Mechanisms of Synthesis of Purine Nucleotides in Heart Muscle Extracts
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Nucleotide Degradation
Nucleotide Degradation Nucleotide Degradation The Digestion Pathway • Ingestion of food always includes nucleic acids. • As you know from BI 421, the low pH of the stomach does not affect the polymer. • In the duodenum, zymogens are converted to nucleases and the nucleotides are converted to nucleosides by non-specific phosphatases or nucleotidases. nucleases • Only the non-ionic nucleosides are taken & phospho- diesterases up in the villi of the small intestine. Duodenum Non-specific phosphatases • In the cell, the first step is the release of nucleosides) the ribose sugar, most effectively done by a non-specific nucleoside phosphorylase to give ribose 1-phosphate (Rib1P) and the free bases. • Most ingested nucleic acids are degraded to Rib1P, purines, and pyrimidines. 1 Nucleotide Degradation: Overview Fate of Nucleic Acids: Once broken down to the nitrogenous bases they are either: Nucleotides 1. Salvaged for recycling into new nucleic acids (most cells; from internal, Pi not ingested, nucleic Nucleosides acids). Purine Nucleoside Pi aD-Rib 1-P (or Rib) 2. Oxidized (primarily in the Phosphorylase & intestine and liver) by first aD-dRib 1-P (or dRib) converting to nucleosides, Bases then to –Uric Acid (purines) –Acetyl-CoA & Purine & Pyrimidine Oxidation succinyl-CoA Salvage Pathway (pyrimidines) The Salvage Pathways are in competition with the de novo biosynthetic pathways, and are both ANABOLISM Nucleotide Degradation Catabolism of Purines Nucleotides: Nucleosides: Bases: 1. Dephosphorylation (via 5’-nucleotidase) 2. Deamination and hydrolysis of ribose lead to production of xanthine. 3. Hypoxanthine and xanthine are then oxidized into uric acid by xanthine oxidase. Spiders and other arachnids lack xanthine oxidase. -
Allopurinol Sodium) for Injection 500 Mg
ALOPRIM® (allopurinol sodium) for Injection 500 mg [al'-ō-prĭm] For Intravenous Infusion Only Rx only DESCRIPTION: ALOPRIM (allopurinol sodium) for Injection is the brand name for allopurinol, a xanthine oxidase inhibitor. ALOPRIM (allopurinol sodium) for Injection is a sterile solution for intravenous infusion only. It is available in vials as the sterile lyophilized sodium salt of allopurinol equivalent to 500 mg of allopurinol. ALOPRIM (allopurinol sodium) for Injection contains no preservatives. The chemical name for allopurinol sodium is 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin 4-one monosodium salt. It is a white amorphous mass with a molecular weight of 158.09 and molecular formula C5H3N4NaO. The structural formula is: The pKa of allopurinol sodium is 9.31. CLINICAL PHARMACOLOGY: Allopurinol acts on purine catabolism without disrupting the biosynthesis of purines. It reduces the production of uric acid by inhibiting the biochemical reactions immediately preceding its formation. The degree of this decrease is dose dependent. Allopurinol is a structural analogue of the natural purine base, hypoxanthine. It is an inhibitor of xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid, the end product of purine metabolism in man. Allopurinol is metabolized to the corresponding xanthine analogue, oxypurinol (alloxanthine), which also is an inhibitor of xanthine oxidase. Reutilization of both hypoxanthine and xanthine for nucleotide and nucleic acid synthesis is markedly enhanced when their oxidations are inhibited by allopurinol and oxypurinol. This reutilization does not disrupt normal nucleic acid anabolism, however, because feedback inhibition is an integral part of purine biosynthesis. -
Calcium 5'-Ribonucleotides
CALCIUM 5'-RIBONUCLEOTIDES Prepared at the 18th JECFA (1974), published in NMRS 54B (1975) and in FNP 52 (1992). Metals and arsenic specifications revised at the 57th JECFA (2001). An ADI ‘not specified’ was established at the 18th JECFA (1974). SYNONYMS Calcium ribonucleotides, INS No. 634 DEFINITION Chemical names (Mixture of) calcium inosine-5'-monophosphate and calcium guanosine-5'- monophosphate Chemical formula C10H11CaN4O8P · x H2O and C10H12CaN5O8P · x H2O Structural formula Calcium 5’-guanylate Calcium 5’-inosinate Assay Not less than 97% and not more than the equivalent of 102% of C10H11CaN4O8P and C10H12CaN5O8P, calculated on the anhydrous basis. The proportion of C10H11CaN4O8P or C10H12CaN5O8P to the sum of them is between 47% and 53%. DESCRIPTION Odourless, white or off-white crystals or powder FUNCTIONAL USES Flavour enhancer CHARACTERISTICS IDENTIFICATION Solubility (Vol. 4) Sparingly soluble in water Test for ribose (Vol. 4) Passes test Test for organic phosphate Passes test (Vol. 4) Test 5 ml of a 1 in 2,000 solution Test for inosinic acid To 2 ml of a 1 in 2,000 solution add 2 ml of 10% hydrochloric acid and 0.1 g of zinc powder, heat in a water bath for 10 min, and filter. Cool the filtrate in ice water, add 1 ml of a 3 in 1,000 sodium nitrite solution, shake well, and allow to stand for 10 min. Add 1 ml of a 1 in 200 ammonium sulfamate solution, shake well, and allow to stand for 5 min. Add 1 ml of a 1 in 500 N-(1- naphthyl)-ethylenediamine dihydrochloride solution. -
