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Marutyan, Seda V., Gayane H. Petrosyan, Syuzan A. Marutyan, Liparit A. Navasardyan, and Armen H. Trchounian. "INFLUENCE OF X-RAY AND MICROWAVE RADIATION ON DEAMINATION OF PURINE NUCLEOTIDES IN YEAST CELLS CANDIDA GUILLIERMONDII NP-4." IZVESTIYA VYSSHIKH UCHEBNYKH ZAVEDENII KHIMIYA KHIMICHESKAYA TEKHNOLOGIYA 62, no. 2 (February 7, 2019): 48–52. http://dx.doi.org/10.6060/ivkkt.20196202.5894.
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In metabolism of living cells a key role play purine nucleotides which cells can be supplied either by de novo synthesis from lower molecular weight precursors, or by alternate ways of nucleotide synthesis or so-called "nucleotide salvage pathways", which allow reusing of intermediate products of nucleotide metabolism in nucleotide synthesis. This way is important in the post-stress repair period, saving energy and substrates in the repairing cells. Purine nucleotides are allosteric inhibitors of enzymes of nucleotide salvage pathways, therefore the increase in their catabolism leads to a decrease of their amount in the cells, which contributes to the intensive work of the nucleotide salvage pathways and provides substrates for DNA synthesis. Investigation of deamination of purine nucleotides in yeasts Candida guilliermondii NP-4 irradiated with X-rays, millimeter and decimeter electromagnetic waves, as well as after post-radiation incubation of cells has been realized. It has been shown that under the influence of X-ray and microwave irradiation in yeasts, the intensity of deamination of purine nucleotide-polyphosphates - ADP, ATP, GDF and GTP, has changed, which in all probability is an adaptive mechanism in the repair of yeasts after irradiation, provides the work of nucleotide salvage pathways, and can be associated with the metabolism of these compounds.
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Rosiers, Christine Des, Stephan Nees, and Eckehart Gerlach. "Purine metabolism in cultured aortic and coronary endothelial cells." Biochemistry and Cell Biology 67, no. 1 (January 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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Vettenranta, K., and K. O. Raivio. "Extracellular adenine nucleotides in human trophoblastic purine nucleotide synthesis." Placenta 10, no. 5 (September 1989): 472. http://dx.doi.org/10.1016/0143-4004(89)90091-x.
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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 (November 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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Arabadjis, P. G., P. C. Tullson, and R. L. Terjung. "Purine nucleoside formation in rat skeletal muscle fiber types." American Journal of Physiology-Cell Physiology 264, no. 5 (May 1, 1993): C1246—C1251. http://dx.doi.org/10.1152/ajpcell.1993.264.5.c1246.
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To determine the capacity for purine nucleotide degradation among skeletal muscle fiber types, we established energy-depleted conditions in muscles of the rat hindlimb by inducing muscle contraction during ischemia. After 5, 10, 15, or 20 min of ischemic contractions, representative muscle sections were freeze-clamped and analyzed for purine nucleotides, nucleosides, and bases. Fast-twitch muscle sections accumulated about fourfold more IMP than the slow-twitch red soleus muscle. Inosine begins to accumulate at < 0.5 mumol/g IMP in slow-twitch muscle and at approximately 2 mumol/g IMP in fast-twitch muscle. This suggests that inosine is formed intracellularly by 5'-nucleotidase acting on IMP and that the activity and/or substrate affinity of the 5'-nucleotidase present in slow-twitch muscle may be higher than in fast-twitch muscle. At similar concentrations of precursor IMP, slow-twitch muscle has a greater capacity for purine nucleoside formation and should be more dependent on salvage and de novo synthesis of purine for the maintenance of muscle adenine nucleotides. Fast-twitch muscles are better able to retain IMP for subsequent reamination due to their lower capacity to degrade IMP to inosine.
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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 (December 3, 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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Mendz, G. L., B. M. Jimenez, S. L. Hazell, A. M. Gero, and W. J. O'Sullivan. "Salvage synthesis of purine nucleotides by Helicobacter pylori." Journal of Applied Bacteriology 77, no. 6 (December 1994): 674–81. http://dx.doi.org/10.1111/j.1365-2672.1994.tb02818.x.
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Brault, Jeffrey J., and Ronald L. Terjung. "Purine salvage to adenine nucleotides in different skeletal muscle fiber types." Journal of Applied Physiology 91, no. 1 (July 1, 2001): 231–38. http://dx.doi.org/10.1152/jappl.2001.91.1.231.
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Rates of purine salvage of adenine and hypoxanthine into the adenine nucleotide (AdN) pool of the different skeletal muscle phenotype sections of the rat were measured using an isolated perfused hindlimb preparation. Tissue adenine and hypoxanthine concentrations and specific activities were controlled over a broad range of purine concentrations, ranging from 3 to 100 times normal, by employing an isolated rat hindlimb preparation perfused at a high flow rate. Incorporation of [3H]adenine or [3H]hypoxanthine into the AdN pool was not meaningfully influenced by tissue purine concentration over the range evaluated (∼0.10–1.6 μmol/g). Purine salvage rates were greater ( P < 0.05) for adenine than for hypoxanthine (35–55 and 20–30 nmol · h−1 · g−1, respectively) and moderately different ( P < 0.05) among fiber types. The low-oxidative fast-twitch white muscle section exhibited relatively low rates of purine salvage that were ∼65% of rates in the high-oxidative fast-twitch red section of the gastrocnemius. The soleus muscle, characterized by slow-twitch red fibers, exhibited a high rate of adenine salvage but a low rate of hypoxanthine salvage. Addition of ribose to the perfusion medium increased salvage of adenine (up to 3- to 6-fold, P < 0.001) and hypoxanthine (up to 6- to 8-fold, P < 0.001), depending on fiber type, over a range of concentrations up to 10 mM. This is consistent with tissue 5-phosphoribosyl-1-pyrophosphate being rate limiting for purine salvage. Purine salvage is favored over de novo synthesis, inasmuch as delivery of adenine to the muscle decreased ( P < 0.005) de novo synthesis of AdN. Providing ribose did not alter this preference of purine salvage pathway over de novo synthesis of AdN. In the absence of ribose supplementation, purine salvage rates are relatively low, especially compared with the AdN pool size in skeletal muscle.
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Kartha, S., and F. G. Toback. "Purine nucleotides stimulate DNA synthesis in kidney epithelial cells in culture." American Journal of Physiology-Renal Physiology 249, no. 6 (December 1, 1985): F967—F972. http://dx.doi.org/10.1152/ajprenal.1985.249.6.f967.
