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1
Nerkar, A. G., S. A. Ghone, and A. K. Thaker. "In SilicoScreening of the Library of Pyrimidine Derivatives as Thymidylate Synthase Inhibitors for Anticancer Activity." E-Journal of Chemistry 6, no. 3 (2009): 665–72. http://dx.doi.org/10.1155/2009/352717.
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We here report the virtual screening of several series of pyrimidine derivatives forin silicoThymidylate Synthase (TS) inhibition to arrive at possible potential inhibitors of TS with acceptable pharmacokinetic or ADME (Absorption, Distribution, Metabolism and Excretion) properties. Library of the molecules was constructed based upon structural modifications of pyrimidines nucleus. Structural modifications in descending order were performed for the series of pyrimidines,vizfrom pyrimidines with five membered heterocyclic ring to pyrimidines with four membered heterocyclic ring to simple pyrimindine carboxylates in an order to arrive at pyrimidines with better inhibition scores (G-Scores) as compared with Raltitrexed (RTX) and active metabolite of 5-Fluorouracil (5-FUMP). The molecules with betterG-Scores were subjected to predict pharmacokinetic or ADME properties. The molecules with acceptable ADME properties and betterG-Scores were prioritized for synthesis and anticancer evaluation. Three molecules from pyrimidine carboxylate series PIC1-31were found acceptable withG-Scores and pharmacokinetic properties. Thus a library of pyrimidine derivatives was constructed based upon the feasibility of synthesis and in silico screened to prioritize the molecules and to obtain potential lead molecules as TS inhibitors.
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Stentoft, Charlotte, Betina Amdisen Røjen, Søren Krogh Jensen, Niels B. Kristensen, Mogens Vestergaard, and Mogens Larsen. "Absorption and intermediary metabolism of purines and pyrimidines in lactating dairy cows." British Journal of Nutrition 113, no. 4 (January 26, 2015): 560–73. http://dx.doi.org/10.1017/s0007114514004000.
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About 20 % of ruminal microbial N in dairy cows derives from purines and pyrimidines; however, their intermediary metabolism and contribution to the overall N metabolism has sparsely been described. In the present study, the postprandial patterns of net portal-drained viscera (PDV) and hepatic metabolism were assessed to evaluate purine and pyrimidine N in dairy cows. Blood was sampled simultaneously from four veins with eight hourly samples from four multi-catheterised Holstein cows. Quantification of twenty purines and pyrimidines was performed with HPLC–MS/MS, and net fluxes were estimated across the PDV, hepatic tissue and total splanchnic tissue (TSP). Concentration differences between veins of fifteen purine and pyrimidine nucleosides (NS), bases (BS) and degradation products (DP) were different from zero (P≤ 0·05), resulting in the net PDV releases of purine NS (0·33–1·3 mmol/h), purine BS (0·0023–0·018 mmol/h), purine DP (7·0–7·8 mmol/h), pyrimidine NS (0·30–2·8 mmol/h) and pyrimidine DP (0·047–0·77 mmol/h). The hepatic removal of purine and pyrimidine was almost equivalent to the net PDV release, resulting in no net TSP release. One exception was uric acid (7·9 mmol/h) from which a large net TSP release originated from the degradation of purine NS and BS. A small net TSP release of the pyrimidine DP β-alanine and β-aminoisobutyric acid ( − 0·032 to 0·37 mmol/h) demonstrated an outlet of N into the circulating N pool. No effect of time relative to feeding was observed (P>0·05). These data indicate that considerable amounts of N are lost in the dairy cow due to prominent intermediary degradation of purines, but that pyrimidine N is reusable to a larger extent.
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Borzenko, Berta, Elena Bakurova, and Ksenia Mironova. "Disorders of purines and pyrimidines metabolism in human gastrointestinal tract cancer." Current Issues in Pharmacy and Medical Sciences 26, no. 4 (December 30, 2013): 369–71. http://dx.doi.org/10.12923/j.2084-980x/26.4/a.02.
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Deng, Wei-Wei, Riko Katahira, and Hiroshi Ashihara. "Short Term Effect of Caffeine on Purine, Pyrimidine and Pyridine Metabolism in Rice (Oryza sativa) Seedlings." Natural Product Communications 10, no. 5 (May 2015): 1934578X1501000. http://dx.doi.org/10.1177/1934578x1501000510.
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As part of our studies on the physiological and ecological function of caffeine, we investigated the effect of exogenously supplied caffeine on purine, pyrimidine and pyridine metabolism in rice seedlings. We examined the effect of 1 mM caffeine on the in situ metabolism of 14C-labelled adenine, guanine, inosine, uridine, uracil, nicotinamide and nicotinic acid. The segments of 4-day-old dark-grown seedlings were incubated with these labelled compounds for 6 h. For purines, the incorporation of radioactivity from [8-14C]adenine and [8-14C]guanine into nucleotides was enhanced by caffeine; in contrast, incorporation into CO2 were reduced. The radioactivity in ureides (allantoin and allantoic acid) from [8-14C]guanine and [8-14C]inosine was increased by caffeine. For pyrimidines, caffeine enhanced the incorporation of radioactivity from [2-14C]uridine into nucleotides, which was accompanied by a decrease in pyrimidine catabolism. Such difference was not found in the metabolism of [2-14C]uracil. Caffeine did not influence the pyridine metabolism of [carbonyl-14C]-nicotinamide and [2-14C]nicotinic acid. The possible control steps of caffeine on nucleotide metabolism in rice are discussed.
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Liu, Xianxian, and Rebecca E. Parales. "Bacterial Chemotaxis to Atrazine and Related s-Triazines." Applied and Environmental Microbiology 75, no. 17 (July 6, 2009): 5481–88. http://dx.doi.org/10.1128/aem.01030-09.
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ABSTRACT Pseudomonas sp. strain ADP utilizes the human-made s-triazine herbicide atrazine as the sole nitrogen source. The results reported here demonstrate that atrazine and the atrazine degradation intermediates N-isopropylammelide and cyanuric acid are chemoattractants for strain ADP. In addition, the nonmetabolized s-triazine ametryn was also an attractant. The chemotactic response to these s-triazines was not specifically induced during growth with atrazine, and atrazine metabolism was not required for the chemotactic response. A cured variant of strain ADP (ADP M13-2) was attracted to s-triazines, indicating that the atrazine catabolic plasmid pADP-1 is not necessary for the chemotactic response and that atrazine degradation and chemotaxis are not genetically linked. These results indicate that atrazine and related s-triazines are detected by one or more chromosomally encoded chemoreceptors in Pseudomonas sp. strain ADP. We demonstrated that Escherichia coli is attracted to the s-triazine compounds N-isopropylammelide and cyanuric acid, and an E. coli mutant lacking Tap (the pyrimidine chemoreceptor) was unable to respond to s-triazines. These data indicate that pyrimidines and triazines are detected by the same chemoreceptor (Tap) in E. coli. We showed that Pseudomonas sp. strain ADP is attracted to pyrimidines, which are the naturally occurring structures closest to triazines, and propose that chemotaxis toward s-triazines may be due to fortuitous recognition by a pyrimidine chemoreceptor in Pseudomonas sp. strain ADP. In competition assays, the presence of atrazine inhibited chemotaxis of Pseudomonas sp. strain ADP to cytosine, and cytosine inhibited chemotaxis to atrazine, suggesting that pyrimidines and s-triazines are detected by the same chemoreceptor.
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Uchida, Michihiko, Ken-Ichi Kamiya, Teruo Yoshimura, Kin-Ya Sasaki, Hiroshi Tsutani, Takanori Ueda, and Toru Nakamura. "163 Transport and intracel lular metabolism of fluorinated pyrimidines." Pediatric Research 24, no. 1 (July 1988): 138. http://dx.doi.org/10.1203/00006450-198807000-00187.
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Martinussen, J., P. S. Andersen, and K. Hammer. "Nucleotide metabolism in Lactococcus lactis: salvage pathways of exogenous pyrimidines." Journal of Bacteriology 176, no. 5 (1994): 1514–16. http://dx.doi.org/10.1128/jb.176.5.1514-1516.1994.
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SASAMOTO, HAMAKO, KOSHI SAITO, and HIROSHI ASHIHARA. "Metabolism of Pyrimidines in Protoplasts from Cultured Catharanthus roseus Cells*." Annals of Botany 60, no. 4 (October 1987): 417–20. http://dx.doi.org/10.1093/oxfordjournals.aob.a087462.
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Ito, Tetsuya, André B. P. van Kuilenburg, Albert H. Bootsma, Anja J. Haasnoot, Arno van Cruchten, Yoshiro Wada, and Albert H. van Gennip. "Rapid Screening of High-Risk Patients for Disorders of Purine and Pyrimidine Metabolism Using HPLC-Electrospray Tandem Mass Spectrometry of Liquid Urine or Urine-soaked Filter Paper Strips." Clinical Chemistry 46, no. 4 (April 1, 2000): 445–52. http://dx.doi.org/10.1093/clinchem/46.4.445.
