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ELife Dec 2023Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms?
Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms?
Topics: Leishmania donovani; Ligands; Phosphotransferases; Cyclic AMP-Dependent Protein Kinases; Purine Nucleosides; Trypanosoma brucei brucei
PubMed: 38126364
DOI: 10.7554/eLife.94720 -
Nature Communications Jul 2020Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype are...
Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we find that purine metabolites, especially guanylates, strongly correlate with radiation resistance. Inhibiting GTP synthesis radiosensitizes GBM cells and patient-derived neurospheres by impairing DNA repair. Likewise, administration of exogenous purine nucleosides protects sensitive GBM models from radiation by promoting DNA repair. Neither modulating pyrimidine metabolism nor purine salvage has similar effects. An FDA-approved inhibitor of GTP synthesis potentiates the effects of radiation in flank and orthotopic patient-derived xenograft models of GBM. High expression of the rate-limiting enzyme of de novo GTP synthesis is associated with shorter survival in GBM patients. These findings indicate that inhibiting purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease.
Topics: Animals; Brain Neoplasms; Cell Line, Tumor; DNA Repair; Female; Glioblastoma; Guanosine Monophosphate; Humans; Male; Mice; Mice, Knockout; Mice, SCID; Purine Nucleosides; Radiation Tolerance; Xenograft Model Antitumor Assays
PubMed: 32732914
DOI: 10.1038/s41467-020-17512-x -
MBio Feb 2023The purine-derived signaling molecules c-di-AMP and (p)ppGpp control /PBP2a-mediated β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) raise the...
The purine-derived signaling molecules c-di-AMP and (p)ppGpp control /PBP2a-mediated β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) raise the possibility that purine availability can control antibiotic susceptibility. Consistent with this, exogenous guanosine and xanthosine, which are fluxed through the GTP branch of purine biosynthesis, were shown to significantly reduce MRSA β-lactam resistance. In contrast, adenosine (fluxed to ATP) significantly increased oxacillin resistance, whereas inosine (which can be fluxed to ATP and GTP via hypoxanthine) only marginally increased oxacillin susceptibility. Furthermore, mutations that interfere with purine synthesis ( operon), transport (NupG, PbuG, PbuX) and the salvage pathway (DeoD2, Hpt) increased β-lactam resistance in MRSA strain JE2. Increased resistance of a mutant was not significantly reversed by guanosine, indicating that NupG is required for guanosine transport, which is required to reduce β-lactam resistance. Suppressor mutants resistant to oxacillin/guanosine combinations contained several purine salvage pathway mutations, including and . Guanosine significantly increased cell size and reduced levels of c-di-AMP, while inactivation of GdpP, the c-di-AMP phosphodiesterase negated the impact of guanosine on β-lactam susceptibility. PBP2a expression was unaffected in or mutants, suggesting that guanosine-induced β-lactam susceptibility may result from dysfunctional c-di-AMP-dependent osmoregulation. These data reveal the therapeutic potential of purine nucleosides, as β-lactam adjuvants that interfere with the normal activation of c-di-AMP are required for high-level β-lactam resistance in MRSA. The clinical burden of infections caused by antimicrobial resistant (AMR) pathogens is a leading threat to public health. Maintaining the effectiveness of existing antimicrobial drugs or finding ways to reintroduce drugs to which resistance is widespread is an important part of efforts to address the AMR crisis. Predominantly, the safest and most effective class of antibiotics are the β-lactams, which are no longer effective against methicillin-resistant Staphylococcus aureus (MRSA). Here, we report that the purine nucleosides guanosine and xanthosine have potent activity as adjuvants that can resensitize MRSA to oxacillin and other β-lactam antibiotics. Mechanistically, exposure of MRSA to these nucleosides significantly reduced the levels of the cyclic dinucleotide c-di-AMP, which is required for β-lactam resistance. Drugs derived from nucleotides are widely used in the treatment of cancer and viral infections highlighting the clinical potential of using purine nucleosides to restore or enhance the therapeutic effectiveness of β-lactams against MRSA and potentially other AMR pathogens.