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Adenine nucleotides infused into animals with acute renal failure appear to enhance recovery of kidney function and structure. To determine whether these compounds could act by a direct effect on renal cell metabolism, their capacity to stimulate DNA synthesis was evaluated in cultures of monkey kidney epithelial cells (BSC-1 line). AMP and ADP enhanced DNA synthesis by threefold more than was previously observed with other mitogens for these cells. Guanosine and inosine and their nucleotides and adenosine and ATP were also mitogenic but to a lesser extent, whereas pyrimidine derivatives were ineffective. In the presence of AMP, autoradiography of [3H]thymidine-labeled cells indicated that a greater number of cells entered the S phase of the cell cycle, and assessment of cell number revealed increased multiplication. The mitogenic effect of adenine nucleotides was not reproduced by agents that raise the cellular content of cAMP and was serum independent. Adenine nucleotides did not alter DNA synthesis when added to cultures of mouse fibroblasts. These results indicate that provision of exogenous purine nucleosides and nucleotides stimulate DNA synthesis in renal epithelial cells in culture.
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YEGUTKIN, Gennady G., Tiina HENTTINEN, Sergei S. SAMBURSKI, Jozef SPYCHALA, and Sirpa JALKANEN. "The evidence for two opposite, ATP-generating and ATP-consuming, extracellular pathways on endothelial and lymphoid cells." Biochemical Journal 367, no. 1 (October 1, 2002): 121–28. http://dx.doi.org/10.1042/bj20020439.
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Extracellular purines are important signalling molecules in the vasculature that are regulated by a network of cell surface ectoenzymes. By using human endothelial cells and normal and leukaemic lymphocytes as enzyme sources, we identified the following purine-converting ectoenzymes: (1) ecto-nucleotidases, NTP diphosphohydrolase/CD39 (EC 3.6.1.5) and ecto-5′-nucleotidase/CD73 (EC 3.1.3.5); (2) ecto-nucleotide kinases, adenylate kinase (EC 2.7.4.3) and nucleoside diphosphate kinase (EC 2.7.4.6); (3) ecto-adenosine deaminase (EC 3.5.4.4). Evidence for this was obtained by using enzyme assays with 3H-labelled nucleotides and adenosine as substrates, direct evaluation of γ-phosphate transfer from [γ-32P]ATP to AMP/NDP, and bioluminescent measurement of extracellular ATP synthesis. In addition, incorporation of radioactivity into an approx. 20kDa surface protein was observed following incubation of Namalwa B cells with [γ-32P]ATP. Thus two opposite, ATP-generating and ATP-consuming, pathways coexist on the cell surface, where basal ATP release, re-synthesis of high-energy phosphoryls, and selective ecto-protein phosphorylation are counteracted by stepwise nucleotide breakdown with subsequent adenosine inactivation. The comparative measurements of enzymic activities indicated the predominance of the nucleotide-inactivating pathway via ecto-nucleotidase reactions on the endothelial cells. The lymphocytes are characterized by counteracting ATP-regenerating/adenosine-eliminating phenotypes, thus allowing them to avoid the lymphotoxic effects of adenosine and maintain surrounding ATP at a steady-state level. These results are in agreement with divergent effects of ATP and adenosine on endothelial function and haemostasis, and provide a novel regulatory mechanism of local agonist availability for nucleotide- or nucleoside-selective receptors within the vasculature.
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Kasiviswanathan, Rajesh, Irina G. Minko, R. Stephen Lloyd, and William C. Copeland. "Translesion Synthesis Past Acrolein-derived DNA Adducts by Human Mitochondrial DNA Polymerase γ." Journal of Biological Chemistry 288, no. 20 (March 30, 2013): 14247–55. http://dx.doi.org/10.1074/jbc.m113.458802.
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Acrolein, a mutagenic aldehyde, is produced endogenously by lipid peroxidation and exogenously by combustion of organic materials, including tobacco products. Acrolein reacts with DNA bases forming exocyclic DNA adducts, such as γ-hydroxy-1,N2-propano-2′-deoxyguanosine (γ-HOPdG) and γ-hydroxy-1,N6-propano-2′-deoxyadenosine (γ-HOPdA). The bulky γ-HOPdG adduct blocks DNA synthesis by replicative polymerases but can be bypassed by translesion synthesis polymerases in the nucleus. Although acrolein-induced adducts are likely to be formed and persist in mitochondrial DNA, animal cell mitochondria lack specialized translesion DNA synthesis polymerases to tolerate these lesions. Thus, it is important to understand how pol γ, the sole mitochondrial DNA polymerase in human cells, acts on acrolein-adducted DNA. To address this question, we investigated the ability of pol γ to bypass the minor groove γ-HOPdG and major groove γ-HOPdA adducts using single nucleotide incorporation and primer extension analyses. The efficiency of pol γ-catalyzed bypass of γ-HOPdG was low, and surprisingly, pol γ preferred to incorporate purine nucleotides opposite the adduct. Pol γ also exhibited ∼2-fold lower rates of excision of the misincorporated purine nucleotides opposite γ-HOPdG compared with the corresponding nucleotides opposite dG. Extension of primers from the termini opposite γ-HOPdG was accomplished only following error-prone purine nucleotide incorporation. However, pol γ preferentially incorporated dT opposite the γ-HOPdA adduct and efficiently extended primers from the correctly paired terminus, indicating that γ-HOPdA is probably nonmutagenic. In summary, our data suggest that acrolein-induced exocyclic DNA lesions can be bypassed by mitochondrial DNA polymerase but, in the case of the minor groove γ-HOPdG adduct, at the cost of unprecedented high mutation rates.
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Rolfes, R. J. "Regulation of purine nucleotide biosynthesis: in yeast and beyond." Biochemical Society Transactions 34, no. 5 (October 1, 2006): 786–90. http://dx.doi.org/10.1042/bst0340786.
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Purine nucleotides are critically important for the normal functioning of cells due to their myriad of activities. It is important for cells to maintain a balance in the pool sizes of the adenine-containing and guanine-containing nucleotides, which occurs by a combination of de novo synthesis and salvage pathways that interconvert the purine nucleotides. This review describes the mechanism for regulation of the biosynthetic genes in the yeast Saccharomyces cerevisiae and compares this mechanism with that described in several microbial species.
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Jancso, Mario A., Susana A. Sculaccio, and Otavio H. Thiemann. "Identification of sugarcane genes involved in the purine synthesis pathway." Genetics and Molecular Biology 24, no. 1-4 (December 2001): 251–55. http://dx.doi.org/10.1590/s1415-47572001000100033.