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Abstract Background: A rapid and specific screening method for patients at risk of inherited disorders of purine and pyrimidine metabolism is desirable because symptoms are varied and nonspecific. The aim of this study was to develop a rapid and specific method for screening with use of liquid urine samples or urine-soaked filter paper strips. Methods: Reverse-phase HPLC was combined with electrospray ionization (ESI), tandem mass spectrometry (MS/MS), and detection performed by multiple reaction monitoring. Transitions and instrument settings were established for 17 purines or pyrimidines. Stable-isotope-labeled reference compounds were used as internal standards when available. Results: Total analysis time of this method was 15 min, approximately one-third that of conventional HPLC with ultraviolet detection. Recoveries were 96–107% in urine with added analyte, with two exceptions (hypoxanthine, 64%; xanthine, 79%), and 89–110% in urine-soaked filter paper strips, with three exceptions (hypoxanthine, 65%; xanthine, 77%; 5-hydroxymethyluracil, 80%). The expected abnormalities were easily found in samples from patients with purine nucleoside phosphorylase deficiency, ornithine transcarbamylase deficiency, molybdenum cofactor deficiency, adenylosuccinase deficiency, or dihydropyrimidine dehydrogenase deficiency. Conclusions: HPLC-ESI MS/MS of urine allows rapid screening for disorders of purine and pyrimidine metabolism. The filter paper strips offer the advantage of easy collection, transport, and storage of the urine samples.
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Sirakanyan, Samuel N., Victor G. Kartsev, Athina Geronikaki, Domenico Spinelli, Anthi Petrou, Elmira K. Hakobyan, Jasmina Glamoclij, Manija Ivanov, Marina Sokovic, and Anush A. Hovakimyan. "Synthesis and Evaluation of Antimicrobial Activity and Molecular Dock - ing of New N-1,3-thiazol-2-ylacetamides of Condensed Pyrido[3',2':4,5] furo(thieno)[3,2-d]pyrimidines." Current Topics in Medicinal Chemistry 20, no. 24 (November 2, 2020): 2192–209. http://dx.doi.org/10.2174/1568026620666200628145308.
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Background: From the literature it is known that many derivatives of fused thienopyrimidines and furopyrimidines possess broad spectrum of biological activity. Objectives: The current studies describe the synthesis and evaluation of antimicrobial activity of some new N-1,3-thiazol-2-ylacetamides of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines. Methods: By cyclocondensation of ethyl 1-aminofuro(thieno)[2,3-b]pyridine-2-carboxylates 1with formamide were converted to the pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidin-7(8)-ones 2.Alkylation of compound 2 with 2-chloro-N-1,3-thiazol-2-ylacetamide led to the aimed N-1,3-thiazol-2-ylaceta-mides of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines 3. Starting from compound 2 the relevant S-alkylated derivatives of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines 6 were also synthesized. Results: All the compounds showed antibacterial activity to non-resistant strains. Compounds 3a-3m showed antibacterial activity with MIC/MBC at 0.08-2.31 mg/mL/0.11-3.75 mg/mL .The two most active compounds, 3j and 6b, appeared to be more active towards MRSA than the reference drugs. Half of the tested compounds appeared to be equipotent/more potent than ketoconazole and more potent than bifonazole. The docking analysis provided useful information about the interactions occurring between the tested compounds and the different enzymes. Conclusion: Gram-negative and Gram-positive bacteria and fungi showed different response towards tested compounds, indicating that different substituents may lead to different modes of action or that the metabolism of some bacteria/fungi was better able to overcome the effect of the compounds or adapt to it.
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Liu, Ji-Long. "May the Force Be with You: Metabolism of Arginine and Pyrimidines." Journal of Genetics and Genomics 42, no. 5 (May 2015): 179–80. http://dx.doi.org/10.1016/j.jgg.2015.05.003.
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Fragoso, Yara Dadalti, and Joseph Bruno Bidin Brooks. "Leflunomide and teriflunomide: altering the metabolism of pyrimidines for the treatment of autoimmune diseases." Expert Review of Clinical Pharmacology 8, no. 3 (February 24, 2015): 315–20. http://dx.doi.org/10.1586/17512433.2015.1019343.
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Martin, William, and Michael J. Russell. "On the origin of biochemistry at an alkaline hydrothermal vent." Philosophical Transactions of the Royal Society B: Biological Sciences 362, no. 1486 (November 3, 2006): 1887–926. http://dx.doi.org/10.1098/rstb.2006.1881.
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A model for the origin of biochemistry at an alkaline hydrothermal vent has been developed that focuses on the acetyl-CoA (Wood–Ljungdahl) pathway of CO 2 fixation and central intermediary metabolism leading to the synthesis of the constituents of purines and pyrimidines. The idea that acetogenesis and methanogenesis were the ancestral forms of energy metabolism among the first free-living eubacteria and archaebacteria, respectively, stands in the foreground. The synthesis of formyl pterins, which are essential intermediates of the Wood–Ljungdahl pathway and purine biosynthesis, is found to confront early metabolic systems with steep bioenergetic demands that would appear to link some, but not all, steps of CO 2 reduction to geochemical processes in or on the Earth's crust. Inorganically catalysed prebiotic analogues of the core biochemical reactions involved in pterin-dependent methyl synthesis of the modern acetyl-CoA pathway are considered. The following compounds appear as probable candidates for central involvement in prebiotic chemistry: metal sulphides, formate, carbon monoxide, methyl sulphide, acetate, formyl phosphate, carboxy phosphate, carbamate, carbamoyl phosphate, acetyl thioesters, acetyl phosphate, possibly carbonyl sulphide and eventually pterins. Carbon might have entered early metabolism via reactions hardly different from those in the modern Wood–Ljungdahl pathway, the pyruvate synthase reaction and the incomplete reverse citric acid cycle. The key energy-rich intermediates were perhaps acetyl thioesters, with acetyl phosphate possibly serving as the universal metabolic energy currency prior to the origin of genes. Nitrogen might have entered metabolism as geochemical NH 3 via two routes: the synthesis of carbamoyl phosphate and reductive transaminations of α-keto acids. Together with intermediates of methyl synthesis, these two routes of nitrogen assimilation would directly supply all intermediates of modern purine and pyrimidine biosynthesis. Thermodynamic considerations related to formyl pterin synthesis suggest that the ability to harness a naturally pre-existing proton gradient at the vent–ocean interface via an ATPase is older than the ability to generate a proton gradient with chemistry that is specified by genes.
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Hirabara, Sandro Massao, Renata Gorjao, Adriana Cristina Levada-Pires, Laureane Nunes Masi, Elaine Hatanaka, Maria Fernanda Cury-Boaventura, Eliane Borges da Silva, et al. "Host cell glutamine metabolism as a potential antiviral target." Clinical Science 135, no. 2 (January 2021): 305–25. http://dx.doi.org/10.1042/cs20201042.
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Abstract A virus minimally contains a nucleic acid genome packaged by a protein coat. The genome and capsid together are known as the nucleocapsid, which has an envelope containing a lipid bilayer (mainly phospholipids) originating from host cell membranes. The viral envelope has transmembrane proteins that are usually glycoproteins. The proteins in the envelope bind to host cell receptors, promoting membrane fusion and viral entry into the cell. Virus-infected host cells exhibit marked increases in glutamine utilization and metabolism. Glutamine metabolism generates ATP and precursors for the synthesis of macromolecules to assemble progeny viruses. Some compounds derived from glutamine are used in the synthesis of purines and pyrimidines. These latter compounds are precursors for the synthesis of nucleotides. Inhibitors of glutamine transport and metabolism are potential candidate antiviral drugs. Glutamine is also an essential nutrient for the functions of leukocytes (lymphocyte, macrophage, and neutrophil), including those in virus-infected patients. The increased glutamine requirement for immune cell functions occurs concomitantly with the high glutamine utilization by host cells in virus-infected patients. The development of antiviral drugs that target glutamine metabolism must then be specifically directed at virus-infected host cells to avoid negative effects on immune functions. Therefore, the aim of this review was to describe the landscape of cellular glutamine metabolism to search for potential candidates to inhibit glutamine transport or glutamine metabolism.
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Gmeiner, William H. "Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine." Molecules 25, no. 15 (July 29, 2020): 3438. http://dx.doi.org/10.3390/molecules25153438.
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We review developments in fluorine chemistry contributing to the more precise use of fluorinated pyrimidines (FPs) to treat cancer. 5-Fluorouracil (5-FU) is the most widely used FP and is used to treat > 2 million cancer patients each year. We review methods for 5-FU synthesis, including the incorporation of radioactive and stable isotopes to study 5-FU metabolism and biodistribution. We also review methods for preparing RNA and DNA substituted with FPs for biophysical and mechanistic studies. New insights into how FPs perturb nucleic acid structure and dynamics has resulted from both computational and experimental studies, and we summarize recent results. Beyond the well-established role for inhibiting thymidylate synthase (TS) by the 5-FU metabolite 5-fluoro-2′-deoxyuridine-5′-O-monophosphate (FdUMP), recent studies have implicated new roles for RNA modifying enzymes that are inhibited by 5-FU substitution including tRNA methyltransferase 2 homolog A (TRMT2A) and pseudouridylate synthase in 5-FU cytotoxicity. Furthermore, enzymes not previously implicated in FP activity, including DNA topoisomerase 1 (Top1), were established as mediating FP anti-tumor activity. We review recent literature summarizing the mechanisms by which 5-FU inhibits RNA- and DNA-modifying enzymes and describe the use of polymeric FPs that may enable the more precise use of FPs for cancer treatment in the era of personalized medicine.
