Oxidative Stress and the Guanosine Nucleotide Triphosphate Pool: Implications for a Biomarker and Mechanism of Impaired Cell Function
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A Biochemical Rationale for the Discrete Behavior of Nitroxyl and Nitric Oxide in the Cardiovascular System
A biochemical rationale for the discrete behavior of nitroxyl and nitric oxide in the cardiovascular system Katrina M. Miranda*†‡, Nazareno Paolocci§, Tatsuo Katori§, Douglas D. Thomas*, Eleonora Ford¶, Michael D. Bartbergerʈ, Michael G. Espey*, David A. Kass§, Martin Feelisch**, Jon M. Fukuto¶, and David A. Wink*† *Radiation Biology Branch, Building 10, Room B3-B69, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; §Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD 21287; ¶Department of Molecular and Medical Pharmacology, Center for the Health Sciences, University of California, Los Angeles, CA 90095; ʈDepartment of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095; and **Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130 Edited by Louis J. Ignarro, University of California School of Medicine, Los Angeles, CA, and approved May 20, 2003 (received for review February 20, 2003) The redox siblings nitroxyl (HNO) and nitric oxide (NO) have often cellular thiol functions (14, 15). Conversely, NO reacts only indi- been assumed to undergo casual redox reactions in biological sys- rectly with thiols after RNOS formation (17). tems. However, several recent studies have demonstrated distinct Contrasting effects are also apparent in vivo or ex vivo,for pharmacological effects for donors of these two species. Here, infu- example in models of ischemia reperfusion injury. Exposure to NO sion of the HNO donor Angeli’s salt into normal dogs resulted in donors at the onset of reperfusion provides protection against elevated plasma levels of calcitonin gene-related peptide, whereas reperfusion injury in the heart and other organs (18–20). -
Molecular Targets and Biological Functions of Camp Signaling in Arabidopsis
biomolecules Article Molecular Targets and Biological Functions of cAMP Signaling in Arabidopsis Ruqiang Xu 1,2,*, Yanhui Guo 1, Song Peng 1, Jinrui Liu 1, Panyu Li 1, Wenjing Jia 1 and Junheng Zhao 1 1 School of Agricultural Sciences, Zhengzhou University, Zhengzhou 450001, China; [email protected] (Y.G.); [email protected] (S.P.); [email protected] (J.L.); [email protected] (P.L.); [email protected] (W.J.); [email protected] (J.Z.) 2 Zhengzhou Research Base, State Key Laboratory of Cotton Biology, Zhengzhou University, Zhengzhou 450001, China * Correspondence: [email protected]; Tel.: +86-0371-6778-5095 Abstract: Cyclic AMP (cAMP) is a pivotal signaling molecule existing in almost all living organisms. However, the mechanism of cAMP signaling in plants remains very poorly understood. Here, we employ the engineered activity of soluble adenylate cyclase to induce cellular cAMP elevation in Arabidopsis thaliana plants and identify 427 cAMP-responsive genes (CRGs) through RNA-seq analysis. Induction of cellular cAMP elevation inhibits seed germination, disturbs phytohormone contents, promotes leaf senescence, impairs ethylene response, and compromises salt stress tolerance and pathogen resistance. A set of 62 transcription factors are among the CRGs, supporting a prominent role of cAMP in transcriptional regulation. The CRGs are significantly overrepresented in the pathways of plant hormone signal transduction, MAPK signaling, and diterpenoid biosynthesis, but + they are also implicated in lipid, sugar, K , nitrate signaling, and beyond. Our results provide a basic framework of cAMP signaling for the community to explore. The regulatory roles of cAMP signaling Citation: Xu, R.; Guo, Y.; Peng, S.; in plant plasticity are discussed. -
Deoxyguanosine Cytotoxicity by a Novel Inhibitor of Furine Nucleoside Phosphorylase, 8-Amino-9-Benzylguanine1