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Nucleotide synthesis is of central importance to all cells. In most organisms, the purine nucleotides are synthesized de novo from non-nucleotide precursors such as amino acids, ammonia and carbon dioxide. An understanding of the enzymes involved in sugarcane purine synthesis opens the possibility of using these enzymes as targets for chemicals which may be effective in combating phytopathogen. Such an approach has already been applied to several parasites and types of cancer. The strategy described in this paper was applied to identify sugarcane clusters for each step of the de novo purine synthesis pathway. Representative sequences of this pathway were chosen from the National Center for Biotechnology Information (NCBI) database and used to search the translated sugarcane expressed sequence tag (SUCEST) database using the available basic local alignment search tool (BLAST) facility. Retrieved clusters were further tested for the statistical significance of the alignment by an implementation (PRSS3) of the Monte Carlo shuffling algorithm calibrated using known protein sequences of divergent taxa along the phylogenetic tree. The sequences were compared to each other and to the sugarcane clusters selected using BLAST analysis, with the resulting table of p-values indicating the degree of divergence of each enzyme within different taxa and in relation to the sugarcane clusters. The results obtained by this strategy allowed us to identify the sugarcane proteins participating in the purine synthesis pathway.
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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 (October 1, 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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KANDEEL, M., T. ANDO, Y. KITAMURA, M. ABDEL-AZIZ, and Y. KITADE. "Mutational, inhibitory and microcalorimetric analyses of Plasmodium falciparum TMP kinase. Implications for drug discovery." Parasitology 136, no. 1 (January 2009): 11–25. http://dx.doi.org/10.1017/s0031182008005301.
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SUMMARYPlasmodium falciparum thymidylate kinase (PfTMK) can tolerate a range of substrates, which distinguishes it from other thymidylate kinases. The enzyme not only phosphorylates TMP and dUMP but can also tolerate bulkier purines, namely, dGMP, GMP, and dIMP. In order to probe the flexibility of PfTMK in accommodating ligands of various sizes, we developed 6 mutant enzymes and subjected these to thermodynamic, inhibitory and catalytic evaluation. Kinase activity was markedly affected by introducing a larger lysine residue instead of A111. The lack of the hydroxyl group after inducing mutation of Y107F affected enzyme activity, and had a more severe impact on dGMP kinase activity. PfTMK can be inhibited by both purine and pyrimidine nucleosides, raising the possibility of developing highly selective drugs. Thermodynamic analysis revealed that enthalpic forces govern both purine and pyrimidine nucleoside monophosphate binding, and the binding affinity of both substrates was highly comparable. The heat produced due to dGMP binding is lower than that attributable to TMP. This indicates that additional interactions occur with TMP, which may be lost with larger dGMP. Targeting PfTMK not only affects thymidine nucleotide synthesis but may also affect purine nucleotides, and thus the enzyme represents an attractive antimicrobial target.
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Camici, Garcia-Gil, Pesi, Allegrini, and Tozzi. "Purine-Metabolising Enzymes and Apoptosis in Cancer." Cancers 11, no. 9 (September 12, 2019): 1354. http://dx.doi.org/10.3390/cancers11091354.
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The enzymes of both de novo and salvage pathways for purine nucleotide synthesis are regulated to meet the demand of nucleic acid precursors during proliferation. Among them, the salvage pathway enzymes seem to play the key role in replenishing the purine pool in dividing and tumour cells that require a greater amount of nucleotides. An imbalance in the purine pools is fundamental not only for preventing cell proliferation, but also, in many cases, to promote apoptosis. It is known that tumour cells harbour several mutations that might lead to defective apoptosis-inducing pathways, and this is probably at the basis of the initial expansion of the population of neoplastic cells. Therefore, knowledge of the molecular mechanisms that lead to apoptosis of tumoural cells is key to predicting the possible success of a drug treatment and planning more effective and focused therapies. In this review, we describe how the modulation of enzymes involved in purine metabolism in tumour cells may affect the apoptotic programme. The enzymes discussed are: ectosolic and cytosolic 5′-nucleotidases, purine nucleoside phosphorylase, adenosine deaminase, hypoxanthine-guanine phosphoribosyltransferase, and inosine-5′-monophosphate dehydrogenase, as well as recently described enzymes particularly expressed in tumour cells, such as deoxynucleoside triphosphate triphosphohydrolase and 7,8-dihydro-8-oxoguanine triphosphatase.
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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 (March 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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Rowe, Peter B., and Annette Kalaizis. "Serine metabolism in rat embryos undergoing organogenesis." Development 87, no. 1 (June 1, 1985): 137–44. http://dx.doi.org/10.1242/dev.87.1.137.
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Rat embryos (9·5 days gestation) were cultured for 48 h in heat-inactivated homologous serum containing [3-14C] serine. Analysis of the distribution of the radioactive label in the conceptus demonstrated that almost one half of the incorporated serine was cleaved to provide one-carbon units for the synthesis of purine and pyrimidine nucleotides. Analysis of the free amino acids in the serum, the exocoelomic fluid and the cells of the yolk sac and the embryo showed that there was a variably selective increase in the concentration of amino acids in the exocoelomic fluid compared with the serum and a significant decrease in the specific radioactivity of the free serine within the conceptus which was the highest in the yolk sac and lowest in the embryo. These findings would support the concept of yolk sac lysosomal degradation of medium serum protein as a major source of amino acids supplying almost 86 % of that required during this phase of embryonic development. The specific radioactivity of purine bases in cellular nucleotides, RNA and DNA was similar to that of the free serine in both yolk sac and embryo. This indicated that an alternative, as yet unidentified source of one-carbon units was available for purine nucleotide biosynthesis. Analysis of the cellular purine nucleotides revealed low ATP/GTP ratios in both the embryo and its yolk sac and this may be related to the undifferentiated state of many of the cells of the conceptus.
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Becker, M. A., and M. Kim. "Regulation of purine synthesis de novo in human fibroblasts by purine nucleotides and phosphoribosylpyrophosphate." Journal of Biological Chemistry 262, no. 30 (October 1987): 14531–37. http://dx.doi.org/10.1016/s0021-9258(18)47828-3.
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Hocek, Michal, Milena Masojídková, Antonín Holý, Graciela Andrei, Robert Snoeck, Jan Balzarini, and Erik De Clercq. "Synthesis and Antiviral Activity of Acyclic Nucleotide Analogues Derived from 6-(Aminomethyl)purines and Purine-6-carboxamidines." Collection of Czechoslovak Chemical Communications 61, no. 10 (1996): 1525–37. http://dx.doi.org/10.1135/cccc19961525.