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Hodges, Craig C., Gerrit J. De Boer, and Javier Avalos. "Uptake and metabolism as mechanisms of selective herbicidal activity of the 1,2,4-triazolo[1,5-a] pyrimidines." Pesticide Science 29, no. 3 (1990): 365–78. http://dx.doi.org/10.1002/ps.2780290311.
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Lirussi, Lisa, Özlem Demir, Panpan You, Antonio Sarno, Rommie E. Amaro, and Hilde Nilsen. "RNA Metabolism Guided by RNA Modifications: The Role of SMUG1 in rRNA Quality Control." Biomolecules 11, no. 1 (January 8, 2021): 76. http://dx.doi.org/10.3390/biom11010076.
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RNA modifications are essential for proper RNA processing, quality control, and maturation steps. In the last decade, some eukaryotic DNA repair enzymes have been shown to have an ability to recognize and process modified RNA substrates and thereby contribute to RNA surveillance. Single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1) is a base excision repair enzyme that not only recognizes and removes uracil and oxidized pyrimidines from DNA but is also able to process modified RNA substrates. SMUG1 interacts with the pseudouridine synthase dyskerin (DKC1), an enzyme essential for the correct assembly of small nucleolar ribonucleoproteins (snRNPs) and ribosomal RNA (rRNA) processing. Here, we review rRNA modifications and RNA quality control mechanisms in general and discuss the specific function of SMUG1 in rRNA metabolism. Cells lacking SMUG1 have elevated levels of immature rRNA molecules and accumulation of 5-hydroxymethyluridine (5hmU) in mature rRNA. SMUG1 may be required for post-transcriptional regulation and quality control of rRNAs, partly by regulating rRNA and stability.
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Lirussi, Lisa, Özlem Demir, Panpan You, Antonio Sarno, Rommie E. Amaro, and Hilde Nilsen. "RNA Metabolism Guided by RNA Modifications: The Role of SMUG1 in rRNA Quality Control." Biomolecules 11, no. 1 (January 8, 2021): 76. http://dx.doi.org/10.3390/biom11010076.
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RNA modifications are essential for proper RNA processing, quality control, and maturation steps. In the last decade, some eukaryotic DNA repair enzymes have been shown to have an ability to recognize and process modified RNA substrates and thereby contribute to RNA surveillance. Single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1) is a base excision repair enzyme that not only recognizes and removes uracil and oxidized pyrimidines from DNA but is also able to process modified RNA substrates. SMUG1 interacts with the pseudouridine synthase dyskerin (DKC1), an enzyme essential for the correct assembly of small nucleolar ribonucleoproteins (snRNPs) and ribosomal RNA (rRNA) processing. Here, we review rRNA modifications and RNA quality control mechanisms in general and discuss the specific function of SMUG1 in rRNA metabolism. Cells lacking SMUG1 have elevated levels of immature rRNA molecules and accumulation of 5-hydroxymethyluridine (5hmU) in mature rRNA. SMUG1 may be required for post-transcriptional regulation and quality control of rRNAs, partly by regulating rRNA and stability.
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Gerrits, G. P., A. A. Haagen, R. A. De Abreu, L. A. Monnens, F. J. Gabreëls, F. J. Trijbels, A. L. Theeuwes, and J. M. van Baal. "Reference values for nucleosides and nucleobases in cerebrospinal fluid of children." Clinical Chemistry 34, no. 7 (July 1, 1988): 1439–42. http://dx.doi.org/10.1093/clinchem/34.7.1439.
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Abstract Disturbances in the metabolism of purines and pyrimidines in neurologically affected patients can be reflected by aberrant concentrations of nucleosides and nucleobases in cerebrospinal fluid (CSF). However, normal values, especially for children at different ages, are lacking. We collected 1000 specimens of CSF from subjects ranging in age from newborn to 18 years, who were undergoing a diagnostic lumbar puncture for several clinical indications. Of these, 78 samples could be used retrospectively as a reference according to our criteria. The analyses were performed with a modified HPLC procedure. None of the substances shows age-dependency except uridine and uric acid. Uridine increases with age, and uric acid increases with age in boys older than 12 years.
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Kosmopoulou, Mariangela, Aikaterini F. Giannopoulou, Aikaterini Iliou, Dimitra Benaki, Aristeidis Panagiotakis, Athanassios D. Velentzas, Eumorphia G. Konstantakou, et al. "Human Melanoma-Cell Metabolic Profiling: Identification of Novel Biomarkers Indicating Metastasis." International Journal of Molecular Sciences 21, no. 7 (March 31, 2020): 2436. http://dx.doi.org/10.3390/ijms21072436.
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Melanoma is the most aggressive type of skin cancer, leading to metabolic rewiring and enhancement of metastatic transformation. Efforts to improve its early and accurate diagnosis are largely based on preclinical models and especially cell lines. Hence, we herein present a combinational Nuclear Magnetic Resonance (NMR)- and Ultra High Performance Liquid Chromatography-High-Resolution Tandem Mass Spectrometry (UHPLC-HRMS/MS)-mediated untargeted metabolomic profiling of melanoma cells, to landscape metabolic alterations likely controlling metastasis. The cell lines WM115 and WM2664, which belong to the same patient, were examined, with WM115 being derived from a primary, pre-metastatic, tumor and WM2664 clonally expanded from lymph-node metastases. Metabolite samples were analyzed using NMR and UHPLC-HRMS. Multivariate statistical analysis of high resolution NMR and MS (positive and negative ionization) results was performed by Principal Component Analysis (PCA), Partial Least Squares-Discriminant Analysis (PLS-DA) and Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA), while metastasis-related biomarkers were determined on the basis of VIP lists, S-plots and Student’s t-tests. Receiver Operating Characteristic (ROC) curves of NMR and MS data revealed significantly differentiated metabolite profiles for each cell line, with WM115 being mainly characterized by upregulated levels of phosphocholine, choline, guanosine and inosine. Interestingly, WM2664 showed notably increased contents of hypoxanthine, myo-inositol, glutamic acid, organic acids, purines, pyrimidines, AMP, ADP, ATP and UDP(s), thus indicating the critical roles of purine, pyrimidine and amino acid metabolism during human melanoma metastasis.
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Curi, Rui, Renata de Siqueira Mendes, Luiz Aurélio de Campos Crispin, Giuseppe Danilo Norata, Sandra Coccuzzo Sampaio, and Philip Newsholme. "A past and present overview of macrophage metabolism and functional outcomes." Clinical Science 131, no. 12 (June 7, 2017): 1329–42. http://dx.doi.org/10.1042/cs20170220.
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In 1986 and 1987, Philip Newsholme et al. reported macrophages utilize glutamine, as well as glucose, at high rates. These authors measured key enzyme activities and consumption and production levels of metabolites in incubated or cultured macrophages isolated from the mouse or rat intraperitoneal cavity. Metabolic pathways essential for macrophage function were then determined. Macrophages utilize glucose to generate (i) ATP in the pathways of glycolysis and mitochondrial oxidative phosphorylation, (ii) glycerol 3-phosphate for the synthesis of phospholipids and triacylglycerols, (iii) NADPH for the production of reactive oxygen species (ROS) and (iv) ribose for the synthesis of RNA and subsequently production and secretion of protein mediators (e.g. cytokines). Glutamine plays an essential role in macrophage metabolism and function, as it is required for energy production but also provides nitrogen for synthesis of purines, pyrimidines and thus RNA. Macrophages also utilize fatty acids for both energy production in the mitochondria and lipid synthesis essential to plasma membrane turnover and lipid meditator production. Recent studies utilizing metabolomic approaches, transcriptional and metabolite tracking technologies have detailed mitochondrial release of tricarboxylic acid (TCA) intermediates (e.g. citrate and succinate) to the cytosol, which then regulate pro-inflammatory responses. Macrophages can reprogramme their metabolism and function according to environmental conditions and stimuli in order to polarize phenotype so generating pro- or anti-inflammatory cells. Changes in macrophage metabolism result in modified function/phenotype and vice versa. The plasticity of macrophage metabolism allows the cell to quickly respond to changes in environmental conditions such as those induced by hormones and/or inflammation. A past and present overview of macrophage metabolism and impact of endocrine regulation and the relevance to human disease are described in this review.
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Gaupp, Rosmarie, Shulei Lei, Joseph M. Reed, Henrik Peisker, Susan Boyle-Vavra, Arnold S. Bayer, Markus Bischoff, et al. "Staphylococcus aureus Metabolic Adaptations during the Transition from a Daptomycin Susceptibility Phenotype to a Daptomycin Nonsusceptibility Phenotype." Antimicrobial Agents and Chemotherapy 59, no. 7 (May 11, 2015): 4226–38. http://dx.doi.org/10.1128/aac.00160-15.
