Journal articles: 'Pyrimidine nucleotides'

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Tomlinson, Patricia Tolson, and Carol J. Lovatt. "Nucleotide Metabolism in ‘Washington’ Navel Orange Fruit: I. Pathways of Synthesis and Catabolism." Journal of the American Society for Horticultural Science 112, no. 3 (May 1987): 529–35. http://dx.doi.org/10.21273/jashs.112.3.529.

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Abstract The capacity of ‘Washington’ navel orange fruit [Citrus sinensis (L.) Osbeck] to synthesize and catabolize purines and pyrimidines was assessed. De novo biosynthesis of purine nucleotide was demonstrated by [14C] bicarbonate incorporation into purine nucleotides, blockage of this process by four known inhibitors, and assimilation of radiolabeled carbon from formate, both carbons of glycine, and carbon-3 of serine into the adenine ring. De novo synthesis of pyrimidines via the orotate pathway in young fruit was demonstrated by incorporation of [14C] bicarbonate and [6-14C]orotic acid into uridine nucleotides, release of 14CO2 from [7-14C]orotic acid, and blockage of these processes by 6-azauridine. Synthesis of purine and pyrimidine nucleotides via salvage reactions was demonstrated by incorporation of radiolabeled bases and ribonucleosides into nucleotides and into nucleic acids. Release of 14CO2 from radiolabeled adenine, adenosine, hypoxanthine, and xanthine, uric acid, urea (purines), uracil, and uridine (pyrimidines) provided evidence the pathways for catabolism (degradation) of purines and pyrimidines in navel orange fruit are similar to those found in microorganisms and animal tissues. To the best of our knowledge, this report is the first to assess the capacity of anabolic and catabolic pathways of purine and pyrimidine nucleotide metabolism in fruit of any species. De novo synthetic activities in orange fruit permit increases in the pools of purine and pyrimidine nucleotides using simple precursors. Further, the patterns of salvage and catabolism suggest riboside pools are reused predominantly as nucleotides, while the majority of base pools are degraded to permit recycling of carbon and nitrogen into other metabolites.

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Weetall, Marla, Kensuke Kojima, Sujan Piya, Christopher Trotta, John Baird, Kylie O'Keefe, Bansri Furia, Gautam M. Borthakur, and Robert Spiegel. "Inhibition of De Novo Pyrimidine Nucleotide Synthesis By the Novel DHODH Inhibitor PTC299 Induces Differentiation and/or Death of AML Cells." Blood 134, Supplement_1 (November 13, 2019): 5152. http://dx.doi.org/10.1182/blood-2019-124569.

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Background: Pyrimidine nucleotides are generated either by de novo synthesis or the salvage pathway in which pyrimidine nucleotides are obtained from the diet. Resting cells typically acquire adequate pyrimidine nucleotides from the salvage pathway. Rapidly proliferating cells, however, are dependent on the de novo synthesis of pyrimidine nucleotides. PTC299 is an inhibitor of dihydroorotate dehydrogenase (DHODH), a rate limiting enzyme for de novo pyrimidine nucleotide synthesis that had previously been in clinical trials for treatment of solid tumors. Results: Using 15N-labelled glutamine, we show that PTC299 reduces de novo pyrimidine nucleotide synthesis in PTC299-sensitive AML cell lines resulting in a depletion of total pyrimidine nucleotides. In parallel to reduction in pyrimidine nucleotides, PTC 299 leads to accumulation of DHO, the substrate of DHODH and unexpectedly, an accumulation of N-carbamoyl aspartate the metabolite above DHO in the de novo pyrimidine nucleotide synthesis pathway. PTC299 was broadly active against leukemia and lymphoma lines, with 80% of the AML lines tested showing sensitivity. Treatment of AML cell lines with PTC299 induced differentiation as shown by increased CD14 and/or reduced proliferation. Using isogenic AML lines, we show that PTC299 reduces the proliferation of both p53 wildtype and p53 deficient leukemia calls with similar potency as measured by the concentration of PTC299 required to reduce cell number by 50% (CC50). In cells expressing wildtype p53, PTC299 increases p53 activation. However, p53- wildtype cells undergo increased apoptosis whereas p53-deficience cells undergo necrosis. PTC299 induced a G1/S cell cycle arrest, also independent of p53 status. PTC299 increased H2A.X (a marker of double stranded DNA breaks) in both p53 wildtype and p53 deficient cells. These data suggest that the depletion of nucleotides results in stalling at the replication fork, and subsequent DNA-breaks. Conclusion: De novo pyrimidine nucleotide synthesis is critical for AML survival and proliferation. Depletion of nucleotides results in reduced proliferation, triggering either differentiation and/or cell death. Disclosures Weetall: PTC Therapeutics: Employment. Trotta:PTC Therapeutics: Employment. Baird:PTC Therapeutics: Employment. O'Keefe:PTC Therapeutics: Employment. Furia:PTC Therapeutics: Employment. Borthakur:PTC Therapeutics: Consultancy; Janssen: Research Funding; AbbVie: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; NKarta: Consultancy; AstraZeneca: Research Funding; Xbiotech USA: Research Funding; Incyte: Research Funding; GSK: Research Funding; Oncoceutics, Inc.: Research Funding; Novartis: Research Funding; Agensys: Research Funding; BMS: Research Funding; Oncoceutics: Research Funding; Cantargia AB: Research Funding; Bayer Healthcare AG: Research Funding; Eisai: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Polaris: Research Funding; Merck: Research Funding; Cyclacel: Research Funding; Eli Lilly and Co.: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Arvinas: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding. Spiegel:PTC Therapeutics: Consultancy.

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Li, Wentao, Ogun Adebali, Yanyan Yang, Christopher P. Selby, and Aziz Sancar. "Single-nucleotide resolution dynamic repair maps of UV damage in Saccharomyces cerevisiae genome." Proceedings of the National Academy of Sciences 115, no. 15 (March 26, 2018): E3408—E3415. http://dx.doi.org/10.1073/pnas.1801687115.

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We have adapted the eXcision Repair-sequencing (XR-seq) method to generate single-nucleotide resolution dynamic repair maps of UV-induced cyclobutane pyrimidine dimers and (6-4) pyrimidine–pyrimidone photoproducts in the Saccharomyces cerevisiae genome. We find that these photoproducts are removed from the genome primarily by incisions 13–18 nucleotides 5′ and 6–7 nucleotides 3′ to the UV damage that generate 21- to 27-nt-long excision products. Analyses of the excision repair kinetics both in single genes and at the genome-wide level reveal strong transcription-coupled repair of the transcribed strand at early time points followed by predominantly nontranscribed strand repair at later stages. We have also characterized the excision repair level as a function of the transcription level. The availability of high-resolution and dynamic repair maps should aid in future repair and mutagenesis studies in this model organism.

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Satterwhite, Christina M., Angela M. Farrelly, and Michael E. Bradley. "Chemotactic, mitogenic, and angiogenic actions of UTP on vascular endothelial cells." American Journal of Physiology-Heart and Circulatory Physiology 276, no. 3 (March 1, 1999): H1091—H1097. http://dx.doi.org/10.1152/ajpheart.1999.276.3.h1091.

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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.

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Tomlinson, Patricia Tolson, and Carol J. Lovatt. "Nucleotide Metabolism in ‘Washington’ Navel Orange Fruit: II. Pathway Capacities During Development." Journal of the American Society for Horticultural Science 112, no. 3 (May 1987): 535–39. http://dx.doi.org/10.21273/jashs.112.3.535.