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The synthesis of a series of 9-(2-phosphonomethoxyalkyl) derivatives of 6-(aminomethyl)purine 11, 2-amino-6-(aminomethyl)purine 12 and purine-6-carboxamidine 14 is reported. The 6-cyanopurines 1 and 2 were selectively alkylated with 2-[bis(isopropyloxy)phosphonylmethoxy]alkyl synthons 3 and 4 at the 9-position. Catalytic hydrogenation of the obtained 9-{2-[bis(isopropyloxy)phosphonylmethoxy]alkyl}-6-cyanopurines 9 and 10 followed by treatment with bromotrimethylsilane afforded the title compounds 11 and 12. Analogous acyclic nucleotides derived from purine-6-carboxamidines 14 were prepared from the cyanopurines 9a and 10a by treatment with sodium methoxide and ammonium chloride followed by deprotection. Compounds 11 and 12 exhibited moderate activity (MIC50 = 3-50 μg/ml) against herpes simplex virus type 1, varicella-zoster virus and Moloney murine sarcoma virus in vitro.
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Suresh, R. Rama, Russell B. Poe, Baorui Lin, Kexin Lv, Ryan G. Campbell, Zhan-Guo Gao, Theodore E. Liston, Kiran S. Toti, and Kenneth A. Jacobson. "Convergent synthesis of 2-thioether-substituted (N)-methanocarba-adenosines as purine receptor agonists." RSC Advances 11, no. 44 (2021): 27369–80. http://dx.doi.org/10.1039/d1ra05096f.
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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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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 (April 1, 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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Pawlowic, Mattie C., Mastanbabu Somepalli, Adam Sateriale, Gillian T. Herbert, Alexis R. Gibson, Gregory D. Cuny, Lizbeth Hedstrom, and Boris Striepen. "Genetic ablation of purine salvage in Cryptosporidium parvum reveals nucleotide uptake from the host cell." Proceedings of the National Academy of Sciences 116, no. 42 (September 30, 2019): 21160–65. http://dx.doi.org/10.1073/pnas.1908239116.
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The apicomplexan parasite Cryptosporidium is a leading global cause of severe diarrheal disease and an important contributor to early-childhood mortality. Waterborne outbreaks occur frequently, even in countries with advanced water treatment capabilities, and there is currently no fully effective treatment. Nucleotide pathways are attractive targets for antimicrobial development, and several laboratories are designing inhibitors of these enzymes as potential treatment for Cryptosporidium infections. Here we take advantage of newly available molecular genetics for Cryptosporidium parvum to investigate nucleotide biosynthesis by directed gene ablation. Surprisingly, we found that the parasite tolerates the loss of classical targets including dihydrofolate reductase-thymidylate synthase (DHFR-TS) and inosine monophosphate dehydrogenase (IMPDH). We show that thymidine kinase provides a route to thymidine monophosphate in the absence of DHFR-TS. In contrast, only a single pathway has been identified for C. parvum purine nucleotide salvage. Nonetheless, multiple enzymes in the purine pathway, as well as the adenosine transporter, can be ablated. The resulting mutants are viable under normal conditions but are hypersensitive to inhibition of purine nucleotide synthesis in their host cell. Cryptosporidium might use as-yet undiscovered purine transporters and salvage enzymes; however, genetic and pharmacological experiments led us to conclude that Cryptosporidium imports purine nucleotides from the host cell. The potential for ATP uptake from the host has significant impact on our understanding of parasite energy metabolism given that Cryptosporidium lacks oxidative phosphorylation and glycolytic enzymes are not constitutively expressed throughout the parasite life cycle.
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Garcia-Gil, Mercedes, Marcella Camici, Simone Allegrini, Rossana Pesi, Edoardo Petrotto, and Maria Tozzi. "Emerging Role of Purine Metabolizing Enzymes in Brain Function and Tumors." International Journal of Molecular Sciences 19, no. 11 (November 14, 2018): 3598. http://dx.doi.org/10.3390/ijms19113598.
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The growing evidence of the involvement of purine compounds in signaling, of nucleotide imbalance in tumorigenesis, the discovery of purinosome and its regulation, cast new light on purine metabolism, indicating that well known biochemical pathways may still surprise. Adenosine deaminase is important not only to preserve functionality of immune system but also to ensure a correct development and function of central nervous system, probably because its activity regulates the extracellular concentration of adenosine and therefore its function in brain. A lot of work has been done on extracellular 5′-nucleotidase and its involvement in the purinergic signaling, but also intracellular nucleotidases, which regulate the purine nucleotide homeostasis, play unexpected roles, not only in tumorigenesis but also in brain function. Hypoxanthine guanine phosphoribosyl transferase (HPRT) appears to have a role in the purinosome formation and, therefore, in the regulation of purine synthesis rate during cell cycle with implications in brain development and tumors. The final product of purine catabolism, uric acid, also plays a recently highlighted novel role. In this review, we discuss the molecular mechanisms underlying the pathological manifestations of purine dysmetabolisms, focusing on the newly described/hypothesized roles of cytosolic 5′-nucleotidase II, adenosine kinase, adenosine deaminase, HPRT, and xanthine oxidase.
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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 (July 26, 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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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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Kore, Anilkumar, Bo Yang, and Balasubramanian Srinivasan. "Recent Developments in the Synthesis of Substituted Purine Nucleosides and Nucleotides." Current Organic Chemistry 18, no. 16 (July 14, 2014): 2072–107. http://dx.doi.org/10.2174/1385272819666140714174457.
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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 (March 1, 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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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 (October 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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Andriotis, Vasilios M. E., and Alison M. Smith. "The plastidial pentose phosphate pathway is essential for postglobular embryo development in Arabidopsis." Proceedings of the National Academy of Sciences 116, no. 30 (July 11, 2019): 15297–306. http://dx.doi.org/10.1073/pnas.1908556116.
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Large numbers of genes essential for embryogenesis in Arabidopsis encode enzymes of plastidial metabolism. Disruption of many of these genes results in embryo arrest at the globular stage of development. However, the cause of lethality is obscure. We examined the role of the plastidial oxidative pentose phosphate pathway (OPPP) in embryo development. In nonphotosynthetic plastids the OPPP produces reductant and metabolic intermediates for central biosynthetic processes. Embryos with defects in various steps in the oxidative part of the OPPP had cell division defects and arrested at the globular stage, revealing an absolute requirement for the production via these steps of ribulose-5-phosphate. In the nonoxidative part of the OPPP, ribulose-5-phosphate is converted to ribose-5-phosphate (R5P)—required for purine nucleotide and histidine synthesis—and subsequently to erythrose-4-phosphate, which is required for synthesis of aromatic amino acids. We show that embryo development through the globular stage specifically requires synthesis of R5P rather than erythrose-4-phosphate. Either a failure to convert ribulose-5-phosphate to R5P or a block in purine nucleotide biosynthesis beyond R5P perturbs normal patterning of the embryo, disrupts endosperm development, and causes early developmental arrest. We suggest that seed abortion in mutants unable to synthesize R5P via the oxidative part of the OPPP stems from a lack of substrate for synthesis of purine nucleotides, and hence nucleic acids. Our results show that the plastidial OPPP is essential for normal developmental progression as well as for growth in the embryo.