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ABSTRACTStaphylococcus aureusis a major cause of nosocomial and community-acquired infections. The success ofS. aureusas a pathogen is due in part to its many virulence determinants and resistance to antimicrobials. In particular, methicillin-resistantS. aureushas emerged as a major cause of infections and led to increased use of the antibiotics vancomycin and daptomycin, which has increased the isolation of vancomycin-intermediateS. aureusand daptomycin-nonsusceptibleS. aureusstrains. The most common mechanism by whichS. aureusacquires intermediate resistance to antibiotics is by adapting its physiology and metabolism to permit growth in the presence of these antibiotics, a process known as adaptive resistance. To better understand the physiological and metabolic changes associated with adaptive resistance, six daptomycin-susceptible and -nonsusceptible isogenic strain pairs were examined for changes in growth, competitive fitness, and metabolic alterations. Interestingly, daptomycin nonsusceptibility coincides with a slightly delayed transition to the postexponential growth phase and alterations in metabolism. Specifically, daptomycin-nonsusceptible strains have decreased tricarboxylic acid cycle activity, which correlates with increased synthesis of pyrimidines and purines and increased carbon flow to pathways associated with wall teichoic acid and peptidoglycan biosynthesis. Importantly, these data provided an opportunity to alter the daptomycin nonsusceptibility phenotype by manipulating bacterial metabolism, a first step in developing compounds that target metabolic pathways that can be used in combination with daptomycin to reduce treatment failures.
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Molina-Quiroz, Roberto C., Cecilia A. Silva, Cristian F. Molina, Lorenzo E. Leiva, Sebastián Reyes-Cerpa, Inés Contreras, and Carlos A. Santiviago. "Exposure to sub-inhibitory concentrations of cefotaxime enhances the systemic colonization of Salmonella Typhimurium in BALB/c mice." Open Biology 5, no. 10 (October 2015): 150070. http://dx.doi.org/10.1098/rsob.150070.
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It has been proposed that sub-inhibitory concentrations of antibiotics play a role in virulence modulation. In this study, we evaluated the ability of Salmonella enterica serovar Typhimurium (hereafter S . Typhimurium) to colonize systemically BALB/c mice after exposure to a sub-inhibitory concentration of cefotaxime (CTX). In vivo competition assays showed a fivefold increase in systemic colonization of CTX-exposed bacteria when compared to untreated bacteria. To identify the molecular mechanisms involved in this phenomenon, we carried out a high-throughput genetic screen. A transposon library of S . Typhimurium mutants was subjected to negative selection in the presence of a sub-inhibitory concentration of CTX and genes related to anaerobic metabolism, biosynthesis of purines, pyrimidines, amino acids and other metabolites were identified as needed to survive in this condition. In addition, an impaired ability for oxygen consumption was observed when bacteria were cultured in the presence of a sub-inhibitory concentration of CTX. Altogether, our data indicate that exposure to sub-lethal concentrations of CTX increases the systemic colonization of S. Typhimurium in BALB/c mice in part by the establishment of a fitness alteration conducive to anaerobic metabolism.
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Ortiz-Pedraza, Yunuen, J. Omar Muñoz-Bello, Leslie Olmedo-Nieva, Adriana Contreras-Paredes, Imelda Martínez-Ramírez, Elizabeth Langley, and Marcela Lizano. "Non-Coding RNAs as Key Regulators of Glutaminolysis in Cancer." International Journal of Molecular Sciences 21, no. 8 (April 20, 2020): 2872. http://dx.doi.org/10.3390/ijms21082872.
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Cancer cells exhibit exacerbated metabolic activity to maintain their accelerated proliferation and microenvironmental adaptation in order to survive under nutrient-deficient conditions. Tumors display an increase in glycolysis, glutaminolysis and fatty acid biosynthesis, which provide their energy source. Glutamine is critical for fundamental cellular processes, where intermediate metabolites produced through glutaminolysis are necessary for the maintenance of mitochondrial metabolism. These include antioxidants to remove reactive oxygen species, and the generation of the nonessential amino acids, purines, pyrimidines and fatty acids required for cellular replication and the activation of cell signaling. Some cancer cells are highly dependent on glutamine consumption since its catabolism provides an anaplerotic pathway to feed the Krebs cycle. Intermediate members of the glutaminolysis pathway have been found to be deregulated in several types of cancers and have been proposed as therapeutic targets and prognostic biomarkers. This review summarizes the main players in the glutaminolysis pathway, how they have been found to be deregulated in cancer and their implications for cancer maintenance. Furthermore, non-coding RNAs are now recognized as new participants in the regulation of glutaminolysis; therefore, their involvement in glutamine metabolism in cancer is discussed in detail.
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Leese, Henry J., Paul J. McKeegan, and Roger G. Sturmey. "Amino Acids and the Early Mammalian Embryo: Origin, Fate, Function and Life-Long Legacy." International Journal of Environmental Research and Public Health 18, no. 18 (September 19, 2021): 9874. http://dx.doi.org/10.3390/ijerph18189874.
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Amino acids are now recognised as having multiple cellular functions in addition to their traditional role as constituents of proteins. This is well-illustrated in the early mammalian embryo where amino acids are now known to be involved in intermediary metabolism, as energy substrates, in signal transduction, osmoregulation and as intermediaries in numerous pathways which involve nitrogen metabolism, e.g., the biosynthesis of purines, pyrimidines, creatine and glutathione. The amino acid derivative S-adenosylmethionine has emerged as a universal methylating agent with a fundamental role in epigenetic regulation. Amino acids are now added routinely to preimplantation embryo culture media. This review examines the routes by which amino acids are supplied to the early embryo, focusing on the role of the oviduct epithelium, followed by an outline of their general fate and function within the embryo. Functions specific to individual amino acids are then considered. The importance of amino acids during the preimplantation period for maternal health and that of the conceptus long term, which has come from the developmental origins of health and disease concept of David Barker, is discussed and the review concludes by considering the potential utility of amino acid profiles as diagnostic of embryo health.
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Zadnova, S. P., D. V. Badanin, N. A. Plekhanov, T. A. Polunina, N. V. Kotova, A. A. Kritsky, A. V. Fedorov, and Ya M. Krasnov. "Comparative Proteomic Profiles of Typical Strain and Genetically Altered Variant of Vibrio cholerae O1, Biovar El Tor." Problems of Particularly Dangerous Infections, no. 3 (October 22, 2020): 150–53. http://dx.doi.org/10.21055/0370-1069-2020-3-150-153.
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Objective of the study was to identify the differences in the production of proteins in typical strain and genetically altered variant of V. cholerae O1, biovar El Tor.Materials and methods. Natural strains M1062 (Astrakhan, 1970) and M1509 (Moscow, 2010) were used as model strains in this work. Strains were cultivated on Luria Bertani agar at 37 °C. Electrophoresis was performed in accordance with W.K. Laemmli technique (1970), mass-spectrometric profiling – the method described by A. Shevchenko et al.Results and discussion. Mass-spectrometric scanning of cell lysates of the examined strains showed significant similarity of their proteomes (615 common proteins). The identified differences pertained to high expression of proteins in the strain M1062, participating in biosynthesis of DNA/RNA, included into “purines, pyrimidines, nucleosides” group, as well as regulatory proteins. In M1509 strain, biosynthesis of the proteins responsible for pathogenesis, adaptation under the influence of unfavorable environmental factors, included into “co-factors, vitamins, pigments” group, involved in lipid, carbohydrate, and protein metabolism, cellular processes, as well as proteins-transporters was increased. It has been suggested that the wide dissemination of El Tor genovariants is probably due to enhanced pathogenic and adaptive properties and also to the considerable transformation of cell metabolism.
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Berndt, Sonja I., David C. Johnson, John Crowley, Brian G. Durie, Robert Hoover, Michael Katz, Nathaniel Rothman, Brian G. Van Ness, Dalsu Baris, and Gareth J. Morgan. "Large Scale Evaluation of Genetic Variation and the Risk of Multiple Myeloma." Blood 112, no. 11 (November 16, 2008): 1679. http://dx.doi.org/10.1182/blood.v112.11.1679.1679.
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Abstract Genetic factors are thought to influence susceptibility to multiple myeloma, but most published studies to date have been small and limited in scope. To identify genetic polymorphisms associated with myeloma risk, we conducted a case-control study of 976 Caucasian myeloma cases enrolled from clinical trials as part of the International Myeloma Foundation’s Bank On A Cure® initiative and 3692 Caucasian controls from the three cohorts [Nurses’ Health Study (NHS), Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and 1958 British Birth Cohort (BC58)] with genome-wide scan data. A candidate gene approach was taken with a preference given to single nucleotide polymorphisms (SNPs) in coding or regulatory regions. A total of 1097 SNPs with a minor allele frequency ≥1% were genotyped in the cases and at least one control population. In order to increase our statistical power, SNPs not genotyped in NHS and PLCO were imputed from the genome scan with MACH using the HapMap CEU population as a referent and included in the analysis if the quality control r2 was high (r2 ≥0.9). Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusting for age, sex, and country as appropriate. We found 26 loci to be associated with myeloma risk with P < 0.01. Of particular interest, we observed an increased risk of myeloma with variants in two genes involved in the metabolism of pyrimidines, DPYD and MTHFR. An increased risk of myeloma was found with two independent SNPs, rs1023244 and rs1399291, in DPYD (ORperGallele = 1.43, 95% CI: 1.16–1.76, P = 0.0008 and ORperTallele = 1.18, 95% CI: 1.06–1.31, P = 0.003, respectively) and with the MTHFR high activity 677C allele (rs1801133, ORperC allele = 1.18, 95% CI: 1.05–1.33, P = 0.006). We also observed significant associations for nonsynonymous SNPs in genes involved in cell cycle checkpoint regulation (ATR, P = 0.009; ZAK, P = 0.007) and the DNA damage bypass pathway (REV3L, P = 0.008), suggesting that alterations in DNA damage mediation may modulate myeloma susceptibility. In conclusion, this large study found SNPs in several pathways, including pyrimidine metabolism and DNA damage mediation, to be associated with myeloma risk. Additional studies are needed to replicate these findings and to further explore genetic variation in these regions.
