, including the 5'-nucleotides. Therefore, we also discuss the total flavor 5'-nucleotides: 5'-guanosine monophosphate (5'-GMP), 5'-inosine monophosphate (5'-IMP), and 5'-xanthosine monophosphate (5'-XMP) in edible mushrooms.
Topics: Agaricales; Animals; Antineoplastic Agents; Cell Line; Deoxyadenosines; Humans; Mice; Nucleic Acids; Nucleosides; Nucleotides
PubMed: 29124970
DOI: 10.1080/07388551.2017.1399102 -
Nature Communications Mar 2023By lacking de novo purine biosynthesis enzymes, Plasmodium falciparum requires purine nucleoside uptake from host cells. The indispensable nucleoside transporter ENT1 of...
By lacking de novo purine biosynthesis enzymes, Plasmodium falciparum requires purine nucleoside uptake from host cells. The indispensable nucleoside transporter ENT1 of P. falciparum facilitates nucleoside uptake in the asexual blood stage. Specific inhibitors of PfENT1 prevent the proliferation of P. falciparum at submicromolar concentrations. However, the substrate recognition and inhibitory mechanism of PfENT1 are still elusive. Here, we report cryo-EM structures of PfENT1 in apo, inosine-bound, and inhibitor-bound states. Together with in vitro binding and uptake assays, we identify that inosine is the primary substrate of PfENT1 and that the inosine-binding site is located in the central cavity of PfENT1. The endofacial inhibitor GSK4 occupies the orthosteric site of PfENT1 and explores the allosteric site to block the conformational change of PfENT1. Furthermore, we propose a general "rocker switch" alternating access cycle for ENT transporters. Understanding the substrate recognition and inhibitory mechanisms of PfENT1 will greatly facilitate future efforts in the rational design of antimalarial drugs.
Topics: Humans; Plasmodium falciparum; Nucleoside Transport Proteins; Nucleobase, Nucleoside, Nucleotide, and Nucleic Acid Transport Proteins; Malaria, Falciparum; Purine Nucleosides; Inosine
PubMed: 36977719
DOI: 10.1038/s41467-023-37411-1