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Jakubowski, H., and E. Goldman. "Evidence for cooperation between cells during sporulation of the yeast Saccharomyces cerevisiae." Molecular and Cellular Biology 8, no. 12 (December 1988): 5166–78. http://dx.doi.org/10.1128/mcb.8.12.5166.
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Diploid Saccharomyces cerevisiae cells heterozygous for the mating type locus (MATa/MAT alpha) undergo meiosis and sporulation when starved for nitrogen in the presence of a poor carbon source such as potassium acetate. Diploid yeast adenine auxotrophs sporulated well at high cell density (10(7) cells per ml) under these conditions but failed to differentiate at low cell density (10(5) cells per ml). The conditional sporulation-deficient phenotype of adenine auxotrophs could be complemented by wild-type yeast cells, by medium from cultures that sporulate at high cell density, or by exogenously added adenine (or hypoxanthine with some mutants). Adenine and hypoxanthine in addition to guanine, adenosine, and numerous nucleotides were secreted into the medium, each in its unique temporal pattern, by sporulating auxotrophic and prototrophic yeast strains. The major source of these compounds was degradation of RNA. The data indicated that differentiating yeast cells cooperate during sporulation in maintaining sufficiently high concentrations of extracellular purines which are absolutely required for sporulation of adenine auxotrophs. Yeast prototrophs, which also sporulated less efficiently at low cell density (10(3) cells per ml), reutilized secreted purines in preference to de novo-made purine nucleotides whose synthesis was in fact inhibited during sporulation at high cell density. Adenine enhanced sporulation of yeast prototrophs at low cell density. The behavior of adenine auxotrophs bearing additional mutations in purine salvage pathway genes (ade apt1, ade aah1 apt1, ade hpt1) supports a model in which secretion of degradation products, uptake, and reutilization of these products is a signal between cells synchronizing the sporulation process.
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Jakubowski, H., and E. Goldman. "Evidence for cooperation between cells during sporulation of the yeast Saccharomyces cerevisiae." Molecular and Cellular Biology 8, no. 12 (December 1988): 5166–78. http://dx.doi.org/10.1128/mcb.8.12.5166-5178.1988.
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Diploid Saccharomyces cerevisiae cells heterozygous for the mating type locus (MATa/MAT alpha) undergo meiosis and sporulation when starved for nitrogen in the presence of a poor carbon source such as potassium acetate. Diploid yeast adenine auxotrophs sporulated well at high cell density (10(7) cells per ml) under these conditions but failed to differentiate at low cell density (10(5) cells per ml). The conditional sporulation-deficient phenotype of adenine auxotrophs could be complemented by wild-type yeast cells, by medium from cultures that sporulate at high cell density, or by exogenously added adenine (or hypoxanthine with some mutants). Adenine and hypoxanthine in addition to guanine, adenosine, and numerous nucleotides were secreted into the medium, each in its unique temporal pattern, by sporulating auxotrophic and prototrophic yeast strains. The major source of these compounds was degradation of RNA. The data indicated that differentiating yeast cells cooperate during sporulation in maintaining sufficiently high concentrations of extracellular purines which are absolutely required for sporulation of adenine auxotrophs. Yeast prototrophs, which also sporulated less efficiently at low cell density (10(3) cells per ml), reutilized secreted purines in preference to de novo-made purine nucleotides whose synthesis was in fact inhibited during sporulation at high cell density. Adenine enhanced sporulation of yeast prototrophs at low cell density. The behavior of adenine auxotrophs bearing additional mutations in purine salvage pathway genes (ade apt1, ade aah1 apt1, ade hpt1) supports a model in which secretion of degradation products, uptake, and reutilization of these products is a signal between cells synchronizing the sporulation process.
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Suzuki, Ichirou, Sadao Kato, Tokuzou Kitada, Nobuhiro Yano, and Toshiki Morichi. "Growth of Lactobacillus bulgaricus in Milk. 2. Characteristics of Purine Nucleotides, Pyrimidine Nucleotides, and Nucleic Acid Synthesis." Journal of Dairy Science 69, no. 4 (April 1986): 971–78. http://dx.doi.org/10.3168/jds.s0022-0302(86)80490-8.
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Lecoq, Karine, Manfred Konrad, and Bertrand Daignan-Fornier. "Yeast GMP Kinase Mutants Constitutively Express AMP Biosynthesis Genes by Phenocopying a Hypoxanthine-Guanine Phosphoribosyltransferase Defect." Genetics 156, no. 3 (November 1, 2000): 953–61. http://dx.doi.org/10.1093/genetics/156.3.953.
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Abstract We have characterized a new locus, BRA3, leading to deregulation of the yeast purine synthesis genes (ADE genes). We show that bra3 mutations are alleles of the GUK1 gene, which encodes GMP kinase. The bra3 mutants have a low GMP kinase activity, excrete purines in the medium, and show vegetative growth defects and resistance to purine base analogs. The bra3 locus also corresponds to the previously described pur5 locus. Several lines of evidence indicate that the decrease in GMP kinase activity in the bra3 mutants results in GMP accumulation and feedback inhibition of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), encoded by the HPT1 gene. First, guk1 and hpt1 mutants share several phenotypes, such as adenine derepression, purine excretion, and 8-azaguanine resistance. Second, overexpression of HPT1 allows suppression of the deregulated phenotype of the guk1 mutants. Third, we show that purified yeast HGPRT is inhibited by GMP in vitro. Finally, incorporation of hypoxanthine into nucleotides is similarly diminished in hpt1 and guk1 mutants in vivo. We conclude that the decrease in GMP kinase activity in the guk1 mutants results in deregulation of the ADE gene expression by phenocopying a defect in HGPRT. The possible occurrence of a similar phenomenon in humans is discussed.
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Alexiou, M., and H. J. Leese. "Purine utilisation, de novo synthesis and degradation in mouse preimplantation embryos." Development 114, no. 1 (January 1, 1992): 185–92. http://dx.doi.org/10.1242/dev.114.1.185.