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Gibb, Andrew A., Pawel K. Lorkiewicz, Yu-Ting Zheng, Xiang Zhang, Aruni Bhatnagar, Steven P. Jones, and Bradford G. Hill. "Integration of flux measurements to resolve changes in anabolic and catabolic metabolism in cardiac myocytes." Biochemical Journal 474, no. 16 (August 7, 2017): 2785–801. http://dx.doi.org/10.1042/bcj20170474.
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Although ancillary pathways of glucose metabolism are critical for synthesizing cellular building blocks and modulating stress responses, how they are regulated remains unclear. In the present study, we used radiometric glycolysis assays, [13C6]-glucose isotope tracing, and extracellular flux analysis to understand how phosphofructokinase (PFK)-mediated changes in glycolysis regulate glucose carbon partitioning into catabolic and anabolic pathways. Expression of kinase-deficient or phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in rat neonatal cardiomyocytes co-ordinately regulated glycolytic rate and lactate production. Nevertheless, in all groups, >40% of glucose consumed by the cells was unaccounted for via catabolism to pyruvate, which suggests entry of glucose carbons into ancillary pathways branching from metabolites formed in the preparatory phase of glycolysis. Analysis of 13C fractional enrichment patterns suggests that PFK activity regulates glucose carbon incorporation directly into the ribose and the glycerol moieties of purines and phospholipids, respectively. Pyrimidines, UDP-N-acetylhexosamine, and the fatty acyl chains of phosphatidylinositol and triglycerides showed lower 13C incorporation under conditions of high PFK activity; the isotopologue 13C enrichment pattern of each metabolite indicated limitations in mitochondria-engendered aspartate, acetyl CoA and fatty acids. Consistent with this notion, high glycolytic rate diminished mitochondrial activity and the coupling of glycolysis to glucose oxidation. These findings suggest that a major portion of intracellular glucose in cardiac myocytes is apportioned for ancillary biosynthetic reactions and that PFK co-ordinates the activities of the pentose phosphate, hexosamine biosynthetic, and glycerolipid synthesis pathways by directly modulating glycolytic intermediate entry into auxiliary glucose metabolism pathways and by indirectly regulating mitochondrial cataplerosis.
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Grewal, Ajmer S., Viney Lather, Neha Charaya, Neelam Sharma, Sukhbir Singh, and Visvaldas Kairys. "Recent Developments in Medicinal Chemistry of Allosteric Activators of Human Glucokinase for Type 2 Diabetes Mellitus Therapeutics." Current Pharmaceutical Design 26, no. 21 (June 24, 2020): 2510–52. http://dx.doi.org/10.2174/1381612826666200414163148.
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Background: Glucokinase (GK), a cytoplasmic enzyme catalyzes the metabolism of glucose to glucose- 6-phosphate with the help of ATP and aids in the controlling of blood glucose levels within the normal range in humans. In pancreatic β-cells, it plays a chief role by controlling the glucose-stimulated secretion of insulin and in liver hepatocyte cells, it controls the metabolism of carbohydrates. GK acts as a promising drug target for the pharmacological treatment of patients with type 2 diabetes mellitus (T2DM) as it plays an important role in the control of carbohydrate metabolism. Methods: Data used for this review was based on the search from several science databases as well as various patent databases. The main data search terms used were allosteric GK activators, diabetes mellitus, type 2 diabetes, glucokinase, glucokinase activators and human glucokinase. Results: This article discusses an overview of T2DM, the biology of GK, the role of GK in T2DM, recent updates in the development of small molecule GK activators reported in recent literature, mechanism of action of GK activators and their clinical status. Conclusion: GK activators are the novel class of pharmacological agents that enhance the catalytic activity of GK enzyme and display their antihyperglycemic effects. Broad diversity of chemical entities including benzamide analogues, carboxamides, acrylamides, benzimidazoles, quinazolines, thiazoles, pyrimidines, pyridines, orotic acid amides, amino acid derivatives, amino phosphates and urea derivatives have been synthesized in past two decades as potent allosteric activators of GK. Presently, the pharmaceutical companies and researchers are focusing on the design and development of liver-selective GK activators for preventing the possible adverse effects associated with GK activators for the long-term treatment of T2DM.
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Hou, Joan Y., James E. Graham, and Josephine E. Clark-Curtiss. "Mycobacterium avium Genes Expressed during Growth in Human Macrophages Detected by Selective Capture of Transcribed Sequences (SCOTS)." Infection and Immunity 70, no. 7 (July 2002): 3714–26. http://dx.doi.org/10.1128/iai.70.7.3714-3726.2002.
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ABSTRACT Selective capture of transcribed sequences (SCOTS) has been employed to identify 54 cDNA molecules that represent 46 genes that are expressed by Mycobacterium avium during growth in human macrophages. Some cDNA molecules correspond to genes that are apparently expressed 48 h after infection of macrophages, while others correspond to genes expressed 110 h after infection, and still others correspond to genes expressed throughout the course of infection in our model system. Genes expressed by M. avium during growth in macrophages include genes encoding enzymes of several biosynthetic pathways (pyrimidines, mycobactin, and polyketides); genes that encode enzymes involved in intermediary metabolism, energy metabolism (tricarboxylic acid cycle, glyoxalate shunt), and nitrogen metabolism; and genes that encode regulatory proteins. A number of genes of unknown function were also identified, including genes that code for proteins similar to members of the PPE family of proteins of Mycobacterium tuberculosis and proteins similar to those encoded by the M. tuberculosis mce genes, which have been previously associated with mycobacterial virulence. The SCOTS technique, followed by enrichment for cDNA molecules that are up-regulated or are uniquely expressed by M. avium during growth in human macrophages (compared to growth in laboratory broth culture), allows recovery and identification of a greater diversity of cDNA molecules than does subtractive hybridization between cDNA mixtures from macrophage-grown and broth-grown M. avium. Data are presented demonstrating the reproducibility of recovery of a subset of cDNA molecules from cDNA mixtures purified by SCOTS on several different occasions. These results further demonstrate the beneficial utility of the SCOTS technique for identifying genes whose products are needed for successful survival and growth by an organism in a specific environment.
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Tavazzi, Barbara, Anna Paola Batocchi, Angela Maria Amorini, Viviana Nociti, Serafina D'Urso, Salvatore Longo, Stefano Gullotta, Marika Picardi, and Giuseppe Lazzarino. "Serum Metabolic Profile in Multiple Sclerosis Patients." Multiple Sclerosis International 2011 (2011): 1–8. http://dx.doi.org/10.1155/2011/167156.
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Multiple sclerosis (MS) is a progressive demyelinating process considered as an autoimmune disease, although the causes of this pathology have not been yet fully established. Similarly to other neurodegenerations, MS is characterized by a series of biochemical changes affecting to different extent neuronal functions; great attention has been given to oxidative/nitrosative stress and to alterations in mitochondrial functions. According to previous data, MS patients show significant changes in the circulating concentrations of different metabolites, although it is still unclear whether uric acid undergoes to decrease, increase, or no change under this pathological condition. In this study, we report the serum metabolic profile in terms of purines, pyrimidines, creatinine, malondialdehyde, ascorbic acid, nitrite, and nitrate in a group of 170 MS patients. The results show increase in circulating uric acid and other oxypurines (hypoxanthine and xanthine), as well as in uridine and β-pseudouridine. The concomitant increase in circulating creatinine, malondialdehyde, nitrite, and nitrate, and decrease in ascorbic acid, demonstrates that MS induces alteration in energy metabolism and in oxidants/antioxidants balance that can be monitored in serum of MS patients.
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Fermo, Elisa, Anna Marcello, Paola Bianchi, Simona Viglio, Laurent R. Chiarelli, Giovanna Valentini, and Alberto Zanella. "Pyrimidine 5′ Nucleotidase Deficiency: Clinical and Molecular Characterization of Two New Italian Patients." Blood 106, no. 11 (November 16, 2005): 3711. http://dx.doi.org/10.1182/blood.v106.11.3711.3711.
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Abstract Hereditary pyrimidine 5′ nucleotidase deficiency (P5′N) is the most frequent abnormality of the red cell nucleotide metabolism causing hereditary non-spherocytic hemolytic anemia. The disorder is characterized by mild-to-moderate hemolytic anemia associated with reticulocytosis and hyperbilirubinemia and the accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte. P5′N-1 gene is localized on 7p15-p14; eighteen mutations have been so far identified in 27 unrelated families, 6 of them of Italian origin. The aim of this study is to describe the hematological, biochemical and molecular characteristics of two new Italian patients affected by P5′N deficiency. Case1: The propositus was a 37 yrs old woman of Northern Italian origin affected by chronic hemolytic anemia with Hb levels ranging from 8.2 to 10.5 g/dL. At the time of the study Hb was 8.4 g/dL, reticulocytes 300x109/L, unconjugated bilirubin 3.2 mg/dL. Peripheral blood smear examination showed basophilic stippling and purines/pyrimidines ratio (OD260/280) was decreased (1, ref. values 1.4 – 2.98). P5′N activity, measured by capillary electrophoresis, was undetectable. Molecular analysis of P5′N-1 gene showed the presence of a new homozygous deletion of two bp (ag) at the splice junction between intron 7 and exon 8, which probably results in a splicing alteration and in the absence of a functional protein. Case2: The propositus, a 37 yrs old woman of Northern Italian origin carrying the hemoglobin variant HbD Punjab, had an history of chronic hemolytic anemia since childhood; at the age of 14 yrs splenectomy and colecystectomy were performed. The patient needed blood transfusions because of exacerbation of anemia (Hb 4.7g/dL) during parvovirus B19 infection. Iron status parameters were increased requiring desferrioxamine treatment. At the time of the study Hb was 9.3 g/dL, reticulocytes 752x109/L, unconjugated bilirubin 13.3 mg/dL. Serum ferritin was 1980 mg/mL and transferrin saturation 115%. The propositus was found to be homozygous for Gilbert’s syndrome and heterozygous for mutation H63D of HFE gene. Basophilic stippling (6%) was observed in peripheral blood smear. Pur/pyr ratio was 0.8 and residual P5′N activity was 40% of normal. Complete sequencing of P5′N-1 gene showed the presence of the frameshift mutation ins GG710-711, already described in Italian and Turkish patients, and the new in-frame aminoacidic deletion of Gln 143.
