scholarly journals Inosine, but none of the 8-oxo-purines, is a plausible component of a primordial version of RNA

2018 ◽  
Vol 115 (52) ◽  
pp. 13318-13323 ◽  
Author(s):  
Seohyun Chris Kim ◽  
Derek K. O’Flaherty ◽  
Lijun Zhou ◽  
Victor S. Lelyveld ◽  
Jack W. Szostak
Keyword(s):  
Rna Replication ◽  
Primer Extension ◽  
Considerable Progress ◽  
Purine Nucleotides ◽  
Pyrimidine Nucleotides ◽  
Abiotic Synthesis ◽  
Template Strand ◽  
Proper Comparison ◽  
Prebiotic Syntheses ◽  
Emergence Of Life

The emergence of primordial RNA-based life would have required the abiotic synthesis of nucleotides, and their participation in nonenzymatic RNA replication. Although considerable progress has been made toward potentially prebiotic syntheses of the pyrimidine nucleotides (C and U) and their 2-thio variants, efficient routes to the canonical purine nucleotides (A and G) remain elusive. Reported syntheses are low yielding and generate a large number of undesired side products. Recently, a potentially prebiotic pathway to 8-oxo-adenosine and 8-oxo-inosine has been demonstrated, raising the question of the suitability of the 8-oxo-purines as substrates for prebiotic RNA replication. Here we show that the 8-oxo-purine nucleotides are poor substrates for nonenzymatic RNA primer extension, both as activated monomers and when present in the template strand; their presence at the end of a primer also strongly reduces the rate and fidelity of primer extension. To provide a proper comparison with 8-oxo-inosine, we also examined primer extension reactions with inosine, and found that inosine exhibits surprisingly rapid and accurate nonenzymatic RNA copying. We propose that inosine, which can be derived from adenosine by deamination, could have acted as a surrogate for G in the earliest stages of the emergence of life.

scholarly journals Regulation of proliferation of LLC-MK2 cells by nucleosides and nucleotides: the role of ecto-enzymes

1996 ◽  
Vol 316 (2) ◽  
pp. 551-557 ◽  
Author(s):  
Raf LEMMENS ◽  
Luc VANDUFFEL ◽  
Henri TEUCHY ◽  
Ognjen CULIC
Keyword(s):  
Cell Proliferation ◽  
Adenine Nucleotides ◽  
Inhibitory Effect ◽  
Pyrimidine Nucleoside ◽  
Purine Nucleotides ◽  
Pyrimidine Nucleotides ◽  
Nucleotides And Nucleosides ◽  
Nucleoside Uptake ◽  
Stimulate Cell Proliferation

1. Using the incorporation of [methyl-3H]thymidine as a proliferation marker, the effects of various nucleosides and nucleotides on endothelial LLC-MK2 cells were studied. We found that ATP, ADP, AMP and adenosine in concentrations of 10 μM or higher stimulate the proliferation of these cells. 2. Inhibition of ecto-ATPase (EC 3.6.1.15), 5´-nucleotidase (EC 3.1.3.5) or alkaline phosphatase (EC 3.1.3.1) significantly diminished the stimulatory effect of ATP, indicating that the effect is primarily caused by adenosine and not by adenine nucleotides. Also, the effect depends only on extracellular nucleosides, since inhibition of nucleoside uptake by dipyridamole has no influence on proliferation. 3. Other purine nucleotides and nucleosides (ITP, GTP, inosine and guanosine) also stimulate cell proliferation, while pyrimidine nucleotides and nucleosides (CTP, UTP, cytidine and uridine) inhibit proliferation. Furthermore, the simultaneous presence of adenosine and any of the other purine nucleosides is not entirely additive in its effect on cell proliferation. At the same time any pyrimidine nucleoside, when added together with adenosine, has the same inhibitory effect as the pyrimidine nucleoside alone. 4. Apparently these proliferative effects are neither caused by any pharmacologically known P1-purinoceptor, nor are they mediated by cyclic AMP, cyclic GMP, or D-myo-inositol 1,4,5-trisphosphate as second messenger, nor by extracellular Ca2+. 5. Therefore, we conclude that various purine and pyrimidine nucleosides can influence the proliferation of LLC-MK2 cells by acting on putative purinergic and pyrimidinergic receptors not previously described.

Do pyrimidine nucleotides regulate translatability of globin mRNA as purine nucleotides do?