Topics: Methicillin-Resistant Staphylococcus aureus; Purine Nucleosides; Bacterial Proteins; Anti-Bacterial Agents; Oxacillin; beta-Lactams; Monobactams; Guanosine; Adenosine Triphosphate; Guanosine Triphosphate; Microbial Sensitivity Tests; Penicillin-Binding Proteins; beta-Lactam Resistance
PubMed: 36507833
DOI: 10.1128/mbio.02478-22 -
International Journal of Molecular... Dec 2022Purine nucleosides represent an interesting group of nitrogen heterocycles, showing a wide range of biological effects. In this study, we designed and synthesized a...
Purine nucleosides represent an interesting group of nitrogen heterocycles, showing a wide range of biological effects. In this study, we designed and synthesized a series of 6,9-disubstituted and 2,6,9-trisubstituted purine ribonucleosides via consecutive nucleophilic aromatic substitution, glycosylation, and deprotection of the ribofuranose unit. We prepared eight new purine nucleosides bearing unique adamantylated aromatic amines at position 6. Additionally, the ability of the synthesized purine nucleosides to form stable host-guest complexes with β-cyclodextrin (β-CD) was confirmed using nuclear magnetic resonance (NMR) and mass spectrometry (ESI-MS) experiments. The in vitro antiproliferative activity of purine nucleosides and their equimolar mixtures with β-CD was tested against two types of human tumor cell line. Six adamantane-based purine nucleosides showed an antiproliferative activity in the micromolar range. Moreover, their effect was only slightly suppressed by the presence of β-CD, which was probably due to the competitive binding of the corresponding purine nucleoside inside the β-CD cavity.
Topics: Humans; Adamantane; Purine Nucleosides; beta-Cyclodextrins; Cell Line, Tumor; Nucleosides
PubMed: 36499470
DOI: 10.3390/ijms232315143 -
Free Radical Biology & Medicine Mar 2022Heme-containing peroxidases catalyze the oxidation of a variety of substrates by consuming hydrogen peroxide (HO), and play diversified roles in physiology and pathology... (Review)
Review
Heme-containing peroxidases catalyze the oxidation of a variety of substrates by consuming hydrogen peroxide (HO), and play diversified roles in physiology and pathology including innate immunity, the synthesis of thyroid hormone and the extracellular matrix, as well as the pathogenesis of several inflammatory diseases. Peroxidasin (PXDN), also known as Vascular Peroxidase-1 (VPO1), is a newly identified peroxidase and expresses in multiple cells and tissues including cardiovascular system and the lung. Recent studies imply its roles in the innate immunity, cardiovascular physiology and diseases, and extracellular matrix formation. Studies on the role of PXDN in human diseases are entering a new and exciting stage, and this review provides the insights into this emerging field of PXDN.