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Abstract Changes in the capacity of ‘Washington’ navel orange [Citrus sinensis (L.) Osbeck] fruit to synthesize (de novo or by salvage) pyrimidine nucleotides, but not purine nucleotides, appears to be related to the stage of fruit development. De novo pyrimidine synthesis in whole-fruit tissue increased 6-fold during Stage I of development (cell division phase), from 10 nmol [14C]bicarbonate incorporated into uridine nucleotides during 5 hr per g dry weight whole-fruit tissue from ovaries harvested at flower petal drop to 57 nmol for 2-month-old fruit. Capacity of peel tissue to synthesize pyrimidine nucleotides de novo decreased following completion of Stage I, from 43 nmol [14C]bicarbonate incorporated into uridine nucleotides during 5 hr per g dry weight of peel tissue from 2-month-old fruit to 11 nmol for 5-month-old (Stage II) fruit. This decrease was not offset by increased salvage of uridine. Capacity of whole-fruit tissue to synthesize purines de novo increased 3-fold during Stage I. Synthetic capacity of peel tissue from Stage I fruit was half that observed for whole-fruit tissue and did not decrease significantly during Stages II (cell enlargement phase) and III (maturation phase). These observations suggest purine synthetic capacity may not be related to stage of development. Changes in protein or glucose contents, or respiratory activity of peel tissue, could not account for the observed reduction in pyrimidine synthetic capacity. Thus, the reduction observed in synthetic activity was specific for pyrimidine nucleotides. The capacity of fast-growing, 1-month-old fruit (high potential to set) to synthesize or catabolize either pyrimidine or purine nucleotides did not differ from that of slow-growing fruit (low potential to set), suggesting that nucleotide synthesis is not limiting to growth.

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6

Szondy, Z., and E. A. Newsholme. "The effect of glutamine concentration on the activity of carbamoyl-phosphate synthase II and on the incorporation of [3H]thymidine into DNA in rat mesenteric lymphocytes stimulated by phytohaemagglutinin." Biochemical Journal 261, no. 3 (August 1, 1989): 979–83. http://dx.doi.org/10.1042/bj2610979.

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The maximum catalytic activities of carbamoyl-phosphate synthase II, a limiting enzyme for pyrimidine nucleotide synthesis, are very much less than those of glutaminase, a limiting enzyme for glutamine utilization, in lymphocytes and macrophages; and the flux through the pathway for pyrimidine formation de novo is only about 0.4% of the rate of glutamine utilization by lymphocytes. The Km of synthase II for glutamine is about 16 microM and the concentration of glutamine necessary to stimulate lymphocyte proliferation half-maximally is about 21 microM. This agreement suggests that the importance of glutamine for these cells is provision of nitrogen for biosynthesis of pyrimidine nucleotides (and probably purine nucleotides). However, the glutamine concentration necessary for half-maximal stimulation of glutamine utilization (glutaminolysis) by the lymphocytes is 2.5 mM. The fact that the rate of glutamine utilization by lymphocytes is markedly in excess of the rate of the pathway for pyrimidine nucleotide synthesis de novo and that the Km and ‘half-maximal concentration’ values are so different, suggests that the glutaminolytic pathway is independent of the use of glutamine nitrogen for pyrimidine synthesis.

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Amici, Adolfo, Monica Emanuelli, Giulio Magni, Nadia Raffaelli, and Silverio Ruggieri. "Pyrimidine nucleotidases from human erythrocyte possess phosphotransferase activities specific for pyrimidine nucleotides." FEBS Letters 419, no. 2-3 (December 15, 1997): 263–67. http://dx.doi.org/10.1016/s0014-5793(97)01464-6.

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8

Bhat, B. M., H. A. Brady, and W. S. Wold. "Virus deletion mutants that affect a 3' splice site in the E3 transcription unit of adenovirus 2." Molecular and Cellular Biology 5, no. 9 (September 1985): 2405–13. http://dx.doi.org/10.1128/mcb.5.9.2405-2413.1985.

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Five viable virus mutants were constructed with deletions near a 3' splice site located at nucleotide 2157 in the E3 transcription unit of adenovirus 2. The mutants were examined for splicing activity at the 2157 3' splice site in vivo by nuclease-gel analysis of steady-state cytoplasmic mRNA. Splicing was not prevented by an exon deletion (dl719) that leaves 16 5'-proximal exon nucleotides intact or by intron deletions that leave 34 (dl717, dl712) or 18 (dl716) 3'-proximal intron nucleotides intact. The sequences deleted in one of these intron mutants (dl716) include the putative branchpoint site used in lariat formation during splicing. Thus, a surrogate branchpoint site apparently can be used for splicing. Another intron mutant (dl714) has a deletion that leaves 15 3'-proximal intron nucleotides intact; remarkably, this deletion virtually abolished splicing, even though the deletion is only 3 nucleotides closer to the splice site than is the deletion in dl716 which splices normally. The three nucleotides deleted in dl714 that are retained by dl716 are the sequence TGT. The TGT sequence is located on the 5' boundary of the pyrimidine-rich region upstream of the nucleotide 2157 3' splice site. Such pyrimidine-rich regions are ubiquitous at 3' splice sites. Most likely, the TGT is required for splicing at the nucleotide 2157 3' splice site. The TGT may be important because of its specific sequence or because it forms the 5' boundary of the pyrimidine-rich region.

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Bhat, B. M., H. A. Brady, and W. S. Wold. "Virus deletion mutants that affect a 3' splice site in the E3 transcription unit of adenovirus 2." Molecular and Cellular Biology 5, no. 9 (September 1985): 2405–13. http://dx.doi.org/10.1128/mcb.5.9.2405.

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Five viable virus mutants were constructed with deletions near a 3' splice site located at nucleotide 2157 in the E3 transcription unit of adenovirus 2. The mutants were examined for splicing activity at the 2157 3' splice site in vivo by nuclease-gel analysis of steady-state cytoplasmic mRNA. Splicing was not prevented by an exon deletion (dl719) that leaves 16 5'-proximal exon nucleotides intact or by intron deletions that leave 34 (dl717, dl712) or 18 (dl716) 3'-proximal intron nucleotides intact. The sequences deleted in one of these intron mutants (dl716) include the putative branchpoint site used in lariat formation during splicing. Thus, a surrogate branchpoint site apparently can be used for splicing. Another intron mutant (dl714) has a deletion that leaves 15 3'-proximal intron nucleotides intact; remarkably, this deletion virtually abolished splicing, even though the deletion is only 3 nucleotides closer to the splice site than is the deletion in dl716 which splices normally. The three nucleotides deleted in dl714 that are retained by dl716 are the sequence TGT. The TGT sequence is located on the 5' boundary of the pyrimidine-rich region upstream of the nucleotide 2157 3' splice site. Such pyrimidine-rich regions are ubiquitous at 3' splice sites. Most likely, the TGT is required for splicing at the nucleotide 2157 3' splice site. The TGT may be important because of its specific sequence or because it forms the 5' boundary of the pyrimidine-rich region.

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Froschauer, Elisabeth M., Nicole Rietzschel, Melanie R. Hassler, Markus Binder, Rudolf J. Schweyen, Roland Lill, Ulrich Mühlenhoff, and Gerlinde Wiesenberger. "The mitochondrial carrier Rim2 co-imports pyrimidine nucleotides and iron." Biochemical Journal 455, no. 1 (September 13, 2013): 57–65. http://dx.doi.org/10.1042/bj20130144.

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Mitochondrial iron uptake is of key importance both for organelle function and cellular iron homoeostasis. The mitochondrial carrier family members Mrs3 and Mrs4 (homologues of vertebrate mitoferrin) function in organellar iron supply, yet other low efficiency transporters may exist. In Saccharomyces cerevisiae, overexpression of RIM2 (MRS12) encoding a mitochondrial pyrimidine nucleotide transporter can overcome the iron-related phenotypes of strains lacking both MRS3 and MRS4. In the present study we show by in vitro transport studies that Rim2 mediates the transport of iron and other divalent metal ions across the mitochondrial inner membrane in a pyrimidine nucleotide-dependent fashion. Mutations in the proposed substrate-binding site of Rim2 prevent both pyrimidine nucleotide and divalent ion transport. These results document that Rim2 catalyses the co-import of pyrimidine nucleotides and divalent metal ions including ferrous iron. The deletion of RIM2 alone has no significant effect on mitochondrial iron supply, Fe–S protein maturation and haem synthesis. However, RIM2 deletion in mrs3/4Δ cells aggravates their Fe–S protein maturation defect. We conclude that under normal physiological conditions Rim2 does not play a significant role in mitochondrial iron acquisition, yet, in the absence of the main iron transporters Mrs3 and Mrs4, this carrier can supply the mitochondrial matrix with iron in a pyrimidine-nucleotide-dependent fashion.

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Deng, Wei-Wei, Riko Katahira, and Hiroshi Ashihara. "Short Term Effect of Caffeine on Purine, Pyrimidine and Pyridine Metabolism in Rice (Oryza sativa) Seedlings." Natural Product Communications 10, no. 5 (May 2015): 1934578X1501000. http://dx.doi.org/10.1177/1934578x1501000510.