1988 ◽  
Vol 20 (10) ◽  
pp. 1051-1059
Author(s):  
Harvey N. Rubin ◽  
Ernest Almendarez ◽  
Mostafa N. Halim
Keyword(s):  
Purine Nucleotides ◽  
Globin Mrna ◽  
Pyrimidine Nucleotides

scholarly journals Geochemical influences on nonenzymatic oligomerization of prebiotically relevant cyclic nucleotides

2019 ◽  
Author(s):  
Shikha Dagar ◽  
Susovan Sarkar ◽  
Sudha Rajamani
Keyword(s):  
Cyclic Nucleotides ◽  
Hot Spring ◽  
Rna World ◽  
Early Earth ◽  
Pyrimidine Nucleotides ◽  
Diurnal Cycles ◽  
Alkaline Conditions ◽  
Purine And Pyrimidine Nucleotides ◽  
The Stability ◽  
Emergence Of Life

AbstractThe spontaneous emergence of RNA on the early Earth continues to remain an enigma in the field of origins of life. Few studies have looked at the nonenzymatic oligomerization of cyclic nucleotides under neutral to alkaline conditions, in fully dehydrated state. Herein, we systematically investigated the oligomerization of cyclic nucleotides under prebiotically relevant conditions, where starting reactants were subjected to repeated dehydration-rehydration (DH-RH) regimes, like they would have been on an early Earth. DH-RH conditions, a recurring geological theme, are driven by naturally occurring processes including diurnal cycles and tidal pool activity. These conditions have been shown to facilitate uphill oligomerization reactions in terrestrial geothermal niches, which are hypothesized to be pertinent sites for the emergence of life. 2′-3′ and 3′-5′ cyclic nucleotides of one purine-based (adenosine) and one pyrimidine-based (cytidine) system were evaluated in this study. Additionally, the effect of amphiphiles was also investigated. Furthermore, to discern the effect of ‘realistic’ conditions on this process, the reactions were also performed using hot spring water samples from an early Earth analogue environment. Our results showed that the oligomerization of cyclic nucleotides under DH-RH conditions resulted in intact informational oligomers. Amphiphiles increased the stability of, both, the starting monomers and the resultant oligomers. In analogue condition reactions, oligomerization of nucleotides and back-hydrolysis of the resultant oligomers was pronounced. Altogether, this study demonstrates how nonenzymatic oligomerization of cyclic purine and pyrimidine nucleotides, under laboratory-simulated and early Earth analogous conditions, could have resulted in RNA oligomers of a putative RNA World.

Effects of Chemopreventive Natural Compounds on the Accuracy of 8-oxo-7,8-dihydro-2′-deoxyguanosine Translesion Synthesis

Planta Medica ◽  
2021 ◽  
Author(s):  
Amandine Nachtergael ◽  
Déborah Lanterbecq ◽  
Martin Spanoghe ◽  
Alexandra Belayew ◽  
Pierre Duez
Keyword(s):  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Primer Extension ◽  
Nuclear Proteins ◽  
Reaction Products ◽  
Primer Extension Assay ◽  
Experimental Conditions ◽  
Repair Synthesis ◽  
Template Strand

AbstractTranslesion synthesis is a DNA damage tolerance mechanism that relies on a series of specialized DNA polymerases able to bypass a lesion on a DNA template strand during replication or post-repair synthesis. Specialized translesion synthesis DNA polymerases pursue replication by inserting a base opposite to this lesion, correctly or incorrectly depending on the lesion nature, involved DNA polymerase(s), sequence context, and still unknown factors. To measure the correct or mutagenic outcome of 8-oxo-7,8-dihydro-2′-deoxyguanosine bypass by translesion synthesis, a primer-extension assay was performed in vitro on a template DNA bearing this lesion in the presence of nuclear proteins extracted from human intestinal epithelial cells (FHs 74 Int cell line); the reaction products were analyzed by both denaturing capillary electrophoresis (to measure the yield of translesion elongation) and pyrosequencing (to determine the identity of the nucleotide inserted in front of the lesion). The influence of 14 natural polyphenols on the correct or mutagenic outcome of translesion synthesis through 8-oxo-7,8-dihydro-2′-deoxyguanosine was then evaluated in 2 experimental conditions by adding the polyphenol either (i) to the reaction mix during the primer extension assay; or (ii) to the culture medium, 24 h before cell harvest and nuclear proteins extraction. Most of the tested polyphenols significantly influenced the outcome of translesion synthesis, either through an error-free (apigenin, baicalein, sakuranetin, and myricetin) or a mutagenic pathway (epicatechin, chalcone, genistein, magnolol, and honokiol).