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The importance of de novo purine synthesis as opposed to the reutilisation of metabolites by salvage pathways, and the nature of the excretory product(s) of purine degradation, have been examined in cultured preimplantation mouse embryos. In the presence of azaserine and mycophenolic acid, which inhibit de novo purine synthesis, embryo cleavage was blocked prior to compaction, the precise stages at which this occurred depended on whether the cultures were established on day 1 or day 2 after fertilisation, and indicated that salvage pathways were insufficient to fulfil the demand for nucleotides during early preimplantation development. The end-product of purine degradation appeared to be xanthine, which was excreted in very small amounts on days 1, 2 and 3, with a pronounced rise from the early to late blastocyst. Uric acid formation or excretion could not be detected. Exogenous hypoxanthine and adenine, which partially inhibited development, were taken up by the embryos and converted to xanthine, most probably by salvage pathways, since the enzyme xanthine oxidase, which converts hypoxanthine directly to xanthine and then to uric acid, could not be detected. Exogenous guanine had little effect on development and was also converted to xanthine, but in this case, the conversion was probably in a single step, via the enzyme guanase.
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Naffouje, Grover, Yu, Sendilnathan, Wolfe, Majd, Smith, et al. "Anti-Tumor Potential of IMP Dehydrogenase Inhibitors: A Century-Long Story." Cancers 11, no. 9 (September 11, 2019): 1346. http://dx.doi.org/10.3390/cancers11091346.
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The purine nucleotides ATP and GTP are essential precursors to DNA and RNA synthesis and fundamental for energy metabolism. Although de novo purine nucleotide biosynthesis is increased in highly proliferating cells, such as malignant tumors, it is not clear if this is merely a secondary manifestation of increased cell proliferation. Suggestive of a direct causative effect includes evidence that, in some cancer types, the rate-limiting enzyme in de novo GTP biosynthesis, inosine monophosphate dehydrogenase (IMPDH), is upregulated and that the IMPDH inhibitor, mycophenolic acid (MPA), possesses anti-tumor activity. However, historically, enthusiasm for employing IMPDH inhibitors in cancer treatment has been mitigated by their adverse effects at high treatment doses and variable response. Recent advances in our understanding of the mechanistic role of IMPDH in tumorigenesis and cancer progression, as well as the development of IMPDH inhibitors with selective actions on GTP synthesis, have prompted a reappraisal of targeting this enzyme for anti-cancer treatment. In this review, we summarize the history of IMPDH inhibitors, the development of new inhibitors as anti-cancer drugs, and future directions and strategies to overcome existing challenges.
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Hernández-Muñoz, Rolando, and Victoria Chagoya de Sánchez. "In vivo correlation between liver and blood energy status as evidenced by chronic treatment of carbon tetrachloride and adenosine to rats." Canadian Journal of Physiology and Pharmacology 72, no. 10 (October 1, 1994): 1252–56. http://dx.doi.org/10.1139/y94-178.
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Several tissues, such as red blood cells, depend on the liver supply of the purine ring for adenine nucleotide synthesis. We explored whether progressive liver damage, induced by carbon tetrachloride (CCl4), is accompanied by alterations in liver and blood energy status. After 4 weeks of CCl4 treatment, liver ATP, ATP/ADP, and energy status were decreased. Blood ATP remained normal, whereas the blood energy status was also diminished. After 8 weeks the changes were more evident, and a significant decrease of total liver nucleotides was also found. In the blood, the changes paralleled those in the liver. Simultaneous administration of adenosine counteracted the CCl4 effects. A good correlation (r = 0.79, p < 0.01) between the liver and blood ATP changes and a very significant relationship between liver and blood ATP/ADP ratio (r = 0.92, p < 0.001) were observed. Therefore, the data suggest that liver function could influence the energy availability in other tissues, such as red blood cells, perhaps as a result of its capacity to provide purine rings for extrahepatic synthesis of adenine nucleotides.Key words: liver–blood ATP interrelationship, cirrhotic rats, carbon tetrachloride, energy parameters, adenosine.
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Kore, Anilkumar R., Bo Yang, and Balasubramanian Srinivasan. "ChemInform Abstract: Recent Developments in the Synthesis of Substituted Purine Nucleosides and Nucleotides." ChemInform 46, no. 2 (December 19, 2014): no. http://dx.doi.org/10.1002/chin.201502258.
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Ravid, Katy, Paula Diamant, and Yoram Avi-Dor. "Interrelation between salvage of purine nucleotides and protein synthesis in rat heart cells." Archives of Biochemistry and Biophysics 236, no. 1 (January 1985): 159–66. http://dx.doi.org/10.1016/0003-9861(85)90615-0.
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Pareek, Vidhi, Hua Tian, Nicholas Winograd, and Stephen J. Benkovic. "Metabolomics and mass spectrometry imaging reveal channeled de novo purine synthesis in cells." Science 368, no. 6488 (April 16, 2020): 283–90. http://dx.doi.org/10.1126/science.aaz6465.
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Metabolons, multiprotein complexes consisting of sequential enzymes of a metabolic pathway, are proposed to be biosynthetic “hotspots” within the cell. However, experimental demonstration of their presence and functions has remained challenging. We used metabolomics and in situ three-dimensional submicrometer chemical imaging of single cells by gas cluster ion beam secondary ion mass spectrometry (GCIB-SIMS) to directly visualize de novo purine biosynthesis by a multienzyme complex, the purinosome. We found that purinosomes comprise nine enzymes that act synergistically, channeling the pathway intermediates to synthesize purine nucleotides, increasing the pathway flux, and influencing the adenosine monophosphate/guanosine monophosphate ratio. Our work also highlights the application of high-resolution GCIB-SIMS for multiplexed biomolecular analysis at the level of single cells.
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Aronov, Alex M., Narsimha R. Munagala, Irwin D. Kuntz, and Ching C. Wang. "Virtual Screening of Combinatorial Libraries across a Gene Family: in Search of Inhibitors of Giardia lamblia Guanine Phosphoribosyltransferase." Antimicrobial Agents and Chemotherapy 45, no. 9 (September 1, 2001): 2571–76. http://dx.doi.org/10.1128/aac.45.9.2571-2576.2001.