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Clare, Constance E., Valerie Pestinger, Wing Yee Kwong, Desmond A. R. Tutt, Juan Xu, Helen M. Byrne, David A. Barrett, Richard D. Emes, and Kevin D. Sinclair. "Interspecific Variation in One-Carbon Metabolism within the Ovarian Follicle, Oocyte, and Preimplantation Embryo: Consequences for Epigenetic Programming of DNA Methylation." International Journal of Molecular Sciences 22, no. 4 (February 12, 2021): 1838. http://dx.doi.org/10.3390/ijms22041838.
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One-carbon (1C) metabolism provides methyl groups for the synthesis and/or methylation of purines and pyrimidines, biogenic amines, proteins, and phospholipids. Our understanding of how 1C pathways operate, however, pertains mostly to the (rat) liver. Here we report that transcripts for all bar two genes (i.e., BHMT, MAT1A) encoding enzymes in the linked methionine-folate cycles are expressed in all cell types within the ovarian follicle, oocyte, and blastocyst in the cow, sheep, and pig; as well as in rat granulosa cells (GCs) and human KGN cells (a granulosa-like tumor cell line). Betaine-homocysteine methyltransferase (BHMT) protein was absent in bovine theca and GCs, as was activity of this enzyme in GCs. Mathematical modeling predicted that absence of this enzyme would lead to more volatile S-adenosylmethionine-mediated transmethylation in response to 1C substrate (e.g., methionine) or cofactor provision. We tested the sensitivity of bovine GCs to reduced methionine (from 50 to 10 µM) and observed a diminished flux of 1C units through the methionine cycle. We then used reduced-representation bisulfite sequencing to demonstrate that this reduction in methionine during bovine embryo culture leads to genome-wide alterations to DNA methylation in >1600 genes, including a cohort of imprinted genes linked to an abnormal fetal-overgrowth phenotype. Bovine ovarian and embryonic cells are acutely sensitive to methionine, but further experimentation is required to determine the significance of interspecific variation in BHMT expression.
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Chandler, Joshua D., Xin Hu, Eun-Ju Ko, Soojin Park, Young-Tae Lee, Michael Orr, Jolyn Fernandes, et al. "Metabolic pathways of lung inflammation revealed by high-resolution metabolomics (HRM) of H1N1 influenza virus infection in mice." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 311, no. 5 (November 1, 2016): R906—R916. http://dx.doi.org/10.1152/ajpregu.00298.2016.
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Influenza is a significant health concern worldwide. Viral infection induces local and systemic activation of the immune system causing attendant changes in metabolism. High-resolution metabolomics (HRM) uses advanced mass spectrometry and computational methods to measure thousands of metabolites inclusive of most metabolic pathways. We used HRM to identify metabolic pathways and clusters of association related to inflammatory cytokines in lungs of mice with H1N1 influenza virus infection. Infected mice showed progressive weight loss, decreased lung function, and severe lung inflammation with elevated cytokines [interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ] and increased oxidative stress via cysteine oxidation. HRM showed prominent effects of influenza virus infection on tryptophan and other amino acids, and widespread effects on pathways including purines, pyrimidines, fatty acids, and glycerophospholipids. A metabolome-wide association study (MWAS) of the aforementioned inflammatory cytokines was used to determine the relationship of metabolic responses to inflammation during infection. This cytokine-MWAS (cMWAS) showed that metabolic associations consisted of distinct and shared clusters of 396 metabolites highly correlated with inflammatory cytokines. Strong negative associations of selected glycosphingolipid, linoleate, and tryptophan metabolites with IFN-γ contrasted strong positive associations of glycosphingolipid and bile acid metabolites with IL-1β, TNF-α, and IL-10. Anti-inflammatory cytokine IL-10 had strong positive associations with vitamin D, purine, and vitamin E metabolism. The detailed metabolic interactions with cytokines indicate that targeted metabolic interventions may be useful during life-threatening crises related to severe acute infection and inflammation.
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Gerth, Ulf, Holger Kock, Ilja Kusters, Stephan Michalik, Robert L. Switzer, and Michael Hecker. "Clp-Dependent Proteolysis Down-Regulates Central Metabolic Pathways in Glucose-Starved Bacillus subtilis." Journal of Bacteriology 190, no. 1 (November 2, 2007): 321–31. http://dx.doi.org/10.1128/jb.01233-07.
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ABSTRACT Entry into stationary phase in Bacillus subtilis is linked not only to a redirection of the gene expression program but also to posttranslational events such as protein degradation. Using 35S-labeled methionine pulse-chase labeling and two-dimensional polyacrylamide gel electrophoresis we monitored the intracellular proteolysis pattern during glucose starvation. Approximately 200 protein spots diminished in the wild-type cells during an 8-h time course. The degradation rate of at least 80 proteins was significantly reduced in clpP, clpC, and clpX mutant strains. Enzymes of amino acid and nucleotide metabolism were overrepresented among these Clp substrate candidates. Notably, several first-committed-step enzymes for biosynthesis of aromatic and branched-chain amino acids, cell wall precursors, purines, and pyrimidines appeared as putative Clp substrates. Radioimmunoprecipitation demonstrated GlmS, IlvB, PurF, and PyrB to be novel ClpCP targets. Our data imply that Clp proteases down-regulate central metabolic pathways upon entry into a nongrowing state and thus contribute to the adaptation to nutrient starvation. Proteins that are obviously nonfunctional, unprotected, or even “unemployed” seem to be recognized and proteolyzed by Clp proteases when the resources for growth become limited.
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Pinedo, H. M., and G. F. Peters. "Fluorouracil: biochemistry and pharmacology." Journal of Clinical Oncology 6, no. 10 (October 1988): 1653–64. http://dx.doi.org/10.1200/jco.1988.6.10.1653.
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Fluorouracil (5FU) is still considered the most active antineoplastic agent in the treatment of advanced colorectal cancer. The drug needs to be converted to the nucleotide level in order to exert its effect. It can be incorporated into RNA leading to interference with the maturation of nuclear RNA. However, its conversion to 5-fluoro-2'deoxy-5' monophosphate (FdUMP) leading to inhibition of thymidylate synthase (TS) and subsequently of DNA synthesis, is considered to be its main mechanism of action. In the presence of a folate cofactor a covalent ternary complex is formed, the stability of which is the main determinant of the action of 5FU. Resistance against 5FU can be mainly attributed to aberrations in its metabolism or to alterations of TS, eg, gene amplification, altered kinetics in respect to nucleotides or folates. Biochemical modulation of 5FU metabolism can be applied to overcome resistance against 5FU. A variety of normal purines, pyrimidines, and other antimetabolites have been studied in this respect, but only some of them have been clinically successful. Delayed administration of uridine has recently been shown to "rescue" mice and patients from toxicity, while pretreatment with leucovorin is the most promising combination to enhance the therapeutic efficacy. 5FU is frequently administered in an intravenous (IV) injection, and shows a rapid distribution and a triphasic elimination. The nonlinearity of 5FU pharmacokinetics is related to saturation of its degradation. Continuous infusion of 5FU led to different kinetics. Regional administration, such as hepatic artery infusion, offers a way to achieve higher drug concentrations in liver metastases and is accompanied by lower systemic concentration. The current status of the biochemical and pharmacokinetic data is reviewed.
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Saada, Ann. "Fishing in the (deoxyribonucleotide) pool." Biochemical Journal 422, no. 3 (August 27, 2009): e3-e6. http://dx.doi.org/10.1042/bj20091194.
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Deoxyribonucleoside triphosphates (dNTPs) are the building blocks of DNA, and a constant supply is essential for the synthesis and maintenance of both the nuclear and mitochondrial genomes. Antiviral nucleoside analogues and inborn errors of nucleotide metabolism frequently cause dNTP pool imbalances, leading to depletion of mtDNA (mitochondrial DNA) in non-replicating tissues. mtDNA depletion, in turn, causes failure of the mitochondrial respiratory chain, resulting in cellular energy depletion and cell death. Accordingly, it is important to understand the origin and regulation of dNTPs in order to develop safe and effective treatments. In this issue of the Biochemical Journal, Morris et al. have pursued the origin of pyrimidines in perfused adult rat heart. They found no evident role for the nucleotide de novo synthesis pathway and also demonstrated that AZT (3′-azido-3′-deoxythymidine; also known as zidovudine) substantially decreased the TTP pool. Their results underscore the general importance of the mitochondrial deoxyribonucleoside salvage pathway in adult tissues, and particularly in AZT-mediated toxicity. Although the role of nucleoside salvaging versus de novo synthesis in humans remains unclear, the study of tissue cultures and animal models contribute to the understanding of the intricate network of biochemical pathways, maintaining the cellular dNTP supply.