Serine metabolism in rat embryos undergoing organogenesis

Development ◽  
1985 ◽  
Vol 87 (1) ◽  
pp. 137-144
Author(s):  
Peter B. Rowe ◽  
Annette Kalaizis
Keyword(s):  
Amino Acids ◽  
Specific Radioactivity ◽  
Yolk Sac ◽  
Purine Nucleotides ◽  
Pyrimidine Nucleotides ◽  
Nucleotide Biosynthesis ◽  
Radioactive Label ◽  
Rat Embryos ◽  
Undifferentiated State ◽  
Unidentified Source

Rat embryos (9·5 days gestation) were cultured for 48 h in heat-inactivated homologous serum containing [3-14C] serine. Analysis of the distribution of the radioactive label in the conceptus demonstrated that almost one half of the incorporated serine was cleaved to provide one-carbon units for the synthesis of purine and pyrimidine nucleotides. Analysis of the free amino acids in the serum, the exocoelomic fluid and the cells of the yolk sac and the embryo showed that there was a variably selective increase in the concentration of amino acids in the exocoelomic fluid compared with the serum and a significant decrease in the specific radioactivity of the free serine within the conceptus which was the highest in the yolk sac and lowest in the embryo. These findings would support the concept of yolk sac lysosomal degradation of medium serum protein as a major source of amino acids supplying almost 86 % of that required during this phase of embryonic development. The specific radioactivity of purine bases in cellular nucleotides, RNA and DNA was similar to that of the free serine in both yolk sac and embryo. This indicated that an alternative, as yet unidentified source of one-carbon units was available for purine nucleotide biosynthesis. Analysis of the cellular purine nucleotides revealed low ATP/GTP ratios in both the embryo and its yolk sac and this may be related to the undifferentiated state of many of the cells of the conceptus.

scholarly journals Activation of NADPH oxidase by purine and pyrimidine nucleotides involves G proteins and is potentiated by chemotactic peptides

1989 ◽  
Vol 259 (3) ◽  
pp. 813-819 ◽  
Author(s):  
R Seifert ◽  
R Burde ◽  
G Schultz
Keyword(s):  
Nadph Oxidase ◽  
Human Neutrophils ◽  
Signal Molecules ◽  
Purine Nucleotides ◽  
Pyrimidine Nucleotides ◽  
Chemotactic Peptides ◽  
Leukaemic Cells ◽  
Purine And Pyrimidine Nucleotides ◽  
Guanine Nucleotide Binding ◽  
Potency Order

Human neutrophils and HL-60 leukaemic cells possess an NADPH oxidase which catalyses superoxide (O2-) formation and is activated by the chemotactic peptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe). In dibutyryl cyclic AMP-differentiated HL-60 cells, ATP and UTP in the presence of cytochalasin B activated O2- formation with EC50 values of 5 microM and efficacies amounting to 30% of that of fMet-Leu-Phe. The potency order of purine nucleotides in activating O2- generation was ATP = adenosine 5′-O-(3-thiotriphosphate) greater than ITP greater than dATP = ADP. Pyrimidine nucleotides activated NADPH oxidase in the potency order UTP greater than dUTP greater than CTP = TTP = UDP. Pertussis toxin completely prevented activation of NADPH oxidase by fMet-Leu-Phe and UTP, whereas the effect of ATP was only partially inhibited. ATP and UTP enhanced O2- generation induced by fMet-Leu-Phe by up to 8-fold, and primed the cells to respond to non-stimulatory concentrations of fMet-Leu-Phe. Activation of NADPH oxidase by UTP but not by ATP was inhibited by various activators of adenylate cyclase. In dimethyl sulphoxide-differentiated HL-60 cells and in human neutrophils, ATP and UTP per se did not activate NADPH oxidase, but they potentiated the effect of fMet-Leu-Phe. Our results suggest that purine and pyrimidine nucleotides act via purino- and novel pyrimidinoceptors respectively, which are coupled to guanine nucleotide-binding proteins leading to the activation of NADPH oxidase. As ATP and UTP are released from cells under physiological and pathological conditions, these nucleotides may play roles as intercellular signal molecules in the activation of O2- formation.

scholarly journals A Potential Role for Aminoacylation in Primordial RNA Copying Chemistry