[CANCER RESEARCH 46, 519-523, February 1986] Potentiation of 2'-Deoxyguanosine Cytotoxicity by a Novel Inhibitor of Furine Nucleoside Phosphorylase, 8-Amino-9-benzylguanine1 Donna S. Shewach,2 Ji-Wang Chern, Katherine E. Pillóte,Leroy B. Townsend, and Peter E. Daddona3 Departments of Internal Medicine [D.S.S., P.E.D.], Biological Chemistry [P.E.D.], and Medicinal Chemistry [J-W.C., K.E.P., L.B.T.], University ol Michigan, Ann Arbor, Michigan 48109 ABSTRACT to the ADA-deficient disease state (2). PNP is an essential enzyme of the purine salvage pathway, We have synthesized and evaluated a series of 9-substituted catalyzing the phosphorolysis of guanosine, inosine, and their analogues of 8-aminoguanine, a known inhibitor of human purine 2'-deoxyribonucleoside derivatives to the respective purine nucleoside phosphorylase (PNP) activity. The ability of these bases. To date, several inhibitors of PNP have been identified, agents to inhibit PNP has been investigated. All compounds were and most of these compounds resemble purine bases or nucleo found to act as competitive (with inosine) inhibitors of PNP, with sides. The most potent inhibitors exhibit apparent K¡values in K¡values ranging from 0.2 to 290 /¿M.Themost potent of these the range of 10~6to 10~7 M (9-12). Using partially purified human analogues, 8-amino-9-benzylguanine, exhibited a K, value that erythrocyte PNP, the diphosphate derivative of acyclovir dis was 4-fold lower than that determined for the parent base, 8- played K¡values of 5.1 x 10~7 to 8.7 x 10~9 M, depending on aminoguanine. -
Nucleotide Metabolism
NUCLEOTIDE METABOLISM General Overview • Structure of Nucleotides Pentoses Purines and Pyrimidines Nucleosides Nucleotides • De Novo Purine Nucleotide Synthesis PRPP synthesis 5-Phosphoribosylamine synthesis IMP synthesis Inhibitors of purine synthesis Synthesis of AMP and GMP from IMP Synthesis of NDP and NTP from NMP • Salvage pathways for purines • Degradation of purine nucleotides • Pyrimidine synthesis Carbamoyl phosphate synthesisOrotik asit sentezi • Pirimidin nükleotitlerinin yıkımı • Ribonükleotitlerin deoksiribonükleotitlere dönüşümü Basic functions of nucleotides • They are precursors of DNA and RNA. • They are the sources of activated intermediates in lipid and protein synthesis (UDP-glucose→glycogen, S-adenosylmathionine as methyl donor) • They are structural components of coenzymes (NAD(P)+, FAD, and CoA). • They act as second messengers (cAMP, cGMP). • They play important role in carrying energy (ATP, etc). • They play regulatory roles in various pathways by activating or inhibiting key enzymes. Structures of Nucleotides • Nucleotides are composed of 1) A pentose monosaccharide (ribose or deoxyribose) 2) A nitrogenous base (purine or pyrimidine) 3) One, two or three phosphate groups. Pentoses 1.Ribose 2.Deoxyribose •Deoxyribonucleotides contain deoxyribose, while ribonucleotides contain ribose. •Ribose is produced in the pentose phosphate pathway. Ribonucleotide reductase converts ribonucleoside diphosphate deoxyribonucleotide. Nucleotide structure-Base 1.Purine 2.Pyrimidine •Adenine and guanine, which take part in the structure -
2'-Deoxyguanosine Toxicity for B and Mature T Lymphoid Cell Lines Is Mediated by Guanine Ribonucleotide Accumulation
2'-deoxyguanosine toxicity for B and mature T lymphoid cell lines is mediated by guanine ribonucleotide accumulation. Y Sidi, B S Mitchell J Clin Invest. 1984;74(5):1640-1648. https://doi.org/10.1172/JCI111580. Research Article Inherited deficiency of the enzyme purine nucleoside phosphorylase (PNP) results in selective and severe T lymphocyte depletion which is mediated by its substrate, 2'-deoxyguanosine. This observation provides a rationale for the use of PNP inhibitors as selective T cell immunosuppressive agents. We have studied the relative effects of the PNP inhibitor 8- aminoguanosine on the metabolism and growth of lymphoid cell lines of T and B cell origin. We have found that 2'- deoxyguanosine toxicity for T lymphoblasts is markedly potentiated by 8-aminoguanosine and is mediated by the accumulation of deoxyguanosine triphosphate. In contrast, the growth of T4+ mature T cell lines and B lymphoblast cell lines is inhibited by somewhat higher concentrations of 2'-deoxyguanosine (ID50 20 and 18 microM, respectively) in the presence of 8-aminoguanosine without an increase in deoxyguanosine triphosphate levels. Cytotoxicity correlates instead with a three- to fivefold increase in guanosine triphosphate (GTP) levels after 24 h. Accumulation of GTP and growth inhibition also result from exposure to guanosine, but not to guanine at equimolar concentrations. B lymphoblasts which are deficient in the purine salvage enzyme hypoxanthine guanine phosphoribosyltransferase are completely resistant to 2'-deoxyguanosine or guanosine concentrations up to 800 microM and do not demonstrate an increase in GTP levels. Growth inhibition and GTP accumulation are prevented by hypoxanthine or adenine, but not by 2'-deoxycytidine. -