Topics: Animals; Deoxyribonucleosides; Extracellular Matrix Proteins; Humans; Hydrogen Peroxide; Mammals; Peroxidase; Peroxidases; Purine Nucleosides; Peroxidasin
PubMed: 35219848
DOI: 10.1016/j.freeradbiomed.2022.02.026 -
Journal of Neurochemistry May 2012Even a short blockade of oxygen flow in brain may lead to the inhibition of oxidative phosphorylation and depletion of cellular ATP, which results in profound... (Review)
Review
Even a short blockade of oxygen flow in brain may lead to the inhibition of oxidative phosphorylation and depletion of cellular ATP, which results in profound deficiencies in cellular function. Following ischemia, dying, injured, and hypoxic cells release soluble purine-nucleotide and -nucleoside pools. Growing evidence suggests that purine nucleosides might act as trophic factors in the CNS and PNS. In addition to equilibrative nucleoside transporters (ENTs) regulating purine nucleoside concentrations intra- and extracellularly, specific extracellular receptor subtypes for these compounds are expressed on neurons, glia, and endothelial cells, mediating stunningly diverse effects. Such effects range from induction of cell differentiation, apoptosis, mitogenesis, and morphogenetic changes, to stimulation of synthesis and/or release of cytokines and neurotrophic factors under both physiological and pathological conditions. Multiple signaling pathways regulate the critical balance between cell death and survival in hypoxia-ischemia. A convergent pathway for the regulation of multiple modalities involved in O₂ sensing is the mitogen activated protein kinase (p42/44 MAPK) or (ERK1/2 extracellular signal-regulated kinases) pathway terminating in a variety of transcription factors, for example, hypoxia-inducible factor 1α. In this review, the coherence of purine nucleoside-related pathways and MAPK activation in the endogenous neuroprotective regulation of the nervous system's development and neuroplasticity under hypoxic stress will be discussed.
Topics: Animals; Carrier Proteins; Humans; Hypoxia, Brain; Nerve Regeneration; Neuroprotective Agents; Purine Nucleosides; Receptors, Purinergic; Signal Transduction
PubMed: 22335456
DOI: 10.1111/j.1471-4159.2012.07692.x -
Journal of the American Chemical Society Oct 2022A new approach for synthesizing polycyclic heterofused 7-deazapurine heterocycles and the corresponding nucleosides was developed based on C-H functionalization of...
A new approach for synthesizing polycyclic heterofused 7-deazapurine heterocycles and the corresponding nucleosides was developed based on C-H functionalization of diverse (hetero)aromatics with dibenzothiophene--oxide followed by the Negishi cross-cooupling with bis(4,6-dichloropyrimidin-5-yl)zinc. This cross-coupling afforded a series of (het)aryl-pyrimidines that were converted to fused deazapurine heterocycles through azidation and thermal cyclization. The fused heterocycles were glycosylated to the corresponding 2'-deoxy- and ribonucleosides, and a series of derivatives were prepared by nucleophilic substitutions at position 4. Four series of new polycyclic thieno-fused 7-deazapurine nucleosides were synthesized using this strategy. Most of the deoxyribonucleosides showed good cytotoxic activity, especially for the CCRF-CEM cell line. Phenyl- and thienyl-substituted thieno-fused 7-deazapurine nucleosides were fluorescent, and the former one was converted to 2'-deoxyribonucleoside triphosphate for enzymatic synthesis of labeled oligonucleotides.
Topics: Nucleosides; Cell Line, Tumor; Ribonucleosides; Pyrimidines; Oxides; Zinc; Oligonucleotides; Deoxyribonucleosides; Purine Nucleosides
PubMed: 36245092
DOI: 10.1021/jacs.2c07517 -
Journal of the American Chemical Society Sep 2021The hypothesis that life on Earth may have started with a heterogeneous nucleic acid genetic system including both RNA and DNA has attracted broad interest. The recent...
The hypothesis that life on Earth may have started with a heterogeneous nucleic acid genetic system including both RNA and DNA has attracted broad interest. The recent finding that two RNA subunits (cytidine, C, and uridine, U) and two DNA subunits (deoxyadenosine, dA, and deoxyinosine, dI) can be coproduced in the same reaction network, compatible with a consistent geological scenario, supports this theory. However, a prebiotically plausible synthesis of the missing units (purine ribonucleosides and pyrimidine deoxyribonucleosides) in a unified reaction network remains elusive. Herein, we disclose a strictly stereoselective and furanosyl-selective synthesis of purine ribonucleosides (adenosine, A, and inosine, I) and purine deoxynucleosides (dA and dI), alongside one another, via a key photochemical reaction of thioanhydroadenosine with sulfite in alkaline solution (pH 8-10). Mechanistic studies suggest an unexpected recombination of sulfite and nucleoside alkyl radicals underpins the formation of the ribo C2'-O bond. The coproduction of A, I, dA, and dI from a common intermediate, and under conditions likely to have prevailed in at least some primordial locales, is suggestive of the potential coexistence of RNA and DNA building blocks at the dawn of life.