2020 ◽  
Author(s):  
Aleksandar Radakovic ◽  
Tom H. Wright ◽  
Victor S. Lelyveld ◽  
Jack W. Szostak
Keyword(s):  
Protein Synthesis ◽  
Fatty Acid ◽  
Amino Acid ◽  
Ribosomal Protein ◽  
Potential Role ◽  
Rna Replication ◽  
Primer Extension ◽  
Functional Link ◽  
Low Magnesium ◽  
Ribosomal Protein Synthesis

ABSTRACTAminoacylated tRNAs are the substrates for ribosomal protein synthesis in all branches of life, implying an ancient origin for aminoacylation chemistry. In the 1970s, Orgel and colleagues reported potentially prebiotic routes to aminoacylated nucleotides and their RNA templated condensation to form amino acid bridged dinucleotides. However, it is unclear whether such reactions would have aided or impeded nonenzymatic RNA replication. Determining whether aminoacylated RNAs could have been advantageous in evolution prior to the emergence of protein synthesis remains a key challenge. We therefore tested the ability of aminoacylated RNA to participate in both templated primer extension and ligation reactions. We find that at low magnesium concentrations that favor fatty acid-based protocells, these reactions proceed orders of magnitude more rapidly than when initiated from the cis-diol of unmodified RNA. We further demonstrate that amino acid bridged RNAs can act as templates in a subsequent round of copying. Our results suggest that aminoacylation facilitated nonenzymatic RNA replication, thus outlining a potentially primordial functional link between aminoacylation chemistry and RNA replication.Abstract Figure

Chemotactic, mitogenic, and angiogenic actions of UTP on vascular endothelial cells

1999 ◽  
Vol 276 (3) ◽  
pp. H1091-H1097 ◽  
Author(s):  
Christina M. Satterwhite ◽  
Angela M. Farrelly ◽  
Michael E. Bradley
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Purine Nucleotides ◽  
Pyrimidine Nucleotides ◽  
Pyrimidine Nucleotide ◽  
Endothelial Repair ◽  
Extracellular Signal ◽  
Chemotactic Factors ◽  
Endothelial Growth Factor

Endothelial cells express receptors for ATP and UTP, and both UTP and ATP elicit endothelial release of vasoactive compounds such as prostacyclin and nitric oxide; however, the distinction between purine and pyrimidine nucleotide signaling is not known. We hypothesized that UTP plays a more important role in endothelial mitogenesis and chemotaxis than does ATP and that UTP is angiogenic. In cultured endothelial cells from guinea pig cardiac vasculature (CEC), both UTP and vascular endothelial growth factor (VEGF) were significant mitogenic and chemotactic factors; in contrast, ATP demonstrated no significant chemotaxis in CEC. In chick chorioallantoic membranes (CAM), UTP and VEGF treatments produced statistically significant increases in CAM vascularity compared with controls. These findings are the first evidence of chemotactic or angiogenic effects of pyrimidines; they suggest a role for pyrimidine nucleotides that is distinct from those assumed by purine nucleotides and provide for the possibility that UTP serves as an extracellular signal for processes such as endothelial repair and angiogenesis.

scholarly journals 2,6-diaminopurine promotes repair of DNA lesions under prebiotic conditions

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rafał Szabla ◽  
Magdalena Zdrowowicz ◽  
Paulina Spisz ◽  
Nicholas J. Green ◽  
Petr Stadlbauer ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Rna Replication ◽  
Dna Lesions ◽  
Unresolved Issue ◽  
Cyclobutane Pyrimidine Dimers ◽  
Dna Oligomers ◽  
Pyrimidine Dimers ◽  
Prebiotic Environments ◽  
Prebiotic Syntheses ◽  
Rna And Dna

AbstractHigh-yielding and selective prebiotic syntheses of RNA and DNA nucleotides involve UV irradiation to promote the key reaction steps and eradicate biologically irrelevant isomers. While these syntheses were likely enabled by UV-rich prebiotic environment, UV-induced formation of photodamages in polymeric nucleic acids, such as cyclobutane pyrimidine dimers (CPDs), remains the key unresolved issue for the origins of RNA and DNA on Earth. Here, we demonstrate that substitution of adenine with 2,6-diaminopurine enables repair of CPDs with yields reaching 92%. This substantial self-repairing activity originates from excellent electron donating properties of 2,6-diaminopurine in nucleic acid strands. We also show that the deoxyribonucleosides of 2,6-diaminopurine and adenine can be formed under the same prebiotic conditions. Considering that 2,6-diaminopurine was previously shown to increase the rate of nonenzymatic RNA replication, this nucleobase could have played critical roles in the formation of functional and photostable RNA/DNA oligomers in UV-rich prebiotic environments.

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