Mechanisms Whereby Extracellular Adenosine 3',5'- Monophosphate Inhibits Phosphate Transport in Cultured Opossum Kidney Cells and in Rat Kidney
Mechanisms whereby extracellular adenosine 3',5'- monophosphate inhibits phosphate transport in cultured opossum kidney cells and in rat kidney. Physiological implication. G Friedlander, … , C Coureau, C Amiel J Clin Invest. 1992;90(3):848-858. https://doi.org/10.1172/JCI115960. Research Article The mechanism of phosphaturia induced by cAMP infusion and the physiological role of extracellular cAMP in modulation of renal phosphate transport were examined. In cultured opossum kidney cells, extracellular cAMP (10-1,000 microM) inhibited Na-dependent phosphate uptake in a time- and concentration-dependent manner. The effect of cAMP was reproduced by ATP, AMP, and adenosine, and was blunted by phosphodiesterase inhibitors or by dipyridamole which inhibits adenosine uptake. [3H]cAMP was degraded extracellularly into AMP and adenosine, and radioactivity accumulated in the cells as labeled adenosine and, subsequently, as adenine nucleotides including cAMP. Radioactivity accumulation was decreased by dipyridamole and by inhibitors of phosphodiesterases and ecto-5'-nucleotidase, assessing the existence of stepwise hydrolysis of extracellular cAMP and intracellular processing of taken up adenosine. In vivo, dipyridamole abolished the phosphaturia induced by exogenous cAMP infusion in acutely parathyroidectomized (APTX) rats, decreased phosphate excretion in intact rats, and blunted phosphaturia induced by PTH infusion in APTX rats. These results indicate that luminal degradation of cAMP into adenosine, followed by cellular uptake of the nucleoside by tubular cells, is a key event which accounts for the phosphaturic effect of exogenous cAMP and for the part of the phosphaturic effect of PTH which is mediated by cAMP added to the tubular lumen under the influence of the hormone. -
Download Product Insert (PDF)
Product Information DEA NONOate Item No. 82100 CAS Registry No.: 372965-00-9 Formal Name: Diethylammonium (Z)-1-(N,N- diethylamino)diazen-1-ium-1,2-diolate O Synonyms: DEA/NO, Diethylamine NONOate N MF: C4H10N3O2 • C4H12N + N N • H N FW: 206.3 2 Purity: ≥98% O- Stability: ≥1 year at -80°C Supplied as: A crystalline solid l UV/Vis.: max: 250 nm Laboratory Procedures For long term storage, keep DEA NONOate sealed under nitrogen at -80°C. It should be stable for at least one year. The crystals are sensitive to moisture and become discolored on exposure to air. Keep the vial sealed until use unless your laboratory is equipped with a glove box with an inert atmosphere for the handling of air sensitive compounds. DEA NONOate is supplied as a crystalline solid. A stock solution may be made by dissolving the DEA NONOate in an organic solvent purged with an inert gas. DEA NONOate is soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide (DMF). The solubility of DEA NONOate is approximately 25 mg/ml in ethanol and 2 mg/ml in DMSO and DMF. Further dilutions of the stock solution into aqueous buffers or isotonic saline should be made prior to performing biological experiments. Ensure that the residual amount of organic solvent is insignificant, since organic solvents may have physiological effects at low concentrations. Organic solvent-free aqueous solutions of DEA NONOate can be prepared by directly dissolving the crystalline compound in aqueous buffers. The solubility of DEA NONOate in PBS (pH 7.2) is approximately 10 mg/ml. -
Genetic Variation in Phosphodiesterase (PDE) 7B in Chronic Lymphocytic Leukemia: Overview of Genetic Variants of Cyclic Nucleotide Pdes in Human Disease