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Tavazzi, Barbara, Giuseppe Lazzarino, Paola Leone, Angela Maria Amorini, Francesco Bellia, Christopher G. Janson, Valentina Di Pietro, et al. "Simultaneous high performance liquid chromatographic separation of purines, pyrimidines, N-acetylated amino acids, and dicarboxylic acids for the chemical diagnosis of inborn errors of metabolism." Clinical Biochemistry 38, no. 11 (November 2005): 997–1008. http://dx.doi.org/10.1016/j.clinbiochem.2005.08.002.
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Dahabiyeh, Lina A., Nouf N. Mahmoud, Mohammad A. Al-Natour, Laudina Safo, Dong-Hyun Kim, Enam A. Khalil, and Rana Abu-Dahab. "Phospholipid-Gold Nanorods Induce Energy Crisis in MCF-7 Cells: Cytotoxicity Evaluation Using LC-MS-Based Metabolomics Approach." Biomolecules 11, no. 3 (February 27, 2021): 364. http://dx.doi.org/10.3390/biom11030364.
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Phospholipid-modified gold nanorods (phospholipid-GNRs) have demonstrated drastic cytotoxicity towards MCF-7 breast cancer cells compared to polyethylene glycol-coated GNRs (PEG-GNRs). In this study, the mechanism of cytotoxicity of phospholipid-GNRs towards MCF-7 cells was investigated using mass spectrometry-based global metabolic profiling and compared to PEGylated counterparts. The results showed that when compared to PEG-GNRs, phospholipid-GNRs induced significant and more pronounced impact on the metabolic profile of MCF-7 cells. Phospholipid-GNRs significantly decreased the levels of metabolic intermediates and end-products associated with cellular energy metabolisms resulting in dysfunction in TCA cycle, a reduction in glycolytic activity, and imbalance of the redox state. Additionally, phospholipid-GNRs disrupted several metabolism pathways essential for the normal growth and proliferation of cancer cells including impairment in purine, pyrimidine, and glutathione metabolisms accompanied by lower amino acid pools. On the other hand, the effects of PEG-GNRs were limited to alteration of glycolysis and pyrimidine metabolism. The current work shed light on the importance of metabolomics as a valuable analytical approach to explore the molecular effects of GNRs with different surface chemistry on cancer cell and highlights metabolic targets that might serve as promising treatment strategy in cancer.
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Recchia, Irene, Nadia Rucci, Alessia Funari, Silvia Migliaccio, Anna Taranta, Maurizio Longo, Michaela Kneissel, Mira Šuša, Doriano Fabbro, and Anna Teti. "Reduction of c-Src activity by substituted 5,7-diphenyl-pyrrolo[2,3-d]-pyrimidines induces osteoclast apoptosis in vivo and in vitro. Involvement of ERK1/2 pathway." Bone 34, no. 1 (January 2004): 65–79. http://dx.doi.org/10.1016/j.bone.2003.06.004.
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Wojtala, Dąbek, Rybaczek, Śliwińska, Świderska, Słapek, El-Osta, and Balcerczyk. "Silencing Lysine-Specific Histone Demethylase 1 (LSD1) Causes Increased HP1-Positive Chromatin, Stimulation of DNA Repair Processes, and Dysregulation of Proliferation by Chk1 Phosphorylation in Human Endothelial Cells." Cells 8, no. 10 (October 7, 2019): 1212. http://dx.doi.org/10.3390/cells8101212.
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: The methylation of histone lysine residues modifies chromatin conformation and regulates the expression of genes implicated in cell metabolism. Lysine-specific demethylase 1 (LSD1) is a flavin-dependent monoamine oxidase that can demethylate mono- and dimethylated histone lysines 4 and 9 (H3K4 and H3K9). The removal of methyl groups from the lysine residues of histone and non-histone proteins was found to be an important regulatory factor of cell proliferation. However, its role has not been fully elucidated. In this study, we assessed LSD1-mediated cell cycle progression using a human endothelial cell model. The short hairpin RNA knockdown of LSD1 inhibits the G2/M phase of cell cycle progression by checkpoint kinase 1 (Chk1) phosphorylation (S137). We observed elevated DNA damage, which was consistent with the increased detection of double-strand breaks as well as purines and pyrimidines oxidation, which accompanied the activation of ATR/ATRIP signaling by H2AXS139 phosphorylation. The irreversible pharmacological inhibition of LSD1 by 2-phenylcyclopropylamine (2-PCPA) inactivated its enzymatic activity, causing significant changes in heterochromatin and euchromatin conformation assessed by chromatin assembly factor 1 subunit A (CAF1A) and heterochromatin protein 1 isoform α and γ (HP1α/γ) immunofluorescence analysis. We conclude that the knockdown of LSD1 in endothelial cells leads to increased HP1-positive chromatin, the stimulation of DNA repair processes, and the dysregulation of proliferation machinery.
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Wevers, Ron A., Udo FH Engelke, Sytske H. Moolenaar, Christa Bräutigam, Jan GN de Jong, Ries Duran, Ronney A. de Abreu, and Albert H. van Gennip. "1H-NMR Spectroscopy of Body Fluids: Inborn Errors of Purine and Pyrimidine Metabolism." Clinical Chemistry 45, no. 4 (April 1, 1999): 539–48. http://dx.doi.org/10.1093/clinchem/45.4.539.
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Abstract Background: The diagnosis of inborn errors of purine and pyrimidine metabolism is often difficult. We examined the potential of 1H-NMR as a tool in evaluation of patients with these disorders. Methods: We performed 1H-NMR spectroscopy on 500 and 600 MHz instruments with a standardized sample volume of 500 μL. We studied body fluids from 25 patients with nine inborn errors of purine and pyrimidine metabolism. Results: Characteristic abnormalities could be demonstrated in the 1H-NMR spectra of urine samples of all patients with diseases in the pyrimidine metabolism. In most urine samples from patients with defects in the purine metabolism, the 1H-NMR spectrum pointed to the specific diagnosis in a straightforward manner. The only exception was a urine from a case of adenine phosphoribosyl transferase deficiency in which the accumulating metabolite, 2,8-dihydroxyadenine, was not seen under the operating conditions used. Similarly, uric acid was not measured. We provide the 1H-NMR spectral characteristics of many intermediates in purine and pyrimidine metabolism that may be relevant for future studies in this field. Conclusion: The overview of metabolism that is provided by 1H-NMR spectroscopy makes the technique a valuable screening tool in the detection of inborn errors of purine and pyrimidine metabolism.
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Wang, Haiwei, Xinrui Wang, Liangpu Xu, Ji Zhang, and Hua Cao. "High expression levels of pyrimidine metabolic rate–limiting enzymes are adverse prognostic factors in lung adenocarcinoma: a study based on The Cancer Genome Atlas and Gene Expression Omnibus datasets." Purinergic Signalling 16, no. 3 (July 8, 2020): 347–66. http://dx.doi.org/10.1007/s11302-020-09711-4.
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Abstract Reprogramming of metabolism is described in many types of cancer and is associated with the clinical outcomes. However, the prognostic significance of pyrimidine metabolism signaling pathway in lung adenocarcinoma (LUAD) is unclear. Using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets, we found that the pyrimidine metabolism signaling pathway was significantly enriched in LUAD. Compared with normal lung tissues, the pyrimidine metabolic rate–limiting enzymes were highly expressed in lung tumor tissues. The high expression levels of pyrimidine metabolic–rate limiting enzymes were associated with unfavorable prognosis. However, purinergic receptors P2RX1, P2RX7, P2RY12, P2RY13, and P2RY14 were relatively downregulated in lung cancer tissues and were associated with favorable prognosis. Moreover, we found that hypo-DNA methylation, DNA amplification, and TP53 mutation were contributing to the high expression levels of pyrimidine metabolic rate–limiting enzymes in lung cancer cells. Furthermore, combined pyrimidine metabolic rate–limiting enzymes had significant prognostic effects in LUAD. Comprehensively, the pyrimidine metabolic rate–limiting enzymes were highly expressed in bladder cancer, breast cancer, colon cancer, liver cancer, and stomach cancer. And the high expression levels of pyrimidine metabolic rate–limiting enzymes were associated with unfavorable prognosis in liver cancer. Overall, our results suggested the mRNA levels of pyrimidine metabolic rate–limiting enzymes CAD, DTYMK, RRM1, RRM2, TK1, TYMS, UCK2, NR5C2, and TK2 were predictive of lung cancer as well as other cancers.
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Hsu, Peggy P., Youmna Kfoury, Najihah Aziz, Jenna Elkhoury, Brittany Hallgren, David T. Scadden, Matthew Vander Heiden, and David B. Sykes. "DHODH Inhibitors in the Treatment of Acute Myeloid Leukemia: Defining the Mechanism of Action and the Basis of the Metabolic Therapeutic Window." Blood 132, Supplement 1 (November 29, 2018): 2716. http://dx.doi.org/10.1182/blood-2018-99-113387.
