Journal articles: 'Purine synthesis'

1

Hasník, Zbyněk, Radek Pohl, Blanka Klepetářová, and Michal Hocek. "Synthesis of (purin-6-yl)acetates and their transformations to 6-(2-hydroxyethyl)- and 6-(carbamoylmethyl)purines." Collection of Czechoslovak Chemical Communications 74, no. 7-8 (2009): 1035–59. http://dx.doi.org/10.1135/cccc2009042.

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A novel approach to the synthesis of (purin-6-yl)acetates was developed based on Pd-catalyzed cross-coupling reactions of 6-chloropurines with a Reformatsky reagent. Their reduction with NaBH4 and treatment with MnO2 gave 6-(2-hydroxyethyl)purines, while reactions with amines in presence of NaCN afforded 6-(carbamoylmethyl)purines. Mesylation of the 6-(2-hydroxyethyl)purines followed by nucleophilic substitutions gave rise to several 6-(2-substituted ethyl)purines. This methodology was successfully applied to the synthesis of substituted purine bases and nucleosides for cytostatic and antiviral activity screening. None of the compounds exerted significant activity.

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2

Becker, Sidney, Jonas Feldmann, Stefan Wiedemann, et al. "Unified prebiotically plausible synthesis of pyrimidine and purine RNA ribonucleotides." Science 366, no. 6461 (2019): 76–82. http://dx.doi.org/10.1126/science.aax2747.

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Theories about the origin of life require chemical pathways that allow formation of life’s key building blocks under prebiotically plausible conditions. Complex molecules like RNA must have originated from small molecules whose reactivity was guided by physico-chemical processes. RNA is constructed from purine and pyrimidine nucleosides, both of which are required for accurate information transfer, and thus Darwinian evolution. Separate pathways to purines and pyrimidines have been reported, but their concurrent syntheses remain a challenge. We report the synthesis of the pyrimidine nucleosides from small molecules and ribose, driven solely by wet-dry cycles. In the presence of phosphate-containing minerals, 5′-mono- and diphosphates also form selectively in one-pot reactions. The pathway is compatible with purine synthesis, allowing the concurrent formation of all Watson-Crick bases.

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3

Itakura, M., N. Maeda, and K. Yamashita. "Increased rate of purine biosynthesis in rat liver after bilateral adrenalectomy." American Journal of Physiology-Endocrinology and Metabolism 251, no. 4 (1986): E373—E378. http://dx.doi.org/10.1152/ajpendo.1986.251.4.e373.

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In bilaterally adrenalectomized rat liver the increased rate of de novo purine synthesis was shown by the increased [14C]glycine incorporation into hepatic acid-soluble purines with unchanged rapidly miscible glycine pool size and its turnover rate and by the increased rate of chasing of radiolabeled purines. At 24 h after adrenalectomy, the rate of de novo purine synthesis increased by 70%, 5-phosphoribosyl-1-pyrophosphate (PRPP) content increased by 200%, the specific activity of amidophosphoribosyltransferase (EC 2.4.2. 14; ATase) did not change, ATP and GTP showed a 33 and 24% decrease, and AMP and ADP showed a 245 and 38% increase. Combined, the metabolic pool size data reflected an unchanged total inhibitory potential on ATase. Replacement with corticosterone acetate for 24 h partially restored some of these abnormalities. These results suggest that the increase in the rate of de novo purine synthesis in adrenalectomized rat liver is secondary to increased catabolism of purine ribonucleotides and mediated by increased PRPP concentrations.

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4

Allen, Shara, Julie L. Zilles, and Diana M. Downs. "Metabolic Flux in Both the Purine Mononucleotide and Histidine Biosynthetic Pathways Can Influence Synthesis of the Hydroxymethyl Pyrimidine Moiety of Thiamine in Salmonella enterica." Journal of Bacteriology 184, no. 22 (2002): 6130–37. http://dx.doi.org/10.1128/jb.184.22.6130-6137.2002.

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ABSTRACT Together, the biosyntheses of histidine, purines, and thiamine pyrophosphate (TPP) contain examples of convergent, divergent, and regulatory pathway integration. Mutations in two purine biosynthetic genes (purI and purH) affect TPP biosynthesis due to flux through the purine and histidine pathways. The molecular genetic characterization of purI mutants and their respective pseudorevertants resulted in the conclusion that <1% of the wild-type activity of the PurI enzyme was sufficient for thiamine but not for purine synthesis. The respective pseudorevertants were found to be informational suppressors. In addition, it was shown that accumulation of the purine intermediate aminoimidazole carboxamide ribotide inhibits thiamine synthesis, specifically affecting the conversion of aminoimidazole ribotide to hydroxymethyl pyrimidine.

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5

Sudhakar Rao, T., and Ganapathi R. Revankar. "Synthesis of certain alkenyl purines and purine analogs." Journal of Heterocyclic Chemistry 32, no. 3 (1995): 1043–49. http://dx.doi.org/10.1002/jhet.5570320362.

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6

Hocek, Michal, Hana Dvořáková, and Ivana Císařová. "Covalent Analogues of DNA Base-Pairs and Triplets V. Synthesis of Purine-Purine and Purine-Pyrimidine Conjugates Connected by Diverse Types of Acyclic Carbon Linkages." Collection of Czechoslovak Chemical Communications 67, no. 10 (2002): 1560–78. http://dx.doi.org/10.1135/cccc20021560.

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The title 1,2-bis(purin-6-yl)acetylenes, -diacetylenes, -ethylenes and -ethanes were prepared as covalent base-pair analogues starting from 6-ethynylpurines and 6-iodopurines by the Sonogashira cross-coupling or oxidative alkyne-dimerization reactions followed by hydrogenations. 6-[(1,3-Dimethyluracil-5-yl)ethynyl]purine (11) was prepared analogously and hydrogenated to the corresponding purine-pyrimidine conjugates linked via vinylene and ethylene linkers. Unlike the cytostatic bis(purin-6-yl)acetylenes and -diacetylenes, the purine-pyrimidine conjugates were inactive. Crystal structures of bis(purin-6-yl)acetylene 6a, -diacetylene 8a and -ethane 5a were determined by single-crystal X-ray diffraction.

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7

Šilhár, Peter, Radek Pohl, Ivan Votruba, and Michal Hocek. "Synthesis of 2-Substituted 6-(Hydroxymethyl)purine Bases and Nucleosides." Collection of Czechoslovak Chemical Communications 70, no. 10 (2005): 1669–95. http://dx.doi.org/10.1135/cccc20051669.

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A facile and efficient methodology of the synthesis of 6-(hydroxymethyl)purine derivatives (bases and nucleosides) was developed based on Pd-catalyzed cross-coupling reactions of 6-halopurines or N-protected 2-amino-6-halopurines with (benzoyloxymethyl)zinc iodide followed by deprotection. Regioselective hydroxymethylations of 2,6-dihalopurines were also studied and used for the synthesis of 2-chloro-6-(hydroxymethyl)- or 2,6-bis(hydroxymethyl)purines. The 6-(hydroxymethyl)purine ribonucleoside 5f exerted high cytostatic effect and moderate inhibition of adenosine deaminase, while all the other derivatives were much less effective or entirely inactive.

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Scott, Andrew, Weihua Zhou, Kari Wilder-Romans, et al. "DDRE-28. MECHANISTIC AND THERAPEUTIC LINKS BETWEEN PURINE BIOSYNTHESIS AND DNA DAMAGE IN GLIOBLASTOMA." Neuro-Oncology Advances 3, Supplement_1 (2021): i12. http://dx.doi.org/10.1093/noajnl/vdab024.050.