Journal of Human Genetics (2011) 56, 676–681 & 2011 The Japan Society of Human Genetics All rights reserved 1434-5161/11 $32.00 www.nature.com/jhg ORIGINAL ARTICLE Genetic variation in phosphodiesterase (PDE) 7B in chronic lymphocytic leukemia: overview of genetic variants of cyclic nucleotide PDEs in human disease Ana M Peiro´ 1,2, Chih-Min Tang1, Fiona Murray1,3, Lingzhi Zhang1, Loren M Brown1, Daisy Chou1, Laura Rassenti4, Thomas A Kipps3,4 and Paul A Insel1,3,4 Expression of cyclic adenosine monophosphate-specific phosphodiesterase 7B (PDE7B) mRNA is increased in patients with chronic lymphocytic leukemia (CLL), thus suggesting that variation may occur in the PDE7B gene in CLL. As genetic variation in other PDE family members has been shown to associate with numerous clinical disorders (reviewed in this manuscript), we sought to identify single-nucleotide polymorphisms (SNPs) in the PDE7B gene promoter and coding region of 93 control subjects and 154 CLL patients. We found that the PDE7B gene has a 5¢ non-coding region SNP À347C4T that occurs with similar frequency in CLL patients (1.9%) and controls (2.7%). Tested in vitro, À347C4T has less promoter activity than a wild-type construct. The low frequency of this 5¢ untranslated region variant indicates that it does not explain the higher PDE7B expression in patients with CLL but it has the potential to influence other settings that involve a role for PDE7B. Journal of Human Genetics (2011) 56, 676–681; doi:10.1038/jhg.2011.80; published online 28 July 2011 Keywords: cAMP; chronic lymphocytic -
Current Advances of Nitric Oxide in Cancer and Anticancer Therapeutics
Review Current Advances of Nitric Oxide in Cancer and Anticancer Therapeutics Joel Mintz 1,†, Anastasia Vedenko 2,†, Omar Rosete 3 , Khushi Shah 4, Gabriella Goldstein 5 , Joshua M. Hare 2,6,7 , Ranjith Ramasamy 3,6,* and Himanshu Arora 2,3,6,* 1 Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Davie, FL 33328, USA; [email protected] 2 John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; [email protected] (A.V.); [email protected] (J.M.H.) 3 Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; [email protected] 4 College of Arts and Sciences, University of Miami, Miami, FL 33146, USA; [email protected] 5 College of Health Professions and Sciences, University of Central Florida, Orlando, FL 32816, USA; [email protected] 6 The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA 7 Department of Medicine, Cardiology Division, Miller School of Medicine, University of Miami, Miami, FL 33136, USA * Correspondence: [email protected] (R.R.); [email protected] (H.A.) † These authors contributed equally to this work. Abstract: Nitric oxide (NO) is a short-lived, ubiquitous signaling molecule that affects numerous critical functions in the body. There are markedly conflicting findings in the literature regarding the bimodal effects of NO in carcinogenesis and tumor progression, which has important consequences for treatment. Several preclinical and clinical studies have suggested that both pro- and antitumori- Citation: Mintz, J.; Vedenko, A.; genic effects of NO depend on multiple aspects, including, but not limited to, tissue of generation, the Rosete, O.; Shah, K.; Goldstein, G.; level of production, the oxidative/reductive (redox) environment in which this radical is generated, Hare, J.M; Ramasamy, R.; Arora, H. -
Nucleotide Metabolism 22
Nucleotide Metabolism 22 For additional ancillary materials related to this chapter, please visit thePoint. I. OVERVIEW Ribonucleoside and deoxyribonucleoside phosphates (nucleotides) are essential for all cells. Without them, neither ribonucleic acid (RNA) nor deoxyribonucleic acid (DNA) can be produced, and, therefore, proteins cannot be synthesized or cells proliferate. Nucleotides also serve as carriers of activated intermediates in the synthesis of some carbohydrates, lipids, and conjugated proteins (for example, uridine diphosphate [UDP]-glucose and cytidine diphosphate [CDP]- choline) and are structural components of several essential coenzymes, such as coenzyme A, flavin adenine dinucleotide (FAD[H2]), nicotinamide adenine dinucleotide (NAD[H]), and nicotinamide adenine dinucleotide phosphate (NADP[H]). Nucleotides, such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), serve as second messengers in signal transduction pathways. In addition, nucleotides play an important role as energy sources in the cell. Finally, nucleotides are important regulatory compounds for many of the pathways of intermediary