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As part of our studies on the physiological and ecological function of caffeine, we investigated the effect of exogenously supplied caffeine on purine, pyrimidine and pyridine metabolism in rice seedlings. We examined the effect of 1 mM caffeine on the in situ metabolism of 14C-labelled adenine, guanine, inosine, uridine, uracil, nicotinamide and nicotinic acid. The segments of 4-day-old dark-grown seedlings were incubated with these labelled compounds for 6 h. For purines, the incorporation of radioactivity from [8-14C]adenine and [8-14C]guanine into nucleotides was enhanced by caffeine; in contrast, incorporation into CO2 were reduced. The radioactivity in ureides (allantoin and allantoic acid) from [8-14C]guanine and [8-14C]inosine was increased by caffeine. For pyrimidines, caffeine enhanced the incorporation of radioactivity from [2-14C]uridine into nucleotides, which was accompanied by a decrease in pyrimidine catabolism. Such difference was not found in the metabolism of [2-14C]uracil. Caffeine did not influence the pyridine metabolism of [carbonyl-14C]-nicotinamide and [2-14C]nicotinic acid. The possible control steps of caffeine on nucleotide metabolism in rice are discussed.

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Wang, Shoushan, Min Zhang, Peng Liu, Shilei Xie, Faliang Cheng, and Lishi Wang. "Formation of pyrimidine–pyrimidine type DNA intrastrand cross-links: a theoretical verification." Physical Chemistry Chemical Physics 19, no. 42 (2017): 28907–16. http://dx.doi.org/10.1039/c7cp06452g.

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Deval, Jérôme, Megan H. Powdrill, Claudia M. D'Abramo, Luciano Cellai, and Matthias Götte. "Pyrophosphorolytic Excision of Nonobligate Chain Terminators by Hepatitis C Virus NS5B Polymerase." Antimicrobial Agents and Chemotherapy 51, no. 8 (May 14, 2007): 2920–28. http://dx.doi.org/10.1128/aac.00186-07.

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ABSTRACT Nonobligate chain terminators, such as 2′-C-methylated nucleotides, block RNA synthesis by the RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV). Previous studies with related viral polymerases have shown that classical chain terminators lacking the 3′-hydroxyl group can be excised in the presence of pyrophosphate (PPi), which is detrimental to the inhibitory activity of these compounds. Here we demonstrate that the HCV RdRp enzyme is capable of removing both obligate and clinically relevant nonobligate chain terminators. Pyrimidines are more efficiently excised than are purines. The presence of the next complementary templated nucleotide literally blocks the excision of obligate chain terminators through the formation of a dead-end complex (DEC). However, 2′-C-methylated CMP is still cleaved efficiently under these conditions. These findings show that a 2′-methylated primer terminus impedes nucleotide binding. The S282T mutation, associated with resistance to 2′-C-methylated nucleotides, does not affect the excision patterns. Thus, the decreased susceptibility to 2′-C-methylated nucleotides appears to be based solely on improved discrimination between the inhibitor and its natural counterpart. In conclusion, our data suggest that the phosphorolytic excision of nonobligate, pyrimidine-based chain terminators can diminish their potency. The templated nucleotide does not appear to provide protection from excision through DEC formation.

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LEMMENS, Raf, Luc VANDUFFEL, Henri TEUCHY, and Ognjen CULIC. "Regulation of proliferation of LLC-MK2 cells by nucleosides and nucleotides: the role of ecto-enzymes." Biochemical Journal 316, no. 2 (June 1, 1996): 551–57. http://dx.doi.org/10.1042/bj3160551.

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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.

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Shanmugasundaram, Muthian, Annamalai Senthilvelan, and Anilkumar R. Kore. "C-5 Substituted Pyrimidine Nucleotides/Nucleosides: Recent Progress in Synthesis, Functionalization, and Applications." Current Organic Chemistry 23, no. 13 (October 9, 2019): 1439–68. http://dx.doi.org/10.2174/1385272823666190809124310.

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The chemistry of C5 substituted pyrimidine nucleotide serves as a versatile molecular biology probe for the incorporation of DNA/RNA that has been involved in various molecular biology applications such as gene expression, chromosome, and mRNA fluorescence in situ hybridization (FISH) experiment, mutation detection on arrays and microarrays, in situ RT-PCR, and PCR. In addition to C5 substituted pyrimidine nucleotide, C5 substituted pyrimidine nucleoside displays a broad spectrum of biological applications such as antibacterial, antiviral and anticancer activities. This review focusses on the recent development in the synthesis of aminoallyl pyrimidine nucleotide, aminopropargyl pyrimidine nucleotide, fluorescent probes containing C5 substituted pyrimidine nucleotide, 2′-deoxycytidine nucleoside containing vinylsulfonamide and acrylamide modification, C5 alkenyl, C5 alkynyl, and C5 aryl pyrimidine nucleosides through palladium-catalyzed reaction, pyrimidine nucleoside containing triazole moiety through Click reaction, 5-isoxazol-3-yl-pyrimidine nucleoside, C5 azide modified pyrimidine nucleoside, 2′-deoxycytidine nucleotide containing photocleavable moiety, and uridine nucleoside containing germane and their biological applications are outlined.

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Canturk, Fazile, Muhammet Karaman, Christopher P. Selby, Michael G. Kemp, Gulnihal Kulaksiz-Erkmen, Jinchuan Hu, Wentao Li, Laura A. Lindsey-Boltz, and Aziz Sancar. "Nucleotide excision repair by dual incisions in plants." Proceedings of the National Academy of Sciences 113, no. 17 (April 11, 2016): 4706–10. http://dx.doi.org/10.1073/pnas.1604097113.

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Plants use light for photosynthesis and for various signaling purposes. The UV wavelengths in sunlight also introduce DNA damage in the form of cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts [(6-4)PPs] that must be repaired for the survival of the plant. Genome sequencing has revealed the presence of genes for both CPD and (6-4)PP photolyases, as well as genes for nucleotide excision repair in plants, such asArabidopsisand rice. Plant photolyases have been purified, characterized, and have been shown to play an important role in plant survival. In contrast, even though nucleotide excision repair gene homologs have been found in plants, the mechanism of nucleotide excision repair has not been investigated. Here we used the in vivo excision repair assay developed in our laboratory to demonstrate thatArabidopsisremoves CPDs and (6-4)PPs by a dual-incision mechanism that is essentially identical to the mechanism of dual incisions in humans and other eukaryotes, in which oligonucleotides with a mean length of 26–27 nucleotides are removed by incising ∼20 phosphodiester bonds 5′ and 5 phosphodiester bonds 3′ to the photoproduct.

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Sprenger, Hans-Georg, Thomas MacVicar, Amir Bahat, Kai Uwe Fiedler, Steffen Hermans, Denise Ehrentraut, Katharina Ried, et al. "Cellular pyrimidine imbalance triggers mitochondrial DNA–dependent innate immunity." Nature Metabolism 3, no. 5 (April 26, 2021): 636–50. http://dx.doi.org/10.1038/s42255-021-00385-9.

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AbstractCytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP–AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS–STING–TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflammation in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS–STING–TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.

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Lafita-Navarro, M. Carmen, Niranjan Venkateswaran, Jessica A. Kilgore, Suman Kanji, Jungsoo Han, Spencer Barnes, Noelle S. Williams, Michael Buszczak, Sandeep Burma, and Maralice Conacci-Sorrell. "Inhibition of the de novo pyrimidine biosynthesis pathway limits ribosomal RNA transcription causing nucleolar stress in glioblastoma cells." PLOS Genetics 16, no. 11 (November 17, 2020): e1009117. http://dx.doi.org/10.1371/journal.pgen.1009117.