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Abstract Glioblastoma (GBM) is the most common and aggressive adult brain cancer. Radiation therapy (RT) is a critical treatment modality, and development of RT resistance is the predominant cause of recurrence and mortality in GBM patients. Using cell line models as well as patient-derived xenografts and neurospheres in orthotopic brain tumor models, we have identified increased rates and dependence upon de novo purine biosynthesis as a hallmark of GBM RT resistance. More recently, we have discovered that radiation treatment acutely stimulates flux through de novo purine synthesis in cell line and neurosphere models of GBM. This RT-induced increase in de novo purine synthesis is dependent on signaling through the DNA damage response and thus appears to be an adaptive mechanism to supply purines to repair radiation-induced DNA damage. To determine whether this regulatory mechanism also exists in vivo, we have used advanced metabolomic and metabolic tracing techniques with 13C-labeled glucose and 15N-labeled glutamine in mice bearing RT-resistant GBM patient-derived orthotopic brain tumors. We found that that orthotopic GBM PDXs had elevated activity of de novo purine synthesis that increased further after RT, while normal cortex had little activity even after RT. These observations have therapeutic relevance, as targeting this metabolic pathway with the FDA-approved purine biosynthesis inhibitor mycophenolate mofetil (MMF) overcomes GBM radiation resistance in mouse models in vivo. The lack of de novo purine synthesis in normal cortex suggests that targeting this pathway may be tumor specific. Collectively our data suggest that de novo synthesis of purines mediates RT resistance in GBM and that treatment of brain tumors with MMF in combination with RT may be a promising therapeutic strategy in patients.

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9

Rosiers, Christine Des, Stephan Nees, and Eckehart Gerlach. "Purine metabolism in cultured aortic and coronary endothelial cells." Biochemistry and Cell Biology 67, no. 1 (1989): 8–15. http://dx.doi.org/10.1139/o89-002.

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Purine salvage pathways in cultured endothelial cells of macrovascular (pig aorta) and microvascular (guinea pig coronary system) origin were investigated by measuring the incorporation of radioactive purine bases (adenine or hypoxanthine) or nucleosides (adenosine or inosine) into purine nucleotides. These precursors were used at initial extracellular concentrations of 0.1, 5, and 500 μM. In both types of endothelial cells, purine nucleotide synthesis occurred with all four substrates. Aortic endothelial cells salvaged adenine best among purines and nucleosides when applied at 0.1 μM. At 5 and 500 μM, adenosine was the best precursor. In contrast, microvascular endothelial cells from the coronary system used adenosine most efficiently at all concentrations studied. The synthetic capacity of salvage pathways was greater than that of the de novo pathway. As measured using radioactive formate or glycine, de novo synthesis of purine nucleotides was barely detectable in aortic endothelial cells, whereas it readily occurred in coronary endothelial cells. Purine de novo synthesis in coronary endothelial cells was inhibited by physiological concentrations of purine bases and nucleosides, and by ribose or isoproterenol. The isoproterenol-induced inhibition was prevented by the β-adrenergic receptor antagonist propranolol. The end product of purine catabolism in aortic endothelial cells was found to be hypoxanthine, whereas coronary endothelial cells degraded hypoxanthine further to xanthine and uric acid, a reaction catalyzed by the enzyme xanthine dehydrogenase.Key words: purine metabolism, aortic endothelial cells, coronary endothelial cells, β-adrenergic receptor.

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10

Xi, Hualin, Barbara L. Schneider, and Larry Reitzer. "Purine Catabolism in Escherichia coliand Function of Xanthine Dehydrogenase in Purine Salvage." Journal of Bacteriology 182, no. 19 (2000): 5332–41. http://dx.doi.org/10.1128/jb.182.19.5332-5341.2000.

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ABSTRACT Escherichia coli is not known to utilize purines, other than adenine and adenosine, as nitrogen sources. We reinvestigated purine catabolism because a computer analysis suggested several potential ς54-dependent promoters within a 23-gene cluster whose products have homology to purine catabolic enzymes. Our results did not provide conclusive evidence that the ς54-dependent promoters are active. Nonetheless, our results suggest that some of the genes are metabolically significant. We found that even though several purines did not support growth as the sole nitrogen source, they did stimulate growth with aspartate as the nitrogen source. Cells produced 14CO2 from minimal medium containing [14C]adenine, which implies allantoin production. However, neither ammonia nor carbamoyl phosphate was produced, which implies that purine catabolism is incomplete and does not provide nitrogen during nitrogen-limited growth. We constructed strains with deletions of two genes whose products might catalyze the first reaction of purine catabolism. Deletion of one eliminated 14CO2 production from [14C]adenine, which implies that its product is necessary for xanthine dehydrogenase activity. We changed the name of this gene to xdhA. The xdhA mutant grew faster with aspartate as a nitrogen source. The mutant also exhibited sensitivity to adenine, which guanosine partially reversed. Adenine sensitivity has been previously associated with defective purine salvage resulting from impaired synthesis of guanine nucleotides from adenine. We propose that xanthine dehydrogenase contributes to this purine interconversion.

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11

Šilhár, Peter, Radek Pohl, Ivan Votruba, Blanka Klepetářová, and Michal Hocek. "Synthesis of 6-Amino-, 6-Methyl- and 6-Aryl-2-(hydroxymethyl)purine Bases and Nucleosides." Collection of Czechoslovak Chemical Communications 71, no. 6 (2006): 788–803. http://dx.doi.org/10.1135/cccc20060788.

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An efficient methodology of the synthesis of 6-substituted 2-(hydroxymethyl)purine derivatives (bases and nucleosides) was developed. Regioselective Pd-catalyzed cross-coupling reactions of 6-chloro-2-iodopurines with [(benzoyloxy)methyl]zinc iodide gave 2-[(benzoyloxy)-methyl]-6-chloropurines that were converted to 2-(hydroxymethyl)adenines by reactions with ammonia and to 6-methyl- or 6-aryl-2-(hydroxymethyl)purines by cross-coupling reactions with trimethylaluminium or arylboronic acids followed by deprotection. The title 6-substituted 2-(hydroxymethyl)purine bases and nucleosides did not exhibit significant cytostatic or anti-HCV activity.

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12

Pons, F. W., U. Neubert, and P. Müller. "Evidence for frameshift mutations in the hisH gene of Escherichia coli causing synthesis of a partially active glutamine amidotransferase." Genetics 120, no. 3 (1988): 657–65. http://dx.doi.org/10.1093/genetics/120.3.657.

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Abstract Among eight strains carrying acridine-induced mutations in hisH, five which mapped at four different sites in the promoter-distal region of the gene showed His+ phenotypes on media containing a purine. By complementation analysis, hisH enzyme was shown to be required for growth on purines. Purine-sensitive His+ revertants of strains able to grow on purines carried second-site mutations which in one case could be shown to map in hisG. Strains able to grow on purines were able to grow on 2-thiazolyl-DL-alanine, too. We conclude that frameshift mutations in the promoter-distal part of the hisH gene of E. coli do not completely abolish the activity of the gene product.

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13

Fedotov, Victor V., Evgeny N. Ulomsky, Konstantin V. Savateev, et al. "A PASE Approach to the Synthesis of Benzimidazopurines as Polycondensed Purine Derivatives." Synthesis 52, no. 23 (2020): 3622–31. http://dx.doi.org/10.1055/s-0040-1707228.

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A highly efficient PASE approach to a new class of polycyclic purine derivatives has been proposed. The strategy includes a consecutive reduction, auto-aromatization, and heterocyclization of the initial nitrobenzimidazopyrimidines obtained by a three-component condensation. It was shown that reduction of nitrobenzimidazopyrimidines by metals in acidic media was more efficient than heterogeneous hydrogenation. Novel derivatives of benz[4,5]imidazo[1,2-a]purines were obtained in good yields and the proposed structure was confirmed by X-ray crystal structure analysis. The obtained convergent benzimidazopurines combine two relevant medicinal chemistry scaffolds – benzimidazole and purine.

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14

Dewhurst, R. J., and A. J. F. Webster. "The effect of dietary sodium on the energetic efficiency of microbial yield from the rumen of sheep." Proceedings of the British Society of Animal Production (1972) 1989 (March 1989): 104. http://dx.doi.org/10.1017/s0308229600010953.