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Abstract Adults diagnosed with acute myeloid leukemia have a poor prognosis, with only 30% surviving at five years. Despite advances in our understanding of the molecular underpinnings of AML, the chemotherapy backbone used to treat most patients (combination cytarabine and anthracycline) remains unchanged since 1973. With the goal of identifying a new differentiation therapy, we previously performed a small molecule phenotypic screen to find compounds that triggered myeloid maturation. Unexpectedly, our most active hits were inhibitors of the enzyme dihydroorotate dehydrogenase (DHODH). The DHODH-inhibitor brequinar demonstrated dramatic activity in vitro and in vivo (Figure 1A), leading to differentiation (Figure 1B) and prolonged survival across multiple AML models when compared to standard induction chemotherapy (iCT) (Figure 1C). Brequinar treatment also depleted leukemia initiating cells in vivo as measured by secondary transplant analysis (Figure 1D). Cancer therapy requires a 'therapeutic window' such that the treatment must target and kill malignant cells before killing normal cells and causing unacceptable side effects. An essential and ubiquitously expressed enzyme, DHODH is not typical among most cancer drug targets and is not known to be mutated or overexpressed in malignant cells. Yet empirically, a DHODH-inhibitor therapeutic window exists. The competitive transplantation of hematopoietic stem cells following 36-days of brequinar treatment (at the same dose that is anti-leukemic and pro-differentiation) does not lead to a competitive disadvantage or deleterious differentiation of normal stem cells (Figure 1E). The basis of this therapeutic window in the case of DHODH inhibitors is not known. Here we address the question: how are malignant cells metabolically programmed such that they are preferentially sensitive to pyrimidine starvation following inhibition of DHODH? Uridine is involved in myriad cellular processes beyond DNA and RNA synthesis, implicating many metabolic pathways (Figure 1F). We are taking an approach of (1) measuring metabolite levels and (2) metabolic pathway flux, as well as (3) using small molecule and genetic perturbations (shRNA) to unravel the differences in pyrimidine metabolism between normal and malignant cells. The mechanism through which treatment with brequinar and inhibition of pyrimidine synthesis results in myeloid differentiation is also not known. Our preliminary data suggest that brequinar treatment not only leads to a rapid depletion of pyrimidines and downstream metabolites, but also to changes in TCA cycle metabolites including succinate and fumarate. Given the importance of these metabolites in the regulation of the TET-family of proteins, we measured changes in 5-hydroxy-methylcytosine as a surrogate for TET-enzyme activity following treatment with brequinar (Figure 1G). An increase in global 5hmC, suggesting an increase in TET-enzyme activity, paralleled the cellular differentiation over the first 72-hours. This is an intriguing association given the importance of TET2 in myeloid differentiation and the observation that inhibition of TET2 contributes to myeloid differentiation arrest. As of summer 2018, two small molecule DHODH inhibitors are in early stage human clinical trials with two more inhibitors poised for 2019. A careful understanding of these metabolic pathways is important to inform the clinical experience of this class of anti-metabolite therapeutics. Understanding the basis of this therapeutic window will be critical to the safe and effective use of DHODH inhibitors in patients with advanced hematologic malignancies. Figure 1. Figure 1. Disclosures Vander Heiden: Agios: Membership on an entity's Board of Directors or advisory committees; Aeglea: Membership on an entity's Board of Directors or advisory committees. Sykes:Clear Creek Bio: Equity Ownership, Other: Co-founder.
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Campbell, Andrew W., Ebere C. Anyanwu, and Mohammed Morad. "Evaluation of the Drug Treatment and Persistence of Onychomycosis." Scientific World JOURNAL 4 (2004): 760–77. http://dx.doi.org/10.1100/tsw.2004.134.
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Onychomycosis is a common nail disease responsible for approximately 50% of diseases of the nail. It occurs more in the elderly, though several cases have been reported among children. Several factors influence, such as climate, geography, and migration. The two dermatophytes most commonly implicated in onychomycosis are Trichophyton rubrum and T. mentagrophytes, accounting for more than 90% of onychomycoses. Nonetheless, several other toxigenic molds have been implicated. For convenience, onychomycosis is divided into four major clinical presentations: distal subungal, which is the most common form of the disease; proximal subungal, which is the most common form found in patients with human immunodeficiency virus infection; superficial; and total dystrophic onychomycosis. Epidemiology of onychomycosis in adults and children is evaluated and the most common clinical symptoms addressed. Although the risk factors are discussed, the multifactorial nature of onychomycosis makes this inexhaustible. The diagnosis and treatments are difficult and the choice of appropriate antifungal drugs complex and require the knowledge of the chemical structures of the metabolites of the molds that cause onychomycosis and their interaction with the antifungal drugs. This is true because most of the antifungal drugs are derived from mold/fungal metabolism. Treatment with griseofulvin and amphotericin is displaced by the use of newer drugs from azole compounds, pyrimidines, and allylamines derivatives. Amorolfine, itraconazole, and ciclopirox nail lacquer solution 8 have gained support globally, but the side effects, drug resistance, and persistence of the disease are still a serious concern to the patients, just as economics and quality of life. Hence, the search for safer and more efficacious drug treatments are continuing.
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Chen, Xueying, Min Zhao, and Hong Qu. "Cellular Metabolic Network Analysis: Discovering Important Reactions inTreponema pallidum." BioMed Research International 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/328568.
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T. pallidum, the syphilis-causing pathogen, performs very differently in metabolism compared with other bacterial pathogens. The desire for safe and effective vaccine of syphilis requests identification of important steps inT. pallidum’s metabolism. Here, we apply Flux Balance Analysis to represent the reactions quantitatively. Thus, it is possible to cluster all reactions inT. pallidum. By calculating minimal cut sets and analyzing topological structure for the metabolic network ofT. pallidum, critical reactions are identified. As a comparison, we also apply the analytical approaches to the metabolic network ofH. pylorito find coregulated drug targets and unique drug targets for different microorganisms. Based on the clustering results, all reactions are further classified into various roles. Therefore, the general picture of their metabolic network is obtained and two types of reactions, both of which are involved in nucleic acid metabolism, are found to be essential forT. pallidum. It is also discovered that both hubs of reactions and the isolated reactions in purine and pyrimidine metabolisms play important roles inT. pallidum. These reactions could be potential drug targets for treating syphilis.
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Hartmann, Susen, Jürgen G. Okun, Christiane Schmidt, Claus-Dieter Langhans, Sven F. Garbade, Peter Burgard, Dorothea Haas, Jörn Oliver Sass, William L. Nyhan, and Georg F. Hoffmann. "Comprehensive Detection of Disorders of Purine and Pyrimidine Metabolism by HPLC with Electrospray Ionization Tandem Mass Spectrometry." Clinical Chemistry 52, no. 6 (June 1, 2006): 1127–37. http://dx.doi.org/10.1373/clinchem.2005.058842.
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Abstract Background: Clinical presentation and disease severity in disorders of purine and pyrimidine metabolism vary considerably. We present a method that allows comprehensive, sensitive, and specific diagnosis of the entire spectrum of abnormalities in purine and pyrimidine metabolism in 1 analytical run. Methods: We used reversed-phase HPLC electrospray ionization tandem mass spectrometry to investigate 24 metabolites of purine and pyrimidine metabolism in urine samples from healthy persons and from patients with confirmed diagnoses of inherited metabolic disorders. Urine samples were filtered and diluted to a creatinine concentration of 0.5 mmol/L. Stable-isotope–labeled internal standards were used for quantification. The metabolites were analyzed by multiple-reaction monitoring in positive and negative ionization modes. Results: Total time of analysis was 20 min. Recovery (n = 8) of a compound after addition of a known concentration was 85%–133%. The mean intraday variation (n = 10) was 12%. The interday variation (n = 7) was ≤17%. Age-related reference intervals were established for each compound. Analysis of patient urine samples revealed major differences in tandem mass spectrometry profiles compared with those of control samples. Twelve deficiencies were reliably detected: hypoxanthine guanine phosphoribosyl transferase, xanthine dehydrogenase, purine nucleoside phosphorylase, adenylosuccinate lyase, uridine monophosphate synthase, adenosine deaminase, adenine phosphoribosyl transferase, molybdenum cofactor, thymidine phosphorylase, dihydropyrimidine dehydrogenase, dihydropyrimidinase, and β-ureidopropionase. Conclusion: This method enables reliable detection of 13 defects in purine and pyrimidine metabolism in a single analytical run.
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Vincenzetti, Silvia, Valeria Polzonetti, Daniela Micozzi, and Stefania Pucciarelli. "Enzymology of Pyrimidine Metabolism and Neurodegeneration." Current Medicinal Chemistry 23, no. 14 (May 13, 2016): 1408–31. http://dx.doi.org/10.2174/0929867323666160411125803.
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Cha, Sungman. "Development of inhibitors of pyrimidine metabolism." Yonsei Medical Journal 30, no. 4 (1989): 315. http://dx.doi.org/10.3349/ymj.1989.30.4.315.
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McClarty, G., and B. Qin. "Pyrimidine metabolism by intracellular Chlamydia psittaci." Journal of Bacteriology 175, no. 15 (1993): 4652–61. http://dx.doi.org/10.1128/jb.175.15.4652-4661.1993.
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