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Glioblastoma is the most common and aggressive type of cancer in the brain; its poor prognosis is often marked by reoccurrence due to resistance to the chemotherapeutic agent temozolomide, which is triggered by an increase in the expression of DNA repair enzymes such as MGMT. The poor prognosis and limited therapeutic options led to studies targeted at understanding specific vulnerabilities of glioblastoma cells. Metabolic adaptations leading to increased synthesis of nucleotides by de novo biosynthesis pathways are emerging as key alterations driving glioblastoma growth. In this study, we show that enzymes necessary for the de novo biosynthesis of pyrimidines, DHODH and UMPS, are elevated in high grade gliomas and in glioblastoma cell lines. We demonstrate that DHODH’s activity is necessary to maintain ribosomal DNA transcription (rDNA). Pharmacological inhibition of DHODH with the specific inhibitors brequinar or ML390 effectively depleted the pool of pyrimidines in glioblastoma cells grown in vitro and in vivo and impaired rDNA transcription, leading to nucleolar stress. Nucleolar stress was visualized by the aberrant redistribution of the transcription factor UBF and the nucleolar organizer nucleophosmin 1 (NPM1), as well as the stabilization of the transcription factor p53. Moreover, DHODH inhibition decreased the proliferation of glioblastoma cells, including temozolomide-resistant cells. Importantly, the addition of exogenous uridine, which reconstitutes the cellular pool of pyrimidine by the salvage pathway, to the culture media recovered the impaired rDNA transcription, nucleolar morphology, p53 levels, and proliferation of glioblastoma cells caused by the DHODH inhibitors. Our in vivo data indicate that while inhibition of DHODH caused a dramatic reduction in pyrimidines in tumor cells, it did not affect the overall pyrimidine levels in normal brain and liver tissues, suggesting that pyrimidine production by the salvage pathway may play an important role in maintaining these nucleotides in normal cells. Our study demonstrates that glioblastoma cells heavily rely on the de novo pyrimidine biosynthesis pathway to generate ribosomal RNA (rRNA) and thus, we identified an approach to inhibit ribosome production and consequently the proliferation of glioblastoma cells through the specific inhibition of the de novo pyrimidine biosynthesis pathway.

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Kennedy, C. F., and S. M. Berget. "Pyrimidine tracts between the 5' splice site and branch point facilitate splicing and recognition of a small Drosophila intron." Molecular and Cellular Biology 17, no. 5 (May 1997): 2774–80. http://dx.doi.org/10.1128/mcb.17.5.2774.

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The minimum size for splicing of a vertebrate intron is approximately 70 nucleotides. In Drosophila melanogaster, more than half of the introns are significantly below this minimum yet function well. Such short introns often lack the pyrimidine tract located between the branch point and 3' splice site common to metazoan introns. To investigate if small introns contain special sequences that facilitate their recognition, the sequences and factors required for the splicing of a 59-nucleotide intron from the D. melanogaster mle gene have been examined. This intron contains only a minimal region of interrupted pyrimidines downstream of the branch point. Instead, two longer, uninterrupted C-rich tracts are located between the 5' splice site and branch point. Both of these sequences are required for maximal in vivo and in vitro splicing. The upstream sequences are also required for maximal binding of factors to the 5' splice site, cross-linking of U2AF to precursor RNA, and assembly of the active spliceosome, suggesting that sequences upstream of the branch point influence events at both ends of the small mle intron. Thus, a very short intron lacking a classical pyrimidine tract between the branch point and 3' splice site requires accessory pyrimidine sequences in the short region between the 5' splice site and branch point.

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Communi, Didier, and Jean-Marie Boeynaems. "Receptors responsive to extracellular pyrimidine nucleotides." Trends in Pharmacological Sciences 18, no. 3 (March 1997): 83–86. http://dx.doi.org/10.1016/s0165-6147(96)01035-8.

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Ashihara, Hiroshi, Kaori Mitsui, and Toshiko Ukaji. "A Simple Analysis of Purine and Pyrimidine Nucleotides in Plant Cells by High-Performance Liquid Chromatography." Zeitschrift für Naturforschung C 42, no. 3 (March 1, 1987): 297–99. http://dx.doi.org/10.1515/znc-1987-0321.

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Abstract Purine and pyrimidine nucleotides, extracted from cultured plant cells with 6 % perchloric acid, were separated directly with HPLC using anion-exchange Shimpack WAX -1 column. More than fifteen nucleoside mono-, di-, and triphosphates and nucleotide sugars were clearly separated and quantified without any interference from plant phenolic compounds.

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22

Morrow, K. A., R. Seifert, V. Kaever, A. L. Britain, S. L. Sayner, C. D. Ochoa, E. A. Cioffi, D. W. Frank, T. C. Rich, and T. Stevens. "Heterogeneity of pulmonary endothelial cyclic nucleotide response to Pseudomonas aeruginosa ExoY infection." American Journal of Physiology-Lung Cellular and Molecular Physiology 309, no. 10 (November 15, 2015): L1199—L1207. http://dx.doi.org/10.1152/ajplung.00165.2015.

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Here, we tested the hypothesis that a promiscuous bacterial cyclase synthesizes purine and pyrimidine cyclic nucleotides in the pulmonary endothelium. To test this hypothesis, pulmonary endothelial cells were infected with a strain of the Gram-negative bacterium Pseudomonas aeruginosa that introduces only exoenzyme Y (PA103 ΔexoUexoT::Tc pUCPexoY; ExoY+) via a type III secretion system. Purine and pyrimidine cyclic nucleotides were simultaneously detected using mass spectrometry. Pulmonary artery (PAECs) and pulmonary microvascular (PMVECs) endothelial cells both possess basal levels of four different cyclic nucleotides in the following rank order: cAMP > cUMP ≈ cGMP ≈ cCMP. Endothelial gap formation was induced in a time-dependent manner following ExoY+ intoxication. In PAECs, intercellular gaps formed within 2 h and progressively increased in size up to 6 h, when the experiment was terminated. cGMP concentrations increased within 1 h postinfection, whereas cAMP and cUMP concentrations increased within 3 h, and cCMP concentrations increased within 4 h postinfection. In PMVECs, intercellular gaps did not form until 4 h postinfection. Only cGMP and cUMP concentrations increased at 3 and 6 h postinfection, respectively. PAECs generated higher cyclic nucleotide levels than PMVECs, and the cyclic nucleotide levels increased earlier in response to ExoY+ intoxication. Heterogeneity of the cyclic nucleotide signature in response to P. aeruginosa infection exists between PAECs and PMVECs, suggesting the intracellular milieu in PAECs is more conducive to cNMP generation.

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23

Flitter, W. D., and R. P. Mason. "The spin trapping of pyrimidine nucleotide free radicals in a Fenton system." Biochemical Journal 261, no. 3 (August 1, 1989): 831–39. http://dx.doi.org/10.1042/bj2610831.

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The reaction of the hydroxyl radical, generated by a Fenton system, with pyrimidine deoxyribonucleotides was investigated by using the e.s.r. technique of spin trapping. The spin trap t-nitrosobutane was employed to trap secondary radicals formed by the reaction of the hydroxyl radical with these nucleotides. The results presented here show that hydroxyl-radical attack on thymidine, 2-deoxycytidine 5-monophosphate and 2-deoxyuridine 5-monophosphate produced nucleotide-derived free radicals. The results indicate that .OH radical attack occurs predominantly at the carbon-carbon double bond of the pyrimidine base. The e.s.r. studies showed a good correlation with previous results obtained by authors who used x- or gamma-ray irradiation to generate the hydroxyl radical. A thiobarbituric acid assay was also used to monitor the damage produced to the nucleotides by the Fenton system. These results showed qualitative agreement with the spin-trapping studies.

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24

Hassan, Mohamed E. "Photochemical synthesis of C(5) alkyl and heteroaryl substituted pyrimidine nucleotides." Collection of Czechoslovak Chemical Communications 50, no. 10 (1985): 2319–23. http://dx.doi.org/10.1135/cccc19852319.

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A simple and direct method for the synthesis of C-5 modified nucleosides is described. Photoirradiation of 2'-deoxyuridine 5'-phosphate (I), in the presence of haloheteroarenes afforded the C-5 heteroaryl substituted nucleotides. 5-(2-Hydroxyethyl)nucleotide also obtained from photocoupling of I with 2-iodoethanol. Photoirradiation of 5-iodo-2-deoxyuridine 5'-phosphate (II), in the presence of methyl acrylate or acrylonitrile, gave 5-(2-methoxycarbonylethenyl) and 5-(2-cyanoethenyl) nucleotide, respectively.