metabolism, inhibiting or activating key enzymes. The purine and pyrimidine bases found in nucleotides can be synthesized de novo or can be obtained through salvage pathways that allow the reuse of the preformed bases resulting from normal cell turnover. [Note: Little of the purines and pyrimidines supplied by diet is utilized and is degraded instead.] II. STRUCTURE Nucleotides are composed of a nitrogenous base; a pentose monosaccharide; and one, two, or three phosphate groups. The nitrogen-containing bases belong to two families of compounds: the purines and the pyrimidines. A. Purine and pyrimidine bases Both DNA and RNA contain the same purine bases: adenine (A) and guanine (G). -
De Novo Deoxyribonucleotide Biosynthesis Regulates Cell Growth
www.nature.com/scientificreports OPEN De novo deoxyribonucleotide biosynthesis regulates cell growth and tumor progression in small‑cell lung carcinoma Ami Maruyama1,2,3, Yuzo Sato1,2,4,5, Joji Nakayama1,2,3, Junko Murai4,5, Takamasa Ishikawa5,6, Tomoyoshi Soga4,5 & Hideki Makinoshima1,2,3,7* Deoxyribonucleotide biosynthesis from ribonucleotides supports the growth of active cancer cells by producing building blocks for DNA. Although ribonucleotide reductase (RNR) is known to catalyze the rate‑limiting step of de novo deoxyribonucleotide triphosphate (dNTP) synthesis, the biological function of the RNR large subunit (RRM1) in small‑cell lung carcinoma (SCLC) remains unclear. In this study, we established siRNA‑transfected SCLC cell lines to investigate the anticancer efect of silencing RRM1 gene expression. We found that RRM1 is required for the full growth of SCLC cells both in vitro and in vivo. In particular, the deletion of RRM1 induced a DNA damage response in SCLC cells and decreased the number of cells with S phase cell cycle arrest. We also elucidated the overall changes in the metabolic profle of SCLC cells caused by RRM1 deletion. Together, our fndings reveal a relationship between the deoxyribonucleotide biosynthesis axis and key metabolic changes in SCLC, which may indicate a possible link between tumor growth and the regulation of deoxyribonucleotide metabolism in SCLC. Small-cell lung carcinoma (SCLC) is a neuroendocrine tumor subtype of lung cancer, and it is associated with a poor prognosis1–3. In particular, SCLC is characterized by early and widespread metastatic dissemination and a remarkable response to chemotherapy that is almost invariably followed by the development of drug resistance4. -
Bioenergetics, ATP & Enzymes
Bioenergetics, ATP & Enzymes Some Important Compounds Involved in Energy Transfer and Metabolism Bioenergetics can be defined as all the energy transfer mechanisms occurring within living organisms. Energy transfer is necessary because energy cannot be created and it cannot be destroyed (1st law of thermodynamics). Organisms can acquire energy from chemicals (chemotrophs) or they can acquire it from light (phototrophs), but they cannot make it. Thermal energy (heat) from the environment can influence the rate of chemical reactions, but is not generally considered an energy source organisms can “capture” and put to specific uses. Metabolism, all the chemical reactions occurring within living organisms, is linked to bioenergetics because catabolic reactions release energy (are exergonic) and anabolic reactions require energy (are endergonic). Various types of high-energy compounds can “donate” the energy required to drive endergonic reactions, but the most commonly used energy source within cells is adenosine triphosphate (ATP), a type of coenzyme. When this molecule is catabolized (broken down), the energy released can be used to drive a wide variety of synthesis reactions. Endergonic reactions required for the synthesis of nucleic acids (DNA and RNA) are exceptions because all the nucleotides incorporated into these molecules are initially high-energy molecules as described below. The nitrogenous base here is adenine, the sugar is the pentose monosaccharide ribose and there are three phosphate groups attached. The sugar and the base form a molecule called a nucleoside, and the number of phosphate groups bound to the nucleoside is variable; thus alternative forms of this molecule occur as adenosine monophosphate (AMP) and adenosine diphosphate (ADP).