Topics: Adenosine; Deoxyribonucleosides; Evolution, Chemical; Hydrogen-Ion Concentration; Models, Chemical; Purine Nucleosides; Ribonucleosides; Sulfites; Ultraviolet Rays
PubMed: 34469129
DOI: 10.1021/jacs.1c07403 -
Nature Jun 2020The nature of the first genetic polymer is the subject of major debate. Although the 'RNA world' theory suggests that RNA was the first replicable information carrier of...
The nature of the first genetic polymer is the subject of major debate. Although the 'RNA world' theory suggests that RNA was the first replicable information carrier of the prebiotic era-that is, prior to the dawn of life-other evidence implies that life may have started with a heterogeneous nucleic acid genetic system that included both RNA and DNA. Such a theory streamlines the eventual 'genetic takeover' of homogeneous DNA from RNA as the principal information-storage molecule, but requires a selective abiotic synthesis of both RNA and DNA building blocks in the same local primordial geochemical scenario. Here we demonstrate a high-yielding, completely stereo-, regio- and furanosyl-selective prebiotic synthesis of the purine deoxyribonucleosides: deoxyadenosine and deoxyinosine. Our synthesis uses key intermediates in the prebiotic synthesis of the canonical pyrimidine ribonucleosides (cytidine and uridine), and we show that, once generated, the pyrimidines persist throughout the synthesis of the purine deoxyribonucleosides, leading to a mixture of deoxyadenosine, deoxyinosine, cytidine and uridine. These results support the notion that purine deoxyribonucleosides and pyrimidine ribonucleosides may have coexisted before the emergence of life.
Topics: Adenosine; Cytidine; DNA; Evolution, Chemical; Origin of Life; Oxidation-Reduction; Purine Nucleosides; Pyrimidine Nucleosides; RNA; Uridine
PubMed: 32494078
DOI: 10.1038/s41586-020-2330-9 -
Current Topics in Medicinal Chemistry 2011Malaria is a leading cause of morbidity and mortality in the tropics. Chemotherapeutic and vector control strategies have been applied for more than a century but have... (Review)
Review
Malaria is a leading cause of morbidity and mortality in the tropics. Chemotherapeutic and vector control strategies have been applied for more than a century but have not been efficient in disease eradication. Increased resistance of malaria parasites to drug treatment and of mosquito vectors to insecticides requires the development of novel chemotherapeutic agents. Malaria parasites exhibit rapid nucleic acid synthesis during their intraerythrocytic growth phase. Plasmodium purine and pyrimidine metabolic pathways are distinct from those of their human hosts. Thus, targeting purine and pyrimidine metabolic pathways provides a promising route for novel drug development. Recent developments in enzymatic transition state analysis have provided an improved route to inhibitor design targeted to specific enzymes, including those of purine and pyrimidine metabolism. Modern transition state analogue drug discovery has resulted in transition state analogues capable of binding to target enzymes with unprecedented affinity and specificity. These agents can provide specific blocks in essential pathways. The combination of tight binding with the high specificity of these logically designed inhibitors, results in low toxicity and minor side effects. These features reduce two of the major problems with the current antimalarials. Transition state analogue design is being applied to generate new lead compounds to treat malaria by targeting purine and pyrimidine pathways.
Topics: Antimalarials; Binding Sites; Drug Design; Enzyme Inhibitors; Humans; Malaria, Falciparum; Models, Molecular; Plasmodium falciparum; Protein Binding; Protozoan Proteins; Purine Nucleosides; Purines; Pyrimidines; Pyrimidinones; Pyrroles; Substrate Specificity
PubMed: 21619511
DOI: 10.2174/156802611796575948