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25

Pal, Sharmistha, Milan Savani, Jakub Kaplan, Sylwia Sylwia A. Stopka, Huy Nguyen, Michael Regan, Nathalie Agar, Samuel McBrayer, and Daphne Haas-Kogan. "TMET-07. MOLECULAR MECHANISM OF EXQUISITE SENSITIVITY OF DIFFUSE MIDLINE GLIOMA TO DE NOVO PYRIMIDINE BIOSYNTHESIS." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii262. http://dx.doi.org/10.1093/neuonc/noac209.1012.

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Abstract Diffuse midline glioma (DMG) is a lethal pediatric brain cancer in dire need for therapeutic breakthroughs. To identify intrinsic addictions and therapeutic targets for DMG, we conducted a genome-wide k¬¬¬¬nockout CRISPR screen that identified de novo pyrimidine biosynthesis pathway as a targetable dependency. Since pyrimidine nucleotides can be synthesized by salvage and de novo pathways, identification of the latter as a dependency indicated a prominent role of de novo pathway in establishing the pyrimidine nucleotide pool in DMG. We investigated the molecular mechanism underlying this dependency using metabolic tracing of 15N-glutamine and genetic approaches. We report that DMG cells derive the majority of UMP (70%) through de novo synthesis, along with significantly elevated flux through the pyrimidine degradation pathway. High flux of 15N- labeled UMP through pyrimidine degradation in DMGs suggests that substrates (uridine and uracil) required for pyrimidine nucleotide salvage are limited, thus enhancing the dependency on de novo biosynthesis. To further confirm the causal role of pyrimidine degradation in driving de novo pathway dependency in DMG, we knocked down DPYD, the enzyme catalyzing the first committed step in pyrimidine degradation, using inducible shRNAs. Knockdown of DPYD diminished sensitivity of DMGs to de novo pathway inhibition as it rescued UMP pools and resultant DNA damage. Conversely, overexpression of DPYD in adult glioblastomas enhanced their sensitivity to de novo pyrimidine synthesis inhibition which was accompanied by greater depletion of UMP and induction of DNA damage. Consistent with this mechanism, we observed downregulation of DPYD in DMGs that acquired resistance to antagonists of de novo pyrimidine synthesis. Taken together, we have uncovered DPYD as a predictive biomarker of sensitivity to de novo pyrimidine synthesis inhibitors.

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26

Walter, Melanie, and Patrick Herr. "Re-Discovery of Pyrimidine Salvage as Target in Cancer Therapy." Cells 11, no. 4 (February 20, 2022): 739. http://dx.doi.org/10.3390/cells11040739.

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Nucleotides are synthesized through two distinct pathways: de novo synthesis and nucleoside salvage. Whereas the de novo pathway synthesizes nucleotides from amino acids and glucose, the salvage pathway recovers nucleosides or bases formed during DNA or RNA degradation. In contrast to high proliferating non-malignant cells, which are highly dependent on the de novo synthesis, cancer cells can switch to the nucleoside salvage pathways to maintain efficient DNA replication. Pyrimidine de novo synthesis remains the target of interest in cancer therapy and several inhibitors showed promising results in cancer cells and in vivo models. In the 1980s and 1990s, poor responses were however observed in clinical trials with several of the currently existing pyrimidine synthesis inhibitors. To overcome the observed limitations in clinical trials, targeting pyrimidine salvage alone or in combination with pyrimidine de novo inhibitors was suggested. Even though this approach showed initially promising results, it received fresh attention only recently. Here we discuss the re-discovery of targeting pyrimidine salvage pathways for DNA replication alone or in combination with inhibitors of pyrimidine de novo synthesis to overcome limitations of commonly used antimetabolites in various preclinical cancer models and clinical trials. We also highlight newly emerged targets in pyrimidine synthesis as well as pyrimidine salvage as a promising target in immunotherapy.

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27

Angle, Carol R., Mark S. Swanson, Sidney J. Stohs, and Rodney S. Markin. "Abnormal Erythrocyte Pyrimidine Nucleotides in Uremic Subjects." Nephron 39, no. 3 (1985): 169–74. http://dx.doi.org/10.1159/000183366.

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28

Marobbio, Carlo Marya Thomas, Maria Antonietta Di Noia, and Ferdinando Palmieri. "Identification of a mitochondrial transporter for pyrimidine nucleotides in Saccharomyces cerevisiae: bacterial expression, reconstitution and functional characterization." Biochemical Journal 393, no. 2 (December 23, 2005): 441–46. http://dx.doi.org/10.1042/bj20051284.

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Pyrimidine (deoxy)nucleoside triphosphates are required in mitochondria for the synthesis of DNA and the various types of RNA present in these organelles. In Saccharomyces cerevisiae, these nucleotides are synthesized outside the mitochondrial matrix and must therefore be transported across the permeability barrier of the mitochondrial inner membrane. However, no protein has ever been found to be associated with this transport activity. In the present study, Rim2p has been identified as a yeast mitochondrial pyrimidine nucleotide transporter. Rim2p (replication in mitochondria 2p) is a member of the mitochondrial carrier protein family having some special features. The RIM2 gene was overexpressed in bacteria. The purified protein was reconstituted into liposomes and its transport properties and kinetic parameters were characterized. It transported the pyrimidine (deoxy)nucleoside tri- and di-phosphates and, to a lesser extent, pyrimidine (deoxy)nucleoside monophosphates, by a counter-exchange mechanism. Transport was saturable, with an apparent Km of 207 μM for TTP, 404 μM for UTP and 435 μM for CTP. Rim2p was strongly inhibited by mercurials, bathophenanthroline, tannic acid and Bromocresol Purple, and partially inhibited by bongkrekic acid. Furthermore, the Rim2p-mediated heteroexchanges, TTP/TMP and TTP/TDP, are electroneutral and probably H+-compensated. The main physiological role of Rim2p is proposed to be to transport (deoxy)pyrimidine nucleoside triphosphates into mitochondria in exchange for intramitochondrially generated (deoxy)pyrimidine nucleoside monophosphates.

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29

David, Onorata, Ugo Ramenghi, Clara Camaschella, Maria Grazia Vota, Luisella Comino, Gian Piero Pescarmona, and Paolo Nicola. "Inhibition of hexose monophosphate shunt in young erythrocytes by pyrimidine nucleotides in hereditary pyrimidine 5‘ nucleotidase deficiency." European Journal of Haematology 47, no. 1 (April 24, 2009): 48–54. http://dx.doi.org/10.1111/j.1600-0609.1991.tb00560.x.

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30

Guo, M., P. C. Lo, and S. M. Mount. "Species-specific signals for the splicing of a short Drosophila intron in vitro." Molecular and Cellular Biology 13, no. 2 (February 1993): 1104–18. http://dx.doi.org/10.1128/mcb.13.2.1104-1118.1993.

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The effects of branchpoint sequence, the pyrimidine stretch, and intron size on the splicing efficiency of the Drosophila white gene second intron were examined in nuclear extracts from Drosophila and human cells. This 74-nucleotide intron is typical of many Drosophila introns in that it lacks a significant pyrimidine stretch and is below the minimum size required for splicing in human nuclear extracts. Alteration of sequences of adjacent to the 3' splice site to create a pyrimidine stretch was necessary for splicing in human, but not Drosophila, extracts. Increasing the size of this intron with insertions between the 5' splice site and the branchpoint greatly reduced the efficiency of splicing of introns longer than 79 nucleotides in Drosophila extracts but had an opposite effect in human extracts, in which introns longer than 78 nucleotides were spliced with much greater efficiency. The white-apricot copia insertion is immediately adjacent to the branchpoint normally used in the splicing of this intron, and a copia long terminal repeat insertion prevents splicing in Drosophila, but not human, extracts. However, a consensus branchpoint does not restore the splicing of introns containing the copia long terminal repeat, and alteration of the wild-type branchpoint sequence alone does not eliminate splicing. These results demonstrate species specificity of splicing signals, particularly pyrimidine stretch and size requirements, and raise the possibility that variant mechanisms not found in mammals may operate in the splicing of small introns in Drosophila and possibly other species.

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31

Guo, M., P. C. Lo, and S. M. Mount. "Species-specific signals for the splicing of a short Drosophila intron in vitro." Molecular and Cellular Biology 13, no. 2 (February 1993): 1104–18. http://dx.doi.org/10.1128/mcb.13.2.1104.