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It has long been recognised that there is a strong positive relationship between the level of absorbed (microbial) purines and purine derivative excretion in the urine. We have used estimates based on urinary allantoin N excretion (AN) to investigate some of the factors influencing the energetic efficiency of microbial yield from the rumen (E). Figures 1 and 2 illustrate the model that has been adopted.It has been tentatively assumed that, at reasonable levels of intake, exogenous purine supply exceeds “a” moles (Figure 2) so that purine salvage is saturated (Condon & Hatfield, 1970), de novo synthesis inoperant (Condon, Hall & Hatfield, 1970) and the net endogenous contribution to AN negligible. In these circumstances AN will be linearly related to microbial (purine) yield from the rumen.

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15

Culic, Ognjen, Ulrich K. M. Decking, and Jürgen Schrader. "Metabolic adaptation of endothelial cells to substrate deprivation." American Journal of Physiology-Cell Physiology 276, no. 5 (1999): C1061—C1068. http://dx.doi.org/10.1152/ajpcell.1999.276.5.c1061.

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Endothelial cells are known to be metabolically rather robust. To study the mechanisms involved, porcine aortic endothelial cells (PAEC), cultured on microcarrier beads, were perfused with glucose (10 mM) or with substrate-free medium. Substrate-free perfusion for 2 h induced an almost complete loss of nucleoside triphosphates (31P-NMR) and decreased heat flux, a measure of total energy turnover, by >90% in parallel microcalorimetric measurements. Heat flux and nucleoside triphosphates recovered after addition of glucose. Because protein synthesis is a major energy consumer in PAEC, the rate of protein synthesis was measured ([14C]leucine incorporation). Reduction or blockade of energy supply resulted in a pronounced reduction in the rate of protein synthesis (up to 80% reduction). Intracellular triglyceride stores were decreased by ∼60% after 2 h of substrate-free perfusion. Under basal perfusion conditions, PAEC released ∼30 pmol purine ⋅ mg protein−1⋅ min−1, i.e., 16% of the cellular ATP per hour, while ATP remained constant. Substrate deprivation increased the release of various purines and pyrimidines about threefold and also induced a twofold rise in purine de novo synthesis ([14C]formate). These results demonstrate that PAEC are capable of recovering from extended periods of substrate deprivation. They can do so by a massive downregulation of their energy expenditure, particularly protein synthesis, while at the same time using endogenous triglycerides as substrates and upregulating purine de novo synthesis to compensate for the loss of purines.

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16

Itakura, M., N. Maeda, M. Tsuchiya, and K. Yamashita. "Glucagon infusion increases rate of purine synthesis de novo in rat liver." American Journal of Physiology-Endocrinology and Metabolism 253, no. 6 (1987): E684—E690. http://dx.doi.org/10.1152/ajpendo.1987.253.6.e684.

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Based on the parallel increases of glucagon, the second peak of hepatic cAMP, and the rate of purine synthesis de novo in the prereplicative period in regenerating rat liver after a 70% hepatectomy, it was hypothesized that glucagon is responsible for the increased rate of purine synthesis de novo. To test this hypothesis, the effect of glucagon or dibutyryl cAMP infusion on the rate of purine synthesis de novo in rat liver was studied. Glucagon infusion but not insulin or glucose infusion increased the rate of purine synthesis de novo, which was assayed by [14C]glycine or [14C]formate incorporation, by 2.7- to 4.3-fold. Glucagon infusion increased cAMP concentrations by 4.9-fold and 5-phosphoribosyl-1-pyrophosphate concentrations by 1.5-fold in liver but did not change the specific activity of amidophosphoribosyltransferase (EC 2.4.2.14) or purine ribonucleotide concentrations. Dibutyryl cAMP infusion also increased the rate of purine synthesis de novo by 2.2- to 4.0-fold. Because glucagon infusion increased the rate of purine synthesis de novo in the presence of unchanged purine ribonucleotide concentrations, it is concluded that glucagon after infusion or in animals after a 70% hepatectomy is playing an anabolic role to increase the rate of purine synthesis de novo by increasing cAMP and 5-phosphoribosyl-1-pyrophosphate concentrations.

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17

Hristov, A. N., T. A. McAllister, D. R. Ouellet, and G. A. Broderick. "Comparison of purines and nitrogen-15 as microbial flow markers in beef heifers fed barley- or corn-based diets." Canadian Journal of Animal Science 85, no. 2 (2005): 211–22. http://dx.doi.org/10.4141/a04-054.

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The objective of this study was to estimate the contribution of microbial purine bases to duodenal purines and to purine derivatives [allantoin and uric acid (PD)] excreted in the urine. Additionally, microbial protein (MCP) flow estimated using duodenal flow of purine bases was compared to estimates using 15N as a microbial marker. Four beef heifers were fed two diets, barley silage/barley grain/soybean meal (diet B) or corn silage/corn grain/corn gluten meal (diet C), in a cross-over design study. (15NH4)2SO4 was infused in the rumen for 8 d to label ruminal microorganisms and their purine bases. Rumen contents, duodenal digesta, urine, and feces were sampled during the last 2 d of tracer infusion and for 48 h after the infusion ceased. The animals consumed more (P < 0.01) dry matter (DM), organic matter (OM), N, and neutral detergent fiber (NDF) with diet B than with diet C. Total tract digestibilities of DM, OM, and NDF were also higher (P < 0.01) with diet B. Ruminal ammonia (P < 0.01), volatile fatty acids (P < 0.05), and acetate (P < 0.01) concentrations and xylanase activity (P < 0.05) were higher with diet B compared with diet C. Flow of MCP to the duodenum was estimated from duodenal samples using purines or 15N as microbial markers, or from urinary PD excretion. The effects of diet or method of measurement on MCP flow were not significant. However, when the urinary PD method was excluded from the analysis, MCP flow was greater (by 26%; P = 0.01) when estimated using 15N vs. the purine-based method. The difference was mainly due to underestimation of the proportion of microbial N in the liquid duodenal digesta with the purine method. Feed purines contributed from 3.5 (liquid digesta phase) to 19.7% (solid digesta phase) of the total purine flow at the duodenum. 15N enrichment of urinary PD was 1.08 of the enrichment of duodenal purines, suggesting that feed purines contributed little N to urinary allantoin and uric acid in cattle. Key words: Allantoin, cattle, microbial protein synthesis, nitrogen-15, purine derivative

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18

Jain, Sunny, Selina Sutchu, Patricia A. Rosa, Rebecca Byram, and Mollie W. Jewett. "Borrelia burgdorferi Harbors a Transport System Essential for Purine Salvage and Mammalian Infection." Infection and Immunity 80, no. 9 (2012): 3086–93. http://dx.doi.org/10.1128/iai.00514-12.

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ABSTRACTBorrelia burgdorferiis the tick-borne bacterium that causes the multistage inflammatory disease Lyme disease.B. burgdorferihas a reduced genome and lacks the enzymes required forde novosynthesis of purines for synthesis of RNA and DNA. Therefore, this obligate pathogen is dependent upon the tick vector and mammalian host environments for salvage of purine bases for nucleic acid biosynthesis. This pathway is vital forB. burgdorferisurvival throughout its infectious cycle, as key enzymes in the purine salvage pathway are essential for the ability of the spirochete to infect mice and critical for spirochete replication in the tick. The transport of preformed purines into the spirochete is the first step in the purine salvage pathway and may represent a novel therapeutic target and/or means to deliver antispirochete molecules to the pathogen. However, the transport systems critical for purine salvage byB. burgdorferihave yet to be identified. Herein, we demonstrate that the genesbbb22andbbb23, present onB. burgdorferi's essential plasmid circular plasmid 26 (cp26), encode key purine transport proteins. BBB22 and/or BBB23 is essential for hypoxanthine transport and contributes to the transport of adenine and guanine. Furthermore,B. burgdorferilackingbbb22-23was noninfectious in mice up to a dose of 1 × 107spirochetes. Together, our data establish thatbbb22-23encode purine permeases critical forB. burgdorferimammalian infectivity, suggesting that this transport system may serve as a novel antimicrobial target for the treatment of Lyme disease.

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Hřebabecký, Hubert, Milena Masojídková, Martin Dračínský, and Antonín Holý. "Synthesis of Novel Conformationally Locked Carbocyclic Nucleosides Derived from 3-(Hydroxymethyl)bicyclo[2.2.1]heptane-2,5-diol." Collection of Czechoslovak Chemical Communications 71, no. 6 (2006): 871–88. http://dx.doi.org/10.1135/cccc20060871.