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ABSTRACT Parasitic protozoa lack the ability to synthesize purine nucleotides de novo, relying instead on purine salvage enzymes for their survival. Guanine phosphoribosyltransferase (GPRT) from the protozoan parasite Giardia lamblia is a potential target for rational antiparasitic drug design, based on the experimental evidence, which indicates the lack of interconversion between adenine and guanine nucleotide pools. The present study is a continuation of our efforts to use three-dimensional structures of parasitic phosphoribosyltransferases (PRTs) to design novel antiparasitic agents. Two micromolar phthalimide-based GPRT inhibitors were identified by screening the in-house phthalimide library. A combination of structure-based scaffold selection using virtual library screening across the PRT gene family and solid phase library synthesis led to identification of smaller (molecular weight, <300) ligands with moderate to low specificity for GPRT; the best inhibitors, GP3 and GP5, had K i values in the 23 to 25 μM range. These results represent significant progress toward the goal of designing potent inhibitors of purine salvage inGiardia parasites. As a second step in this process, altering the phthalimide moiety to optimize interactions in the guanine-binding pocket of GPRT is expected to lead to compounds with promising activity against G. lamblia PRT.
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Cai, Zhaohui, T. Jake Liang, and Guangxiang Luo. "Effects of Mutations of the Initiation Nucleotides on Hepatitis C Virus RNA Replication in the Cell." Journal of Virology 78, no. 7 (April 1, 2004): 3633–43. http://dx.doi.org/10.1128/jvi.78.7.3633-3643.2004.
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ABSTRACT Replication of nearly all RNA viruses depends on a virus-encoded RNA-dependent RNA polymerase (RdRp). Our earlier work found that purified recombinant hepatitis C virus (HCV) RdRp (NS5B) was able to initiate RNA synthesis de novo by using purine (A and G) but not pyrimidine (C and U) nucleotides (G. Luo et al., J. Virol. 74:851-863, 2000). For most human RNA viruses, the initiation nucleotides of both positive- and negative-strand RNAs were found to be either an adenylate (A) or guanylate (G). To determine the nucleotide used for initiation and control of HCV RNA replication, a genetic mutagenesis analysis of the nucleotides at the very 5′ and 3′ ends of HCV RNAs was performed by using a cell-based HCV replicon replication system. Either a G or an A at the 5′ end of HCV genomic RNA was able to efficiently induce cell colony formation, whereas a nucleotide C at the 5′ end dramatically reduced the efficiency of cell colony formation. Likewise, the 3′-end nucleotide U-to-C mutation did not significantly affect the efficiency of cell colony formation. In contrast, a U-to-G mutation at the 3′ end caused a remarkable decrease in cell colony formation, and a U-to-A mutation resulted in a complete abolition of cell colony formation. Sequence analysis of the HCV replicon RNAs recovered from G418-resistant Huh7 cells revealed several interesting findings. First, the 5′-end nucleotide G of the replicon RNA was changed to an A upon multiple rounds of replication. Second, the nucleotide A at the 5′ end was stably maintained among all replicon RNAs isolated from Huh7 cells transfected with an RNA with a 5′-end A. Third, initiation of HCV RNA replication with a CTP resulted in a >10-fold reduction in the levels of HCV RNAs, suggesting that initiation of RNA replication with CTP was very inefficient. Fourth, the 3′-end nucleotide U-to-C and -G mutations were all reverted back to a wild-type nucleotide U. In addition, extra U and UU residues were identified at the 3′ ends of revertants recovered from Huh7 cells transfected with an RNA with a nucleotide G at the 3′ end. We also determined the 5′-end nucleotide of positive-strand RNA of some clinical HCV isolates. Either G or A was identified at the 5′ end of HCV RNA genome depending on the specific HCV isolate. Collectively, these findings demonstrate that replication of positive-strand HCV RNA was preferentially initiated with purine nucleotides (ATP and GTP), whereas the negative-strand HCV RNA replication is invariably initiated with an ATP.
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Mannix, R. J., T. Moatter, K. A. Kelley, and M. E. Gerritsen. "Cellular signaling responses mediated by a novel nucleotide receptor in rabbit microvessel endothelium." American Journal of Physiology-Heart and Circulatory Physiology 265, no. 2 (August 1, 1993): H675—H680. http://dx.doi.org/10.1152/ajpheart.1993.265.2.h675.
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The adenine nucleotide, ATP, elicits an elevation in intracellular ionized calcium concentration ([Ca2+]i) and phospholipase C-mediated phosphatidylinositol hydrolysis and stimulates the synthesis of the prostaglandins E2 and I2 in cultured endothelial cells derived from rabbit cardiac muscle. Use of various ATP analogues indicated that these events did not fit the classical definition of P1 or P2 purinergic receptors and, furthermore, indicated that the receptor(s) mediating these activities was not specific for purines. The rank order of agonist potency on prostaglandin release, elevations in [Ca2+]i, and inositol phosphate response was UTP > or = ATP > ADP > ADP[beta]S = 2-methylthio ATP > adenosine, suggesting that these three cellular responses are coupled to the same or similar receptors. However, the sensitivity of these three cellular responses to added nucleotides was somewhat different. The half-maximum effective concentration (EC50) for ATP stimulation of prostaglandin release was 100 microM, for inositol phosphate turnover it was 25 microM, and for elevations in [Ca2+]i it was < 1 microM. Similar discrepancies in EC50 UTP values for these three cellular responses were also noted. These observations indicate that purine and pyrimidine nucleotides elicit at least three cellular responses in rabbit cardiac muscle microvessel endothelial cells, all demonstrating similar rank orders of potency. However, the differences in EC50 suggest that if these responses are mediated by a single receptor type, it exhibits divergent coupling to various cellular signaling pathways.
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Tullson, P. C., and R. L. Terjung. "Adenine nucleotide synthesis in exercising and endurance-trained skeletal muscle." American Journal of Physiology-Cell Physiology 261, no. 2 (August 1, 1991): C342—C347. http://dx.doi.org/10.1152/ajpcell.1991.261.2.c342.
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Strenuous exercise leads to increased efflux of purine nucleoside and base that should necessitate recovery of adenine nucleotides by either the de novo synthesis or salvage pathway. De novo synthesis of adenine nucleotide was measured in quiescent and contracting muscle of sedentary and exercise-trained rats using an isolated perfused hindquarter preparation. Synthesis rates were assessed by measuring the incorporation of [1-14C]glycine into adenine nucleotide in muscles of both resting and stimulated hindlimbs after 1 h of either low- or high-energy demand isometric contractions. In nonstimulated sedentary and trained muscles, rates of de novo synthesis were similar. The effect of muscle contractions on de novo synthesis varied among muscle fiber types. Contracting, nonfatigued fast-twitch muscle sections showed significant declines in de novo synthesis in both sedentary and trained groups. Rates in slow-twitch red fibers and fatigued fast-twitch white fiber sections were not different from rest. Supplementing the perfusate with 5 mM ribose caused de novo synthesis to rise three- to fourfold in each of the fiber sections. However, the response in synthesis rates due to exercise was similar with or without ribose supplementation. De novo synthesis does not increase during exercise but exhibits an unchanged or reduced rate depending on the expected energy balance within the cell. This would occur if the energy state of muscle exerts significant control over de novo synthesis of adenine nucleotide.