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The effects of branchpoint sequence, the pyrimidine stretch, and intron size on the splicing efficiency of the Drosophila white gene second intron were examined in nuclear extracts from Drosophila and human cells. This 74-nucleotide intron is typical of many Drosophila introns in that it lacks a significant pyrimidine stretch and is below the minimum size required for splicing in human nuclear extracts. Alteration of sequences of adjacent to the 3' splice site to create a pyrimidine stretch was necessary for splicing in human, but not Drosophila, extracts. Increasing the size of this intron with insertions between the 5' splice site and the branchpoint greatly reduced the efficiency of splicing of introns longer than 79 nucleotides in Drosophila extracts but had an opposite effect in human extracts, in which introns longer than 78 nucleotides were spliced with much greater efficiency. The white-apricot copia insertion is immediately adjacent to the branchpoint normally used in the splicing of this intron, and a copia long terminal repeat insertion prevents splicing in Drosophila, but not human, extracts. However, a consensus branchpoint does not restore the splicing of introns containing the copia long terminal repeat, and alteration of the wild-type branchpoint sequence alone does not eliminate splicing. These results demonstrate species specificity of splicing signals, particularly pyrimidine stretch and size requirements, and raise the possibility that variant mechanisms not found in mammals may operate in the splicing of small introns in Drosophila and possibly other species.

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32

Price, Neil P. J., Michael A. Jackson, Karl E. Vermillion, Judith A. Blackburn, and Trina M. Hartman. "Rhodium-catalyzed reductive modification of pyrimidine nucleosides, nucleotide phosphates, and sugar nucleotides." Carbohydrate Research 488 (February 2020): 107893. http://dx.doi.org/10.1016/j.carres.2019.107893.

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33

Balasubramaniyam, Thananjeyan, Kwnag-Im Oh, Ho-Seong Jin, Hye-Bin Ahn, Byeong-Seon Kim, and Joon-Hwa Lee. "Non-Canonical Helical Structure of Nucleic Acids Containing Base-Modified Nucleotides." International Journal of Molecular Sciences 22, no. 17 (September 2, 2021): 9552. http://dx.doi.org/10.3390/ijms22179552.

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Chemically modified nucleobases are thought to be important for therapeutic purposes as well as diagnosing genetic diseases and have been widely involved in research fields such as molecular biology and biochemical studies. Many artificially modified nucleobases, such as methyl, halogen, and aryl modifications of purines at the C8 position and pyrimidines at the C5 position, are widely studied for their biological functions. DNA containing these modified nucleobases can form non-canonical helical structures such as Z-DNA, G-quadruplex, i-motif, and triplex. This review summarizes the synthesis of chemically modified nucleotides: (i) methylation, bromination, and arylation of purine at the C8 position and (ii) methylation, bromination, and arylation of pyrimidine at the C5 position. Additionally, we introduce the non-canonical structures of nucleic acids containing these modifications.

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34

Rubin, Harvey N., Ernest Almendarez, and Mostafa N. Halim. "Do pyrimidine nucleotides regulate translatability of globin mRNA as purine nucleotides do?" International Journal of Biochemistry 20, no. 10 (January 1988): 1051–59. http://dx.doi.org/10.1016/0020-711x(88)90249-2.

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35

Devroede, Neel, Nadine Huysveld, and Daniel Charlier. "Mutational Analysis of Intervening Sequences Connecting the Binding Sites for Integration Host Factor, PepA, PurR, and RNA Polymerase in the Control Region of the Escherichia coli carAB Operon, Encoding Carbamoylphosphate Synthase." Journal of Bacteriology 188, no. 9 (May 1, 2006): 3236–45. http://dx.doi.org/10.1128/jb.188.9.3236-3245.2006.

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ABSTRACT Transcription of the carAB operon encoding the unique carbamoylphosphate synthase of Escherichia coli reflects the dual function of carbamoylphosphate in the biosynthesis of arginine and pyrimidine nucleotides. The tandem pair of promoters is regulated by various mechanisms depending on the needs of both pathways and the maintenance of a pyrimidine/purine nucleotide balance. Here we focus on the linker regions that impose the distribution of target sites for DNA-binding proteins involved in pyrimidine- and purine-specific repression of the upstream promoter P1. We introduced deletions and insertions, and combinations thereof, in four linkers connecting the binding sites for integration host factor (IHF), PepA, PurR, and RNA polymerase and studied the importance of phasing and spacing of the targets and the importance of the nucleotide sequence of the linkers. The two PepA binding sites must be properly aligned and separated with respect to each other and to the promoter for both pyrimidine- and purine-mediated repression. Similarly, the phasing and spacing of the IHF and PEPA2 sites are strictly constrained but only for pyrimidine-specific repression. The IHF target is even dispensable for purine-mediated regulation. Thus, a correct localization of PepA within the higher-order nucleoprotein complex is a prerequisite for the establishment of pyrimidine-mediated repression and for the coupling between purine- and pyrimidine-dependent regulation. Our data also suggest the existence of a novel cis-acting pyrimidine-specific regulatory target located around position −60. Finally, the analysis of a P1 derivative devoid of its control region has led to a reappraisal of the effect of excess adenine on P1 and has revealed that P1 has no need for a UP element.

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36

Nikolov, E. N., and M. D. Dabeva. "Re-utilization of pyrimidine nucleotides during rat liver regeneration." Biochemical Journal 228, no. 1 (May 15, 1985): 27–33. http://dx.doi.org/10.1042/bj2280027.

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The changes in the specific radioactivities of the pool of total acid-soluble uridine nucleotides and of uridine and cytidine components of total cellular and nuclear RNA were monitored in regenerating rat liver for 12 days after partial hepatectomy. Evidence is presented for the re-utilization of pyrimidine nucleotides derived from cytoplasmic RNA degradation for the synthesis of new RNA. The extent of recycling was assessed and the true rate of rRNA turnover determined more accurately. The reutilization of the uridine components of RNA was 7.0%/day during the proliferative and 3.2%/day during the post-proliferative phase, whereas that of the cytidine nucleotides was more pronounced (9.6%/day and 18.1%/day respectively). The results reveal the existence of partial compartmentalization of pyrimidine ribonucleoside triphosphate pools in the nucleus and cytoplasm of rat liver cells.

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37

Martinussen, Jan, and Karin Hammer. "The carB Gene Encoding the Large Subunit of Carbamoylphosphate Synthetase from Lactococcus lactis Is Transcribed Monocistronically." Journal of Bacteriology 180, no. 17 (September 1, 1998): 4380–86. http://dx.doi.org/10.1128/jb.180.17.4380-4386.1998.

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ABSTRACT The biosynthesis of carbamoylphosphate is catalyzed by the heterodimeric enzyme carbamoylphosphate synthetase. The genes encoding the two subunits of this enzyme in procaryotes are normally transcribed as an operon, but the gene encoding the large subunit (carB) in Lactococcus lactis is shown to be transcribed as an isolated unit. Carbamoylphosphate is a precursor in the biosynthesis of both pyrimidine nucleotides and arginine. By mutant analysis,L. lactis is shown to possess only onecarB gene; the same gene product is thus required for both biosynthetic pathways. Furthermore, arginine may satisfy the requirement for carbamoylphosphate in pyrimidine biosynthesis through degradation by means of the arginine deiminase pathway. The expression of the carB gene is subject to regulation at the level of transcription by pyrimidines, most probably by an attenuator mechanism. Upstream of the carB gene, an open reading frame showing a high degree of similarity to those of glutathione peroxidases from other organisms was identified.

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38

Kuznetsova, Aleksandra A., Timofey E. Tyugashev, Irina V. Alekseeva, Nadezhda A. Timofeyeva, Olga S. Fedorova, and Nikita A. Kuznetsov. "Insight into the mechanism of DNA synthesis by human terminal deoxynucleotidyltransferase." Life Science Alliance 5, no. 12 (August 1, 2022): e202201428. http://dx.doi.org/10.26508/lsa.202201428.