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(1R*,2R*,3R*,4R*,5R*,6S*)-3-Amino-5-(benzyloxy)-6-(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol (18) was prepared in seven easy steps from benzyl (1R*,2S*,3S*,4S*)-3-(benzyloxy)bicyclo[2.2.1]hept-5-ene-2-carboxylate (10). Reaction of amine18with ethylN-((2E)-3-ethoxymethacryloyl)carbamate afforded 1-[(1R*,2R*,3R*,4R*,5S*,6R*)-6-(benzyloxy)-3-hydroxy-5- (hydroxymethyl)bicyclo[2.2.1]heptan-2-yl]-5-methylpyrimidine-2,4(1H,3H)-dione (21) and after deprotection by transfer hydrogenation, free thymine analogue22. The thymine derivative21was converted to 2,3'-anhydronucleoside26. Treatment of the benzyl derivative18with sodium in liquid ammonia led to amine19, which was used as key intermediate for the construction of (1R*,2R*,3R*,4R*,5R*,6S*)-3-(6-chloro-9H-purin-9-yl)-6-(hydroxymethyl)-bicyclo[2.2.1]heptane-2,5-diol (28) and (1R*,2R*,3R*,4R*,5R*,6S*)-3-(2-amino-6-chloro-9H-purin-9-yl)-6-(hydroxymethyl)bicyclo[2.2.1]heptane-2,5-diol (33). Ammonolysis of28led to 6-amino-9H-purine derivative29. 6-(Dimethylamino)-9H-purine analogue30and 6-(cyclopropylamino)-9H-purine analogues31and34were prepared by aminolysis of corresponding chloropurine derivatives.

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20

RAO, T. S., and G. R. REVANKAR. "ChemInform Abstract: Synthesis of Certain Alkenyl Purines and Purine Analogues." ChemInform 26, no. 47 (2010): no. http://dx.doi.org/10.1002/chin.199547188.

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21

Enos-Berlage, Jodi L., and Diana M. Downs. "Biosynthesis of the Pyrimidine Moiety of Thiamine Independent of the PurF Enzyme (Phosphoribosylpyrophosphate Amidotransferase) in Salmonella typhimurium: Incorporation of Stable Isotope-Labeled Glycine and Formate." Journal of Bacteriology 181, no. 3 (1999): 841–48. http://dx.doi.org/10.1128/jb.181.3.841-848.1999.

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ABSTRACT Genetic analyses have suggested that the pyrimidine moiety of thiamine can be synthesized independently of the first enzyme of de novo purine synthesis, phosphoribosylpyrophosphate amidotransferase (PurF), in Salmonella typhimurium. To obtain biochemical evidence for and to further define this proposed synthesis, stable isotope labeling experiments were performed with two compounds, [2-13C]glycine and [13C]formate. These compounds are normally incorporated into thiamine pyrophosphate (TPP) via steps in the purine pathway subsequent to PurF. Gas chromatography-mass spectrometry analyses indicated that both of these compounds were incorporated into the pyrimidine moiety of TPP in apurF mutant. This result clearly demonstrated that the pyrimidine moiety of thiamine was being synthesized in the absence of the PurF enzyme and strongly suggested that this synthesis utilized subsequent enzymes of the purine pathway. These results were consistent with an alternative route to TPP that bypassed only the first enzyme in the purine pathway. Experiments quantitating cellular thiamine monophosphate (TMP) and TPP levels suggested that the alternative route to TPP did not function at the same capacity as the characterized pathway and determined that levels of TMP and TPP in the wild-type strain were significantly altered by the presence of purines in the medium.

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22

Xu, Zhongnan, Yuqing Wang, Yucheng Zheng, Zhixing Huang, Lutz Ackermann, and Zhixiong Ruan. "Manganese- and rhenium-catalyzed C–H enaminylation: expedient access to novel indole–purine hybrids with anti-tumor bioactivities." Organic Chemistry Frontiers 7, no. 22 (2020): 3709–14. http://dx.doi.org/10.1039/d0qo01120g.

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The C–H enaminylation of novel 6-(1H-indol-1-yl)-purines with ketenimines was accomplished by means of aqueous manganese and rhenium catalysis, which sets the stage for the facile synthesis of indole–purine hybrids with anti-tumor bioactivities.

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23

Boss, G. R. "Purine deoxynucleosides and adenosine dialdehyde decrease 5-amino-4-imidazolecarboxamide (Z-base)-dependent purine nucleotide synthesis in cultured T and B lymphoblasts." Biochemical Journal 242, no. 2 (1987): 425–31. http://dx.doi.org/10.1042/bj2420425.

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Deoxyadenosine (dAdo) and deoxyguanosine (dGuo) decrease methionine synthesis from homocysteine in cultured lymphoblasts; because of the possible trapping of 5-methyltetrahydrofolate this could lead to decreased purine nucleotide synthesis. Since purine deoxynucleosides could also inhibit purine synthesis de novo at an early step not involving folate metabolism, we measured in azaserine-treated cells 5-amino-4-imidazolecarboxamide (Z-base)-dependent purine nucleotide synthesis using [14C]formate. In the T lymphoblasts, Z-base-dependent purine nucleotide synthesis was decreased 26% by 0.3 microM-dAdo, 21% by 1 microM-dGuo and 28% by 1 microM-adenosine dialdehyde, a potent S-adenosylhomocysteine hydrolase inhibitor; homocysteine fully reversed the inhibitions. The B lymphoblasts were considerably less sensitive to the deoxynucleoside-induced decrease in Z-base-dependent purine nucleotide synthesis, with 100 microM-dAdo required for significant inhibition and no inhibition by dGuo at this concentration; homocysteine partly reversed the inhibition by dAdo. The observed decrease in Z-base-dependent purine nucleotide synthesis could not be attributed either to dUMP depletion changing the folate pools or to decreased ATP availability because dUrd was without effect and during the experimental period the intracellular ATP concentration did not change significantly. Cells with 5,10-methylenetetrahydrofolate reductase deficiency were relatively resistant to inhibition of Z-base-dependent purine nucleotide synthesis by dAdo and adenosine dialdehyde. Our results suggest that deoxynucleosides decrease purine nucleotide synthesis by trapping 5-methyltetrahydrofolate.

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24

Šála, Michal, Hubert Hřebabecký, Martin Dračínský, et al. "Synthesis of novel racemic carbocyclic nucleosides derived from 5,6-disubstituted norbornene." Collection of Czechoslovak Chemical Communications 75, no. 1 (2009): 1–20. http://dx.doi.org/10.1135/cccc2009116.

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Novel class of the carbocyclic nucleosides based on bicyclo[2.2.1]heptene/heptane was prepared by two approaches. Thymine analogues were synthesized starting from methyl (1R*,4S*)-bicyclo[2.2.1]hepta-2,5-diene-2-carboxylate1by Michael addition of the thymine salt to the double bond as the key step. The yield and ratio of the isomers of this reaction depended on the used base (DBU, K2CO3). Purine nucleoside analogues were synthesized by the linear synthesis, the purine nucleobase was build-up on the amino group. The amino groups (exo/endoconfiguration) were introduced to the scaffold by the Curtius rearrangement. Norbornene analogues were converted to saturated andcis-hydroxylated nucleoside derivatives. [(1R*,2S*,3S*,4S*)-3-(6-Chloro-9H-purin-9-yl)bicyclo[2.2.1]hept-5-en-2-yl]methanol (13a) and [(1R*,2R*,3R*,4S*)-3-(6-chloro-9H-purin-9-yl)bicyclo[2.2.1]hept-5-en-2-yl]methanol (13b) showed moderate activity againstCoxsackievirus CVB3.

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25

Hřebabecký, Hubert, Milena Masojídková, and Antonín Holý. "Synthesis of Novel Conformationally Locked Carbocyclic Nucleosides Derived from 5,5- and 6,6-Bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol." Collection of Czechoslovak Chemical Communications 70, no. 4 (2005): 519–38. http://dx.doi.org/10.1135/cccc20050519.