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Hrinczenko, Borys. "Metabolic Profiling in Sickle Cell Disease." Blood 118, no. 21 (November 18, 2011): 4837. http://dx.doi.org/10.1182/blood.v118.21.4837.4837.
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Abstract Abstract 4837 Sickle cell disease (SCD) is a genetic blood disorder of hemoglobin with patients (pts) suffering from multiple complications. Patients are exposed to the clinical consequences of a hemolytic anemia associated with episodes of vascular vaso-occlusion. Lifelong episodes of painful crises lead to end-organ damage with shortened lifespan. The mutated hemoglobin S in the red cell polymerizes during hypoxia (venous circulation) leading to tissue inflammation and ischemia. The FDA approved drug hydroxyurea used to treat SCD increases fetal hemoglobin production thereby inhibiting hemoglobin S polymerization. Hydroxyurea therapy has been shown to improve morbidity and mortality in SCD patients. The metabolic demands of SCD patients are increased due to chronic hemolysis. The dietary supplement folic acid is recommended to meet some of the excess metabolic requirements. However, metabolic pathways associated with SCD are poorly understood or even explored. The components of the purine nucleotide synthetic pathway were analyzed in the serum of adult SCD patients in steady state. Purine nucleotides are made available for cells via two routes, either by de novo synthesis or by reusing of catabolized purine bases, mainly hypoxanthine. Salvaging the purine ring is more efficient in terms of ATP equivalents than de novo purine synthesis. Xanthine oxidase catalyzes the final reactions of the purine catabolism by consecutive oxidation of hypoxanthine to xanthine to uric acid. Levels of hypoxanthine, xanthine, uric acid as well as xanthine oxidase enzymatic activity (μU/mL) were evaluated in (1) SCD patients (n=5-9), (2) in SCD patients treated with hydroxyurea (n=5-9), and (3) normal adult controls (n=12). Hypoxanthine (μM), xanthine (μM) and uric acid (μM) levels all showed statistically significant (p<0.05) elevations in SCD patients when compared to controls; 14 ± 1 vs. 5 ± 1, 66 ± 8 vs. 22 ± 5, 1142 ± 60 vs. 735 ± 33, respectively. Xanthine oxidase enzymatic activity (μU/mL) also showed statistically significant (p<0.05) increases in SCD pts of 4.3 ± 1.1 vs. 0.9 ± 0.3 when compared to controls. However, SCD pts treated with hydroxyurea showed a statistically significant (p<0.05) drop of hypoxanthine, xanthine, and uric acid levels and also xanthine oxidase activity when compared to SCD pts; 8 ± 1 vs. 14 ± 1, 38 ± 5 vs. 66 ± 8, 780 ± 88 vs. 1142 ± 60, respectively. Furthermore, the hypoxanthine, xanthine, and uric acid levels and xanthine oxidase activity of SCD pts who were taking hydroxyurea were not statistically different from controls. Since levels of hypoxanthine, xanthine, and uric acid were all elevated in SCD pts this suggests that the nucleotide synthetic pathway may not have switched to the more efficient salvage pathway, as would be expected if the uric acid level were low or normal. Furthermore, an unexpected added benefit of hydroxyurea therapy may include down regulation of the overactive purine nucleotide synthetic pathway in SCD pts. The significant increase of purine related compounds such as hypoxanthine and xanthine without a decrease in uric acid suggest that metabolically active cells are not shunting purine bases to the more efficient salvage pathway for synthesis of nucleic acids and higher energy needs. The high proliferate erythropoietic turnover rate of chronic hemolysis requires large quantities of purine bases for transmission of ATP and synthesis of nucleic acids. The metabolic changes in SCD suggest that there is an ineffectual shunting of purine bases to the more efficient salvage pathway. Hydroxyurea therapy may allow for shunting to the more energy efficient salvage pathway resulting in less total body metabolic expenditure. Alternatively, hydroxyurea as a ribonucleotide reductase inhibitor decreases hematopoietic cell turnover which may lead to less purine metabolic requirements. Future metabolic studies will explore this and identify other important pathways for potential therapeutic intervention in SCD. Disclosures: No relevant conflicts of interest to declare.
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Moffatt, Barbara A., and Hiroshi Ashihara. "Purine and Pyrimidine Nucleotide Synthesis and Metabolism." Arabidopsis Book 1 (January 2002): e0018. http://dx.doi.org/10.1199/tab.0018.
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Rotllán, P., and M. T. Miras-Portugal. "Purine Nucleotide Synthesis in Adrenal Chromaffin Cells." Journal of Neurochemistry 44, no. 4 (April 1985): 1029–36. http://dx.doi.org/10.1111/j.1471-4159.1985.tb08721.x.
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REVANKAR, G. R., and R. K. ROBINS. "ChemInform Abstract: The Synthesis and Chemistry of Heterocyclic Analogs of Purine Nucleosides and Nucleotides." ChemInform 23, no. 11 (August 22, 2010): no. http://dx.doi.org/10.1002/chin.199211303.
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Nandasoma, Udvitha, Christopher McCormick, Stephen Griffin, and Mark Harris. "Nucleotide requirements at positions +1 to +4 for the initiation of hepatitis C virus positive-strand RNA synthesis." Journal of General Virology 92, no. 5 (May 1, 2011): 1082–86. http://dx.doi.org/10.1099/vir.0.028423-0.
Full textAbstract:
RNA virus genome replication requires initiation at the precise terminus of the template RNA. To investigate the nucleotide requirements for initiation of hepatitis C virus (HCV) positive-strand RNA replication, a hammerhead ribozyme was inserted at the 5′ end of an HCV subgenomic replicon, allowing the generation of replicons with all four possible nucleotides at position 1. This analysis revealed a preference for a purine nucleotide at this position for initiation of RNA replication. The sequence requirements at positions 2–4 in the context of the J6/JFH-1 virus were also examined by selecting replication-competent virus from a pool containing randomized residues at these positions. There was strong selection for both the wild-type cytosine at position 2, and the wild-type sequence at positions 2–4 (CCU). An adenine residue was well tolerated at positions 3 and 4, which suggests that efficient RNA replication is less dependent on these residues.