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Terminal deoxynucleotidyltransferase (TdT) is a member of the DNA polymerase X family that is responsible for random addition of nucleotides to single-stranded DNA. We present investigation into the role of metal ions and specific interactions of dNTP with active-site amino acid residues in the mechanisms underlying the recognition of nucleoside triphosphates by human TdT under pre–steady-state conditions. In the elongation mode, the ratios of translocation and dissociation rate constants, as well as the catalytic rate constant were dependent on the nature of the nucleobase. Preferences of TdT in dNTP incorporation were researched by molecular dynamics simulations of complexes of TdT with a primer and dNTP or with the elongated primer. Purine nucleotides lost the “summarised” H-bonding network after the attachment of the nucleotide to the primer, whereas pyrimidine nucleotides increased the number and relative lifetime of H-bonds in the post-catalytic complex. The effect of divalent metal ions on the primer elongation revealed that Me2+ cofactor can significantly change parameters of the primer elongation by strongly affecting the rate of nucleotide attachment and the polymerisation mode.

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39

JEKABSONS, Mika B., Karim S. ECHTAY, and Martin D. BRAND. "Nucleotide binding to human uncoupling protein-2 refolded from bacterial inclusion bodies." Biochemical Journal 366, no. 2 (September 1, 2002): 565–71. http://dx.doi.org/10.1042/bj20020469.

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Experiments were performed to test the hypothesis that recombinant human uncoupling protein-2 (UCP2) ectopically expressed in bacterial inclusion bodies binds nucleotides in a manner identical with the nucleotide-inhibited uncoupling that is observed in kidney mitochondria. For this, sarkosyl-solubilized UCP2 inclusion bodies were treated with the polyoxyethylene ether detergent C12E9 and hydroxyapatite. Protein recovered from hydroxyapatite chromatography was approx. 90% pure UCP2, as judged by Coomassie Blue and silver staining of polyacrylamide gels. Using fluorescence resonance energy transfer, N-methylanthraniloyl-tagged purine nucleoside di- and tri-phosphates exhibited enhanced fluorescence with purified UCP2. Dissociation constants determined by least-squares non-linear regression indicated that the affinity of UCP2 for these fluorescently tagged nucleotides was 3–5μM or perhaps an order of magnitude stronger, depending on the model used. Competition experiments with [8-14C]ATP demonstrated that UCP2 binds unmodified purine and pyrimidine nucleoside triphosphates with 2–5μM affinity. Affinities for ADP and GDP were approx. 10-fold lower. These data indicate that: UCP2 (a) is at least partially refolded from sarkosyl-solubilized bacterial inclusion bodies by a two-step treatment with C12E9 detergent and hydroxyapatite; (b) binds purine and pyrimidine nucleoside triphosphates with low micromolar affinity; (c) binds GDP with the same affinity as GDP inhibits superoxide-stimulated uncoupling by kidney mitochondria; and (d) exhibits a different nucleotide preference than kidney mitochondria.

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40

Frosina, G., P. Fortini, O. Rossi, F. Carrozzino, A. Abbondandolo, and E. Dogliotti. "Repair of abasic sites by mammalian cell extracts." Biochemical Journal 304, no. 3 (December 15, 1994): 699–705. http://dx.doi.org/10.1042/bj3040699.

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Hamster cell extracts that perform repair synthesis on covalently closed circular DNA containing pyrimidine dimers, were used to study the repair of apurinic/apyrimidinic (AP) sites and methoxyamine (MX)-modified AP sites. Plasmid molecules were heat-treated at pH 5 and incubated with MX when required. The amount of damage introduced ranged from 0.2 to 0.9 AP sites/kb. Extracts were prepared from the Chinese hamster ovary CHO-9 cell line and from its derivative, 43-3B clone which is mutated in the nucleotide excision repair (NER) ERCC1 gene. AP and MX-AP sites stimulated repair synthesis by CHO-9 cell extracts. The level of synthesis correlated with the number of lesions and was of similar magnitude to the repair stimulated by 4.3 u.v. photoproducts/kb. Repair of AP and MX-AP sites was faster than the repair of u.v. damage and was independent of ERCC1 gene product. The high level of repair replication was due to a very efficient and rapid incision of plasmids carrying AP or MX-AP sites, performed by abundant AP endonucleases present in the extract. The calculated average repair patch sizes were: 7 nucleotides per AP site; 10 nucleotides per MX-AP site; 28 nucleotides per (6-4) u.v. photoproduct or cyclobutane pyrimidine dimer. The data indicate that AP and MX-AP sites are very efficiently repaired by base-excision repair in mammalian cells and suggest that MX-AP sites may also be processed via alternative repair mechanisms.

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Seifert, R., R. Burde, and G. Schultz. "Activation of NADPH oxidase by purine and pyrimidine nucleotides involves G proteins and is potentiated by chemotactic peptides." Biochemical Journal 259, no. 3 (May 1, 1989): 813–19. http://dx.doi.org/10.1042/bj2590813.

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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.

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Chander, Preethi, Kari M. Halbig, Jamie K. Miller, Christopher J. Fields, Heather K. S. Bonner, Gail K. Grabner, Robert L. Switzer, and Janet L. Smith. "Structure of the Nucleotide Complex of PyrR, the pyr Attenuation Protein from Bacillus caldolyticus, Suggests Dual Regulation by Pyrimidine and Purine Nucleotides." Journal of Bacteriology 187, no. 5 (March 1, 2005): 1773–82. http://dx.doi.org/10.1128/jb.187.5.1773-1782.2005.

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ABSTRACT PyrR is a protein that regulates the expression of genes and operons of pyrimidine nucleotide biosynthesis (pyr genes) in many bacteria. PyrR acts by binding to specific sequences on pyr mRNA and causing transcriptional attenuation when intracellular levels of uridine nucleotides are elevated. PyrR from Bacillus subtilis has been purified and extensively studied. In this work, we describe the purification to homogeneity and characterization of recombinant PyrR from the thermophile Bacillus caldolyticus and the crystal structures of unliganded PyrR and a PyrR-nucleotide complex. The B. caldolyticus pyrR gene was previously shown to restore normal regulation of the B. subtilis pyr operon in a pyrR deletion mutant. Like B. subtilis PyrR, B. caldolyticus PyrR catalyzes the uracil phosphoribosyltransferase reaction but with maximal activity at 60°C. Crystal structures of B. caldolyticus PyrR reveal a dimer similar to the B. subtilis PyrR dimer and, for the first time, binding sites for nucleotides. UMP and GMP, accompanied by Mg2+, bind specifically to PyrR active sites. Nucleotide binding to PyrR is similar to other phosphoribosyltransferases, but Mg2+ binding differs. GMP binding was unexpected. The protein bound specific sequences of pyr RNA 100 to 1,000 times more tightly than B. subtilis PyrR, depending on the RNA tested and the assay method; uridine nucleotides enhanced RNA binding, but guanosine nucleotides antagonized it. The new findings of specific GMP binding and its antagonism of RNA binding suggest cross-regulation of the pyr operon by purines.

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Pels Rijcken, W. R., B. Overdijk, D. H. van den Eijnden, and W. Ferwerda. "Pyrimidine nucleotide metabolism in rat hepatocytes: evidence for compartmentation of nucleotide pools." Biochemical Journal 293, no. 1 (July 1, 1993): 207–13. http://dx.doi.org/10.1042/bj2930207.

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Pyrimidine nucleotide metabolism in rat hepatocytes was studied by measurement of the labelling kinetics of the various intermediates after double labelling with [14C]orotic acid and [3H]cytidine, the precursors for the de novo and the salvage pathways respectively. For the uridine nucleotides, differences were found for the 14C/3H ratios in the UDP-sugars, in UMP (of RNA) and in their precursor UTP, suggesting the existence of separated flows of the radioactive precursors through the de novo and the salvage pathways. Higher ratios in the UDP-sugars, which are synthesized in the cytoplasm, and a lower ratio in UMP (of RNA) relative to the 14C/3H ratio in UTP indicated that UTP derived from orotic acid is preferentially used for the cytoplasmic biosynthesis of the UDP-sugars. Uridine, derived from cytidine, is preferentially used for the nuclear-localized synthesis of RNA. In contrast to these findings, the 14C/3H ratios in the cytidine derivatives CMP-NeuAc and CMP (of RNA), and in the liponucleotides CDP-choline and CDP-ethanolamine, were all lower than that in the precursor CTP. This indicates a preferential utilization of the salvage-derived CTP for the synthesis of the liponucleotides as well as for RNA and CMP-NeuAc. Similar conclusions could be drawn from experiments in which the intracellular amounts of several uridine- and cytidine-nucleotide-containing derivatives were increased by preincubating the hepatocytes with unlabelled pyrimidine nucleotides or ethanolamine. Based on these data, we propose a refined model for the intracellular compartmentation of pyrimidine nucleotide biosynthesis in which three pools of UTP are distinguished: a pool of de novo-derived molecules and a pool of salvage-derived molecules, both of which are channelled to the site of utilization; in addition an ‘overflow’ pool exists, consisting of molecules having escaped from channelling. An overflow pool could also be distinguished for CTP, but no discrimination between de novo and salvage-derived molecules could be made.