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(1R*,2R*,3R*,4S*)-3-Amino-6,6-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol (13) was prepared from (bicyclo[2.2.1]hept-5-ene-2,2-diyl)dimethyl dibenzoate (7) viacis-diol8, cyclic sulfate10, and azide12. (1R*,2R*,3S*,4S*)-3-Amino-6,6-bis(hydroxymethyl)bicyclo[2.2.1]-heptan-2-ol (18) and (1R*,2S*,3S*,4S*)-3-amino-5,5-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol (19) were obtained by addition of chromyl azide to double bond of7, chromatographic separation, debenzoylation and hydrogenation of resulting azides14and16. The amines13,18, and19were used to build (1R*,2R*,3R*,4S*)- (21a), (1R*,2R*,3S*,4S*)-3-(6-chloro-9H-purin-9-yl)-6,6-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol (21b), and (1R*,2S*,3S*,4S*)-3-(6-chloro-9H-purin-9-yl)-5,5-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol (21c), respectively. Ammonolysis of these compounds led to 6-amino-9H-purine derivatives22a-22c. 6-(Dimethylamino)-9H-purine analogues23a-23cand 6-(cyclopropylamino)-9H-purine analogues24a-24cwere prepared by aminolysis of21a-21c. Reaction of amines13,18, and19with ethylN-((2E)-3-ethoxymethacryloyl)carbamate afforded thymine derivatives28a-28c.

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26

Zhou, Weihua, Yangyang Yao, Andrew Scott, et al. "DDRE-24. TARGETING PURINE METABOLISM TO OVERCOME GLIOBLASTOMA THERAPY RESISTANCE." Neuro-Oncology Advances 3, Supplement_1 (2021): i11. http://dx.doi.org/10.1093/noajnl/vdab024.046.

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Abstract Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming radiation (RT) resistance. To discover genotype-independent mediators of RT resistance, we correlated RT resistance with the concentration of approximately 700 metabolites across 23 GBM cell lines. Purine metabolites, especially those containing the base guanine, were most correlated with RT resistance. Similarly, increased abundance of tumor purines was associated with decreased survival in GBM patients treated with RT. This relationship is causal. Purine supplementation protected RT-sensitive GBMs from RT and promoted the repair of RT-induced double strand DNA breaks (DSBs). In vitro and in vivo stable isotope tracing confirmed that GBM cell lines and orthotopic patient-derived xenografts primarily generated purines through the de novo synthetic pathway. RT treatment further increased de novo purine synthesis in GBM through signaling via the DNA damage response. Inhibition of de novo GTP synthesis with mycophenolic acid (MPA) sensitized multiple GBM cell lines and neurospheres to RT by slowing the repair of RT-induced DSBs. MPA-induced radiosensitization was GTP-dependent as it was rescued by nucleoside supplementation. Modulating pyrimidine metabolism affected neither RT resistance nor DSB repair, suggesting these GTP-specific effects are due to active signaling rather than its ability to act as a physical substrate for DNA repair and candidate signaling molecules have been identified. These results were recapitulated in vivo with mycophenolate mofetil (MMF), the orally bioavailable FDA-approved prodrug of MPA. MMF potentiated RT efficacy, reduced tumor guanylates and slowed the repair of RT-induced DSBs across multiple models. Because de novo purine synthesis is activated by many of the oncogenic alterations that drive GBM, its inhibition is a promising genotype-independent strategy to overcome GBM RT resistance. We have now begun a clinical trial to determine whether combining MMF and RT is safe and potentially efficacious in patients with GBM.

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27

ZINN, R. A., and F. N. OWENS. "A RAPID PROCEDURE FOR PURINE MEASUREMENT AND ITS USE FOR ESTIMATING NET RUMINAL PROTEIN SYNTHESIS." Canadian Journal of Animal Science 66, no. 1 (1986): 157–66. http://dx.doi.org/10.4141/cjas86-017.

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A rapid method for separation and quantitation of purines was applied to ruminal and intestinal digesta for estimating net microbial protein synthesis in the rumen. The procedure combines standard literature methods for hydrolysis of nucleotides by perchloric acid followed by precipitation of free purines with silver nitrate to separate the purines from interfering compounds. Acid resolubilized purines were quantitated spectrophotometrically at 260 nm. Microbial protein was estimated by the ratio of purines to N of isolated bacteria. The procedure is rapid, simple, precise and not costly. Duodenal passage of microbial N estimated by this procedure for steers fed semipurified and purified diets containing no protein was highly correlated (R2 = 0.98; P < 0.01) with duodenal passage of tungstic acid precipitable N. Results indicate that purines may be useful as a marker for quantitating microbial protein. Key words: Purine, RNA, DNA, microbial protein

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28

Kapadiya, Khushal, Kishor Kavadia, Jyoti Gohel, and Ranjan Khunt. "Regioselective synthesis of triazolo[3,4-e]purine derivatives and their anti-cancer activity against NCI-60 cell-lines." Folia Medica 63, no. 2 (2021): 213–20. http://dx.doi.org/10.3897/folmed.63.e52891.

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Introduction: Due to the vast medicinal importance of purine nucleoside, a hybrid molecule of triazole with purine ring might explode a lead molecule in the pharma sector and based on the last decade’s studies suggested that the nitrogen-rich molecules possess a wide range of medicinal importance. Aim: Due to the vast application of purine nucleoside itself in the field of cancer research, we synthesized triazolo[3,4-e]purines and screened them for their anti-cancer study against NCI-60 cell lines by the protocol used by NIH. Materials and methods: The targeted molecules, 4-chloro-5a,6-dihydro-8-substitutedphenyl-1H-[1,2,4]triazolo[3,4-e]purine derivatives (4a-4h) were synthesized in a two-step procedure by nucleophilic substitution (SN) at C-2 chlorine followed by formation of the triazole ring by acid-catalyzed reaction in the polar protic solvent. Results: It was observed that the regioselective approach followed in C-2 chlorine replacement instead of C-6 chlorine during SN reaction. One-dose response of selected three molecules (4a, 4b, and 4c) showed that 4b (K-562: 64.47 µM & SR: 63.38 µM; mean GI50: 99.09 µM) was found to be more potent than 4a and 4c. Conclusions: We have described in this study the general synthetic method for triazolo[3,4-e]purines as an innovative class of potential anticancer agents. The dose-response curve in the sense of mean GI50 for three compounds across all 60 cell lines, 4b can be served as lead after necessary modification.

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29

Bach, T., H. Guthmann, and M. Könemann. "Stepwise Synthesis of Tetrameric Purine." Synfacts 2007, no. 4 (2007): 0383. http://dx.doi.org/10.1055/s-2007-968317.

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30

Saathoff, Miranda, Jack Shireman, Eunus Ali, Cheol Park, Issam Ben-Sahra, and Atique Ahmed. "DRES-09. REGULATORY EFFECTS OF THE CILIARY GTPASE ARL13B ON PURINE METABOLISM IN GBM." Neuro-Oncology 21, Supplement_6 (2019): vi73. http://dx.doi.org/10.1093/neuonc/noz175.297.

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Abstract Glioblastoma (GBM) is the most common form of adult primary brain cancer. Despite an aggressive treatment regimen – surgical resection, irradiation, and temozolomide (TMZ) chemotherapy – patients’ prognosis is still grim. TMZ acts by methylating purines, specifically at the O6 and N7 positions of guanine, to induce cytotoxic DNA double-strand breaks. We thus wanted to explore how purine metabolism may contribute to TMZ-resistance. In mammalian cells, purine nucleotides can be recycled by the salvage pathway or generated via de novo synthesis. The salvage pathway is energetically inexpensive relative to de novo thus, highly proliferative GBM cells preferentially utilize the salvage pathway. We have shown that salvage synthesis is reduced in response to TMZ (p-value=0.0021), hinting that the cells may utilize de novo to evade therapy induced alkylation of purines. Using immunoprecipitation-mass spectroscopy analysis, we found a novel interaction between the ciliary GTPase ARL13B and IMPDH2, the rate-limiting enzyme in de novo synthesis. We have shown that this interaction, occurring at the C-terminal domain of ARL13B, plays a significant role in the regulation of purine biosynthesis as abolishing it through ARL13B knockdown reduced flux through de novo (p-value< 0.0001) synthesis as measured by the specific activity of IMPDH2. Further, the lentiviral-mediated rescue of ARL13B brings IMPDH2 activity back to basal levels (p< 0.0001). Given its canonical function as a GTPase, we hypothesize that ARL13B acts as a novel regulator of de novo synthesis by sequestering GDP, allowing IMPDH2 to sense and respond to the cytosolic levels of guanine nucleotides. Without ARL13B the de novo pathway is halted, forcing the cells to rely on salvage to replenish nucleotide pools. Reliance on this pathway in the presence of TMZ causes cells to incorporate damaged nucleotides as a result of the drug’s alkylating action leading to the increased therapeutic efficacy of TMZ.