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44

Chiarelli, Laurent, Andrea Mattevi, Alessandro Galizzi, Elisa Fermo, Paola Bianchi, Alberto Zanella, and Giovanna Valentini. "Functional Analysis of Two Mutants of Pyrimidine 5′ Nucleotidase Causing Nonspherocytic Hemolytic Anemia." Blood 104, no. 11 (November 16, 2004): 1592. http://dx.doi.org/10.1182/blood.v104.11.1592.1592.

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Abstract Pyrimidine 5′-nucleotidase type-I (P5′N-1) catalyzes the dephosphorylation of UMP and CMP to their respective nucleosides. In red blood cells, the enzyme has a major role in the catabolism of nucleotides formed from RNA degradation. P5′N-1 possesses also phospho-transferase activity suggesting an additional role of the enzyme in nucleotide metabolism. P5′N-1 deficiency is an autosomal recessive disorder characterized by hemolytic nonspherocytic anemia, heavy basophilic stippling in the peripheral blood smear, and accumulation of pyrimidine nucleotides within the erythrocytes. P5′N-1 deficiency is the third most common RBC enzymopathy causing hemolysis after G6PD and PK deficiency. Fourteen different mutations have been identified at the DNA level to date including four missense mutations. To increase our understanding on molecular basis of the P5′N-1 deficiency, after mutants N190S and G241R (Chiarelli et al, Blood 2003, abstract; Chiarelli et al, The Hematology Journal 2004, abstract), we have undertaken the biochemical characterization of D98V and L142P enzymes, identified respectively in a Norwegian family and in Japanese patients. The proteins were produced in E. coli cells as recombinant forms, and purified to homogeneity. The L142P protein showed a drastic reduction in the thermal stability (t1/2 at 37°C about 6 min compared to a fully stable wild-type), and kinetic properties slightly altered (kcat values nearly halved and Km 3–5 times higher). D98V exhibited reduced heat stability (t1/2 at 37° about 25 min) and catalytic efficiency turned especially versus UMP (about 25 times) owing the increased Km values. Thus, the decreased activity observed in Japanese patients homozygous for the L142P mutation is essentially due to lowered enzyme levels caused by protein instability, whereas the D98V mutation of Norwegian patients alters both stability and catalytic efficiency. We suggest that substitution D98V affects an amino acid residue involved in substrates binding site.

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45

Nicoloff, Hervé, Aram Elagöz, Florence Arsène-Ploetze, Benoît Kammerer, Jan Martinussen, and Françoise Bringel. "Repression of the pyr Operon in Lactobacillus plantarum Prevents Its Ability To Grow at Low Carbon Dioxide Levels." Journal of Bacteriology 187, no. 6 (March 15, 2005): 2093–104. http://dx.doi.org/10.1128/jb.187.6.2093-2104.2005.

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ABSTRACT Carbamoyl phosphate is a precursor for both arginine and pyrimidine biosynthesis. In Lactobacillus plantarum, carbamoyl phosphate is synthesized from glutamine, ATP, and carbon dioxide by two sets of identified genes encoding carbamoyl phosphate synthase (CPS). The expression of the carAB operon (encoding CPS-A) responds to arginine availability, whereas pyrAaAb (encoding CPS-P) is part of the pyrR1BCAaAbDFE operon coding for the de novo pyrimidine pathway repressed by exogenous uracil. The pyr operon is regulated by transcription attenuation mediated by a trans-acting repressor that binds to the pyr mRNA attenuation site in response to intracellular UMP/phosphoribosyl pyrophosphate pools. Intracellular pyrimidine triphosphate nucleoside pools were lower in mutant FB335 (carAB deletion) harboring only CPS-P than in the wild-type strain harboring both CPS-A and CPS-P. Thus, CPS-P activity is the limiting step in pyrimidine synthesis. FB335 is unable to grow in the presence of uracil due to a lack of sufficient carbamoyl phosphate required for arginine biosynthesis. Forty independent spontaneous FB335-derived mutants that have lost regulation of the pyr operon were readily obtained by their ability to grow in the presence of uracil and absence of arginine; 26 harbored mutations in the pyrR1-pyrB loci. One was a prototroph with a deletion of both pyrR1 and the transcription attenuation site that resulted in large amounts of excreted pyrimidine nucleotides and increased intracellular UTP and CTP pools compared to wild-type levels. Low pyrimidine-independent expression of the pyr operon was obtained by antiterminator site-directed mutagenesis. The resulting AE1023 strain had reduced UTP and CTP pools and had the phenotype of a high-CO2-requiring auxotroph, since it was able to synthesize sufficient arginine and pyrimidines only in CO2-enriched air. Therefore, growth inhibition without CO2 enrichment may be due to low carbamoyl phosphate pools from lack of CPS activity.

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Fairlamb, Max S., Amy M. Whitaker, and Bret D. Freudenthal. "Apurinic/apyrimidinic (AP) endonuclease 1 processing of AP sites with 5′ mismatches." Acta Crystallographica Section D Structural Biology 74, no. 8 (July 24, 2018): 760–68. http://dx.doi.org/10.1107/s2059798318003340.

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Despite the DNA duplex being central to biological functions, many intricacies of this molecule, including the dynamic nature of mismatched base pairing, are still unknown. The unique conformations adopted by DNA mismatches can provide insight into the forces at play between nucleotides. Moreover, DNA-binding proteins apply their own individualized steric and electrochemical influences on the nucleotides that they interact with, further altering base-pairing conformations. Here, seven X-ray crystallographic structures of the human nuclease apurinic/apyrimidinic (AP) endonuclease 1 (APE1) in complex with its substrate target flanked by a 5′ mismatch are reported. The structures reveal how APE1 influences the conformations of a variety of different mismatched base pairs. Purine–purine mismatches containing a guanine are stabilized by a rotation of the guanine residue about the N-glycosidic bond to utilize the Hoogsteen edge for hydrogen bonding. Interestingly, no rotation of adenine, the other purine, is observed. Mismatches involving both purine and pyrimidine bases adopt wobble conformations to accommodate the mismatch. Pyrimidine–pyrimidine mismatches also wobble; however, the smaller profile of a pyrimidine base results in a gap between the Watson–Crick faces that is reduced by a C1′–C1′ compression. These results advance our understanding of mismatched base pairing and the influence of a bound protein.

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Pesini, Alba, Eldris Iglesias, Nuria Garrido, M. Pilar Bayona-Bafaluy, Julio Montoya, and Eduardo Ruiz-Pesini. "OXPHOS, Pyrimidine Nucleotides, and Alzheimer's Disease: A Pharmacogenomics Approach." Journal of Alzheimer's Disease 42, no. 1 (August 11, 2014): 87–96. http://dx.doi.org/10.3233/jad-140384.

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48

Mendz, G. L., B. M. Jimenez, S. L. Hazell, A. M. Gero, and W. J. O'Sullivan. "De novo synthesis of pyrimidine nucleotides by Helicobacter pylori." Journal of Applied Bacteriology 77, no. 1 (July 1994): 1–8. http://dx.doi.org/10.1111/j.1365-2672.1994.tb03036.x.

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49

Andersson, Marianne, Lillemor Lewan, and Unne Stenram. "Compartmentation of purine and pyrimidine nucleotides in animal cells." International Journal of Biochemistry 20, no. 10 (January 1988): 1039–50. http://dx.doi.org/10.1016/0020-711x(88)90248-0.

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50

Charczuk, Roland, Christoph Tamm, Bruno Suri, and Thomas A. Bickle. "An unusual base pairing between pyrimidine and pyridine nucleotides." Nucleic Acids Research 14, no. 23 (1986): 9530. http://dx.doi.org/10.1093/nar/14.23.9530.

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Journal articles on the topic 'Pyrimidine nucleotides'

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