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31

Šála, Michal, Hubert Hřebabecký, Milena Masojídková, and Antonín Holý. "Synthesis of Novel Racemic Conformationally Locked Carbocyclic Nucleosides Derived from 7-Substituted Bicyclo[2.2.1]hept-5-ene-2,2-dimethanols." Collection of Czechoslovak Chemical Communications 71, no. 5 (2006): 635–49. http://dx.doi.org/10.1135/cccc20060635.

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(1R*,4R*,7S*)-7-Aminobicyclo[2.2.1]hept-5-ene-2,2-dimethanol (15) was prepared in four easy steps from bicyclo[2.2.1]hept-5-ene-2,2-dimethanol (10). Reaction of amine 15 with ethyl N-((E)-3-ethoxymethacryloyl)carbamate afforded thymine derivatives 17a. The amine 15 was used to construct 6-chloro-9H-purine derivative 19a, 2-amino-6-chloro-9H-purine derivative 22a. Ammonolysis of 19a led to the adenine derivative 20a. Treatment of 22a with trifluoroacetic acid afforded guanine nucleoside 23a. (1R*,4R*,7S*)-7-[6-(Cyclopropylamino)-9H-purin-9-yl]bicyclo[2.2.1]hept-5-ene-2,2-dimethanol (21a) and (1R*,4R*,7S*)-7-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]bicyclo[2.2.1]hept-5-ene-2,2-dimethanol (24a) were prepared by aminolysis of 19a and 22a. Saturated nucleosides 17b, 20b, 21b, 23b, 24b were obtained by hydrogenation on palladium catalyst.

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32

Zilles, Julie L., T. Joseph Kappock, JoAnne Stubbe, and Diana M. Downs. "Altered Pathway Routing in a Class ofSalmonella enterica Serovar Typhimurium Mutants Defective in Aminoimidazole Ribonucleotide Synthetase." Journal of Bacteriology 183, no. 7 (2001): 2234–40. http://dx.doi.org/10.1128/jb.183.7.2234-2240.2001.

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ABSTRACT In Salmonella enterica serovar Typhimurium, purine nucleotides and thiamine are synthesized by a branched pathway. The last known common intermediate, aminoimidazole ribonucleotide (AIR), is formed from formylglycinamidine ribonucleotide (FGAM) and ATP by AIR synthetase, encoded by the purI gene in S. enterica. Reduced flux through the first five steps of de novo purine synthesis results in a requirement for purines but not necessarily thiamine. To examine the relationship between the purine and thiamine biosynthetic pathways, purI mutants were made (J. L. Zilles and D. M. Downs, Genetics 143:37–44, 1996). Unexpectedly, some mutantpurI alleles (R35C/E57G and K31N/A50G/L218R) allowed growth on minimal medium but resulted in thiamine auxotrophy when exogenous purines were supplied. To explain the biochemical basis for this phenotype, the R35C/E57G mutant PurI protein was purified and characterized kinetically. The Km of the mutant enzyme for FGAM was unchanged relative to the wild-type enzyme, but theV max was decreased 2.5-fold. TheKm for ATP of the mutant enzyme was 13-fold increased. Genetic analysis determined that reduced flux through the purine pathway prevented PurI activity in the mutant strain, andpurR null mutations suppressed this defect. The data are consistent with the hypothesis that an increased FGAM concentration has the ability to compensate for the lower affinity of the mutant PurI protein for ATP.

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33

Derzelle, Sylviane, Alexander Bolotin, Michel-Yves Mistou, and Françoise Rul. "Proteome Analysis of Streptococcus thermophilus Grown in Milk Reveals Pyruvate Formate-Lyase as the Major Upregulated Protein." Applied and Environmental Microbiology 71, no. 12 (2005): 8597–605. http://dx.doi.org/10.1128/aem.71.12.8597-8605.2005.

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ABSTRACT We investigated the adaptation to milk of Streptococcus thermophilus LMG18311 using a proteomic approach. Two-dimensional electrophoresis of cytosolic proteins were performed after growth in M17 medium or in milk. A major modification of the proteome concerned proteins involved in the supply of amino acids, like the peptidase PepX, and several enzymes involved in amino acid biosynthesis. In parallel, we observed the upregulation of the synthesis of seven enzymes directly involved in the synthesis of purines, as well as formyl-tetrahydrofolate (THF) synthetase and serine hydroxy-methyl transferase, two enzymes responsible for the synthesis of compounds (THF and glycine, respectively) feeding the purine biosynthetic pathway. The analysis also revealed a massive increase in the synthesis of pyruvate formate-lyase (PFL), the enzyme which converts pyruvate into acetyl coenzyme A and formate. PFL has been essentially studied for its role in mixed-acid product formation in lactic acid bacteria during anaerobic fermentation. However, formate is an important methyl group donor for anabolic pathway through the formation of folate derivates. We hypothesized that PFL was involved in purine biosynthesis during growth in milk. We showed that PFL expression was regulated at the transcriptional level and that pfl transcription occurred during the exponential growth phase in milk. The complementation of milk with formate or purine bases was shown to reduce pfl expression, to suppress PFL synthesis, and to stimulate growth of S. thermophilus. These results show a novel regulatory mechanism controlling the synthesis of PFL and suggest an unrecognized physiological role for PFL as a formate supplier for anabolic purposes.

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34

Onidani, Kaoru, Nami Miura, Yuki Sugiura, et al. "Possible Therapeutic Strategy Involving the Purine Synthesis Pathway Regulated by ITK in Tongue Squamous Cell Carcinoma." Cancers 13, no. 13 (2021): 3333. http://dx.doi.org/10.3390/cancers13133333.

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The epidermal growth factor receptor is the only available tyrosine kinase molecular target for treating oral cancer. To improve the prognosis of tongue squamous cell carcinoma (TSCC) patients, a novel molecular target for tyrosine kinases is thus needed. We examined the expression of interleukin-2–inducible T-cell kinase (ITK) using immunohistochemistry, and the biological function of ITK was investigated using biochemical, phosphoproteomic, and metabolomic analyses. We found that ITK is overexpressed in TSCC patients with poor outcomes. The proliferation of oral cancer cell lines expressing ITK via transfection exhibited significant increases in three-dimensional culture assays and murine inoculation models with athymic male nude mice as compared with mock control cells. Suppressing the kinase activity using chemical inhibitors significantly reduced the increase in cell growth induced by ITK expression. Phosphoproteomic analyses revealed that ITK expression triggered phosphorylation of a novel tyrosine residue in trifunctional purine biosynthetic protein adenosine-3, an enzyme in the purine biosynthesis pathway. A significant increase in de novo biosynthesis of purines was observed in cells expressing ITK, which was abolished by the ITK inhibitor. ITK thus represents a potentially useful target for treating TSCC through modulation of purine biosynthesis.

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Fridman, Alla, Arindam Saha, Adriano Chan, Darren E. Casteel, Renate B. Pilz, and Gerry R. Boss. "Cell cycle regulation of purine synthesis by phosphoribosyl pyrophosphate and inorganic phosphate." Biochemical Journal 454, no. 1 (2013): 91–99. http://dx.doi.org/10.1042/bj20130153.

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Cells must increase synthesis of purine nucleotides/deoxynucleotides before or during S-phase. We found that rates of purine synthesis via the de novo and salvage pathways increased 5.0- and 3.3-fold respectively, as cells progressed from mid-G1-phase to early S-phase. The increased purine synthesis could be attributed to a 3.2-fold increase in intracellular PRPP (5-phosphoribosyl-α-1-pyrophosphate), a rate-limiting substrate for de novo and salvage purine synthesis. PRPP can be produced by the oxidative and non-oxidative pentose phosphate pathways, and we found a 3.1-fold increase in flow through the non-oxidative pathway, with no change in oxidative pathway activity. Non-oxidative pentose phosphate pathway enzymes showed no change in activity, but PRPP synthetase is regulated by phosphate, and we found that phosphate uptake and total intracellular phosphate concentration increased significantly between mid-G1-phase and early S-phase. Over the same time period, PRPP synthetase activity increased 2.5-fold when assayed in the absence of added phosphate, making enzyme activity dependent on cellular phosphate at the time of extraction. We conclude that purine synthesis increases as cells progress from G1- to S-phase, and that the increase is from heightened PRPP synthetase activity due to increased intracellular phosphate.

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ITAYA, Taisuke, Yasutaka TAKADA, Tae KANAI, and Tozo FUJII. "Purines. LXXVIII. An Alternative Synthesis of the Sea Anemone Purine Alkaloid Caissarone." CHEMICAL & PHARMACEUTICAL BULLETIN 45, no. 11 (1997): 1867–69. http://dx.doi.org/10.1248/cpb.45.1867.

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37

Jiménez, Alberto, María A. Santos, Markus Pompejus, and José L. Revuelta. "Metabolic Engineering of the Purine Pathway for Riboflavin Production in Ashbya gossypii." Applied and Environmental Microbiology 71, no. 10 (2005): 5743–51. http://dx.doi.org/10.1128/aem.71.10.5743-5751.2005.

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ABSTRACT Purine nucleotides are essential precursors for living organisms because they are involved in many important processes, such as nucleic acid synthesis, energy supply, and the biosynthesis of several amino acids and vitamins such as riboflavin. GTP is the immediate precursor for riboflavin biosynthesis, and its formation through the purine pathway is subject to several regulatory mechanisms in different steps. Extracellular purines repress the transcription of most genes required for de novo ATP and GTP synthesis. Additionally, three enzymes of the pathway, phosphoribosyl pyrophosphate (PRPP) amidotransferase, adenylosuccinate synthetase, and IMP dehydrogenase, are subject to feedback inhibition by their end products. Here we report the characterization and manipulation of the committed step in the purine pathway of the riboflavin overproducer Ashbya gossypii. We report that phosphoribosylamine biosynthesis in A. gossypii is negatively regulated at the transcriptional level by extracellular adenine. Furthermore, we show that ATP and GTP exert a strong inhibitory effect on the PRPP amidotransferase from A. gossypii. We constitutively overexpressed the AgADE4 gene encoding PRPP amidotransferase in A. gossypii, thereby abolishing the adenine-mediated transcriptional repression. In addition, we replaced the corresponding residues (aspartic acid310, lysine333, and alanine417) that have been described to be important for PRPP amidotransferase feedback inhibition in other organisms by site-directed mutagenesis. With these manipulations, we managed to enhance metabolic flow through the purine pathway and to increase the production of riboflavin in the triple mutant strain 10-fold (228 mg/liter).

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38

Lin, Xiaoyu, and Morris J. Robins. "Nucleic Acid Related Compounds. 136. Synthesis of 2-Amino- and 2,6-Diaminopurine Derivatives via Inverse-Electron-Demand Diels-Alder Reactions." Collection of Czechoslovak Chemical Communications 71, no. 7 (2006): 1029–41. http://dx.doi.org/10.1135/cccc20061029.

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Thermal inverse-electron-demand Diels-Alder reactions of 5-aminoimidazoles and 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine (2) with spontaneous retro-Diels-Alder loss of ethyl cyanoformate and elimination of ammonia give 2,6-bis(ethoxycarbonyl)purines. A report that selective alkaline hydrolysis followed by acid-catalyzed decarboxylation gave 6-(ethoxycarbonyl)purine products was not in harmony with known reactions in purine chemistry. Our reinvestigation has shown that the 6-(ethoxycarbonyl) group undergoes preferential base-promoted hydrolysis, as expected, but regioselectivity for attack of hydroxide at the carbonyl group at C6 is not high (relative to hydrolysis of both C2 and C6 esters). The structure of 9-benzyl-2-(ethoxycarbonyl)purine was determined by X-ray crystallography and confirmed by Curtius rearrangement of the azidocarbonyl analogue to give 2-amino-6-benzylpurine. Acid-catalyzed decarboxylation of the 2,6-dicarboxylate formed during hydrolysis gave 9-benzylpurine, and Curtius rearrangement of 2,6-bis(azidocarbonyl)-9-benzylpurine gave 2,6-diamino-9-benzylpurine. Attempted applications of inverse-electron-demand Diels-Alder reactions of 2 with nucleoside derivatives were problematic.

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39

Hřebabecký, Hubert, Milena Masojídková, and Antonín Holý. "Synthesis of Racemic 9-(6- and 2,6-Substituted 9H-Purin-9-yl)-5-oxatricyclo[4.2.1.03,7]nonane-3-methanols, Novel Conformationally Locked Carbocyclic Nucleosides." Collection of Czechoslovak Chemical Communications 70, no. 1 (2005): 103–23. http://dx.doi.org/10.1135/cccc20050103.

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(1R*,3R*,6R*,7S*,9S*)- and (1R*,3R*,6R*,7S*,9R*)-9-Amino-5-oxatricyclo[4.2.1.03,7]nonane-3-methanols (16aand17a) were prepared from 2-(hydroxymethyl)bicyclo[2.2.1]hept-5-ene-2-methanol (10) in five easy steps. The amines16aand17awere used to construct 6-chloro-9H-purine20and21, 2-amino-6-chloro-9H-purine30and31, and 6-chloro-8-methyl-9H-purine analogues34and35. Ammonolysis of these compounds led to 6-amino-9H-purine22aand23a, 2,6-diamino-9H-purine32and33, and 6-amino-8-methyl-9H-purine derivatives of 5-oxatricyclo[4.2.1.03,7]nonane-3-methanol36and37. (1R*,3R*,6R*,7S*,9S*)- and (1R*,3R*,6R*,7S*,9R*)-9-[6-(Dimethylamino)-9H-purin-9-yl]-5-oxatricyclo[4.2.1.03,7]nonane-3-methanols (22band23b), and (1R*,3R*,6R*,7S*,9S*)- and (1R*,3R*,6R*,7S*,9R*)-9-[6-(cyclopropylamino)-9H-purin-9-yl]-5-oxatricyclo[4.2.1.03,7]nonane-3-methanols (22cand23c) were prepared by aminolysis of20and21.

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40

Burres, Neal S., and Carol E. Cass. "The effects of hypoxanthine on methotrexate-induced differentiation of cultured human choriocarcinoma (BeWo) cells." Biochemistry and Cell Biology 64, no. 8 (1986): 811–15. http://dx.doi.org/10.1139/o86-109.

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When cultured human choriocarcinoma (BeWo) cells arc exposed to methotrexate, proliferation ceases and cells undergo a complex differentiative response that resembles development of normal trophoblast. Although thymidylate starvation has been shown to be causative in methotrexate-induced expression of syncytiotrophoblastic markers by BeWo cells, the role of purine deprivation is uncertain since previous studies utilized growth media containing exogenous purines. This work investigated the effects of hypoxanthine on methotrexate-induced cell enlargement, expression of placental alkaline phosphatase, and morphological differentiation to the syncytiotrophoblast-like phenotype. When methotrexate exposures (1 μM, 48 h) were conducted in a purine-frec basal medium supplemented with dialyzed fetal bovine serum, RNA synthesis was greatly reduced and cell enlargement did not occur. Specific methods for removing purines (charcoal extraction and xanthine oxidase treatment) decreased the ability of serum to support cell enlargement during methotrexate exposures, whereas addition of hypoxanthine to culture fluids restored its ability to support maximal increases in cell mass, confirming that purines were the factors lost during dialysis. In contrast, morphological differentiation to the syncytiotrophoblast-like phenotype and increased expression of placental alkaline phosphatase were unaffected by the availability of purines during exposure to methotrexate.

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41

Al-Azmi, Amal, and K. Anita Kumari. "Synthesis of 6-Substituted Purine Derivatives." HETEROCYCLES 78, no. 12 (2009): 2951. http://dx.doi.org/10.3987/com-09-11794.

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42

Kreimeyer, Annett, Joël Ughetto-Monfrin, Abdelkader Namane, and Tam Huynh-Dinh. "Synthesis of acylphosphates of purine ribonucleosides." Tetrahedron Letters 37, no. 48 (1996): 8739–42. http://dx.doi.org/10.1016/s0040-4039(96)02016-3.

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43

Wyngaarden, James B., Harold R. Silberman, and John H. Sadler. "FEEDBACK MECHANISMS INFLUENCING PURINE RIBOTIDE SYNTHESIS*." Annals of the New York Academy of Sciences 75, no. 1 (2006): 45–60. http://dx.doi.org/10.1111/j.1749-6632.1958.tb36850.x.

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44

Lakshman, M., P. Lagisetty, and L. Russon. "Synthesis of C6-Azolyl Purine Nucleosides." Synfacts 2006, no. 8 (2006): 0763. http://dx.doi.org/10.1055/s-2006-941970.

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45

Chapeau, Marie Christine, and Lawrence J. Marnett. "Enzymic synthesis of purine deoxynucleoside adducts." Chemical Research in Toxicology 4, no. 6 (1991): 636–38. http://dx.doi.org/10.1021/tx00024a006.

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Karskela, Tuomas, Karel D. Klika та Harri Lönnberg. "Synthesis of 7-substituted 3-β-D-ribofuranosyl-3H-imidazo[2,1-i]purines". Collection of Czechoslovak Chemical Communications 76, № 8 (2011): 1043–54. http://dx.doi.org/10.1135/cccc2011069.

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A method for the synthesis of 7-substituted 3-β-D-ribofuranosyl-3H-imidazo[2,1-i]purines has been devised whereby compounds were prepared in a few steps from a common intermediate, 3-(2′,3′-O-isopropylidene-β-D-ribofuranosyl)-3H-imidazo[2,1-i]purine-7-carbaldehyde, obtained from the reaction of 2′,3′-O-isopropylideneadenosine with bromomalonaldehyde. The formyl group of the carbaldehyde was subsequently reductively aminated and the resulting secondary amines were then further derivatized either by acylation, lactamization or reductive alkylation.

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47

Khaliullin, Ferkat, and Yuliya Shabalina. "Thietanyl Protection in the Synthesis of 8-Substituted 1-Benzyl-3-methyl-3,7-dihydro- 1H-purine-2,6-diones." Current Organic Synthesis 17, no. 7 (2020): 535–39. http://dx.doi.org/10.2174/1570179417666200628015511.

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Aim and Objective: 1-Аlkyl-3,7-dihydro-1H-purine-2,6-diones containing no substituents in the N7 position can be synthesized only using protecting groups, for example, benzyl protection. However, in the case of synthesis of 1-benzyl-3,7-dihydro-1H-purine-2,6-diones, the use of benzyl protection may lead to simultaneous debenzylation of both N1 and N7 positions. Therefore, it is necessary to use other protective groups for the synthesis of 1-benzyl-3,7-dihydro-1H-purine-2,6-diones. Materials and Methods: 8-Bromo- and 8-amino-substituted 1-benzyl-3-methyl-3,7-dihydro-1H-purine-2,6-diones unsubstituted in the N7 position were synthesized with the use of thietanyl protecting group. The thietane ring was introduced via the reaction of 8-bromo-3-methyl-3,7-dihydro-1H-purine-2,6-dione with 2-chloromethylthiirane, giving rise to 8-bromo-3-methyl-7-(thietan-3-yl)-3,7-dihydro-1H-purine-2,6-dione. The subsequent alkylation with benzyl chloride yielded 1-benzyl-8-bromo-3-methyl-7-(thietan-3-yl)-3,7-dihydro-1H-purine-2,6-dione, which was oxidized with hydrogen peroxide to be converted to 1-benzyl-8-bromo-3-methyl-7-(1,1-dioxothietan- 3-yl)-3,7-dihydro-1H-purine-2,6-dione. This product reacted with amines to give 8-amino-substituted 1-benzyl-3- methyl-7-(1,1-dioxothietan-3-yl)-3,7-dihydro-1H-purine-2,6-diones. The reaction of 8-substituted 1-benzyl-3- methyl-7-(1,1-dioxothietan-3-yl)-3,7-dihydro-1H-purine-2,6-diones with sodium isopropoxide resulted in the removal of the thietanyl protection and afforded target 8-substituted 1-benzyl-3-methyl-3,7-dihydro-1H-purine-2,6- diones. The structures of the targets compounds have been deduced upon their elemental analysis and spectral data (IR, 1H NMR, 13C NMR and 15N NMR). Results and Discussion: A new 8-substituted 1-benzyl-3-methyl-3,7-dihydro-1H-purine-2,6-diones unsubstituted in the N7 position were synthesized using thietanyl protecting group. Conclusion: The present study described a new route to synthesize some new 1,8-disubstituted 3-methyl-3,7- dihydro-1H-purine-2,6-diones unsubstituted in the N7 position starting from available 8-bromo-3-methyl-3,7- dihydro-1H-purine-2,6-dione with use of thietanyl protecting group. The advantages of this protocol are the possibility of the synthesis of 1-benzyl-substituted 3,7-dihydro-1H-purine-2,6-diones, the stability of the thietanyl protecting group upon nucleophilic substitution by amines of the bromine atom in the position 8, as well as mild conditions, and simple execution of experiments.

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Göttle, Martin, Heike Burhenne, Diane Sutcliffe, and H. A. Jinnah. "Purine metabolism during neuronal differentiation: the relevance of purine synthesis and recycling." Journal of Neurochemistry 127, no. 6 (2013): 805–18. http://dx.doi.org/10.1111/jnc.12366.

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Buček, Jan, Marek Zatloukal, Libor Havlíček, et al. "Total synthesis of [ 15 N]-labelled C6-substituted purines from [ 15 N]-formamide—easy preparation of isotopically labelled cytokinins and derivatives." Royal Society Open Science 5, no. 11 (2018): 181322. http://dx.doi.org/10.1098/rsos.181322.

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Cytokinins (CKs) and their metabolites and derivatives are essential for cell division, plant growth regulation and development. They are typically found at minute concentrations in plant tissues containing very complicated biological matrices. Therefore, defined standards labelled with stable isotopes are required for precise metabolic profiling and quantification of CKs, as well as in vivo elucidation of CK biosynthesis in various plant species. In this work, 11 [ 15 N]-labelled C6-purine derivatives were prepared, among them 5 aromatic ( 4, 5, 6, 7, 8 ) and 3 isoprenoid ( 9, 10, 11 ) CKs. Compared to current methods, optimized syntheses of 6-amino-9H-[ 15 N 5 ]-purine (adenine) and 6-chloro-9H-[ 15 N 4 ]-purine (6-chloropurine) were performed to achieve more effective, selective and generally easier approaches. The chemical identity and purity of prepared compounds were confirmed by physico-chemical analyses (TLC; HRMS; HPLC–MS; 1 H, 13 C, 15 N NMR). The presented approach is applicable for the synthesis of any other desired [ 15 N 4 ]-labelled C6-substituted purine derivatives.

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Kim, Seohyun Chris, Derek K. O’Flaherty, Lijun Zhou, Victor S. Lelyveld, and Jack W. Szostak. "Inosine, but none of the 8-oxo-purines, is a plausible component of a primordial version of RNA." Proceedings of the National Academy of Sciences 115, no. 52 (2018): 13318–23. http://dx.doi.org/10.1073/pnas.1814367115.

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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.

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Journal articles on the topic 'Purine synthesis'

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