Effects of Allopurinol and Oxipurinol on Purine Synthesis in Cultured Human Cells
Effects of allopurinol and oxipurinol on purine synthesis in cultured human cells William N. Kelley, James B. Wyngaarden J Clin Invest. 1970;49(3):602-609. https://doi.org/10.1172/JCI106271. Research Article In the present study we have examined the effects of allopurinol and oxipurinol on thed e novo synthesis of purines in cultured human fibroblasts. Allopurinol inhibits de novo purine synthesis in the absence of xanthine oxidase. Inhibition at lower concentrations of the drug requires the presence of hypoxanthine-guanine phosphoribosyltransferase as it does in vivo. Although this suggests that the inhibitory effect of allopurinol at least at the lower concentrations tested is a consequence of its conversion to the ribonucleotide form in human cells, the nucleotide derivative could not be demonstrated. Several possible indirect consequences of such a conversion were also sought. There was no evidence that allopurinol was further utilized in the synthesis of nucleic acids in these cultured human cells and no effect of either allopurinol or oxipurinol on the long-term survival of human cells in vitro could be demonstrated. At higher concentrations, both allopurinol and oxipurinol inhibit the early steps ofd e novo purine synthesis in the absence of either xanthine oxidase or hypoxanthine-guanine phosphoribosyltransferase. This indicates that at higher drug concentrations, inhibition is occurring by some mechanism other than those previously postulated. Find the latest version: https://jci.me/106271/pdf Effects of Allopurinol and Oxipurinol on Purine Synthesis in Cultured Human Cells WILLIAM N. KELLEY and JAMES B. WYNGAARDEN From the Division of Metabolic and Genetic Diseases, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27706 A B S TR A C T In the present study we have examined the de novo synthesis of purines in many patients. -
Alternative Pathways of Glucose Metabolism II. Nucleotides from The
Alternative Pathways of Glucose Metabolism II . Nucleotides from the Acid-soluble Fraction of Normal and Tumor Tissues and Studies on Nucleic Acid Synthesis in Tumors*t HANNS SCHMITZ4 VAN R. POTTER, ROBERT B. HTJRLBERT,@ AND DWAIN M. WHITE (McArdie Memovial Laboratory, the Medical School, University of Wisconain, Madison, WI..) The first paper (18) in this series on the alterna MATERIALS AND METHODS tive pathways of glucose metabolism established The present study has involved the measure the fact that radioactivity from glucose-i-C'4 was ment of the specific activities of the free 5' mono-, readily incorporated into the pentose moiety of the di-, and triphosphates of adenosine, guanosine, ribonucleic and desoxyribonucleic acids of Flexner cytidine, and uridine from the acid-soluble extract Jobling tumors in rats, and described the over-all of tumor tissue in relation to the specific activities distribution of radioactivity in the acid-soluble of the corresponding nucleotides that were oh and acid-insoluble fractions of tumor and liver tis tamed by chemical or enzymatic hydrolysis of the sue at various time periods. The acid-soluble frac nucleic acids from the same tissue samples, at tion of tissue contains an appreciable amount of specified time intervals after the injection of glu free nucleotides which are possible intermediary cose-1-C'4. The experimental plan corresponds compounds in the synthesis of the nucleic acids exactly to that described in the preceding paper; (6, 7, 8, 9, 13, 16). It was noted (18) that as the C'4 many of -
Mechanism of Excessive Purine Biosynthesis in Hypoxanthine- Guanine Phosphoribosyltransferase Deficiency
Mechanism of excessive purine biosynthesis in hypoxanthine- guanine phosphoribosyltransferase deficiency Leif B. Sorensen J Clin Invest. 1970;49(5):968-978. https://doi.org/10.1172/JCI106316. Research Article Certain gouty subjects with excessive de novo purine synthesis are deficient in hypoxanthineguanine phosphoribosyltransferase (HG-PRTase [EC 2.4.2.8]). The mechanism of accelerated uric acid formation in these patients was explored by measuring the incorporation of glycine-14C into various urinary purine bases of normal and enzyme-deficient subjects during treatment with the xanthine oxidase inhibitor, allopurinol. In the presence of normal HG-PRTase activity, allopurinol reduced purine biosynthesis as demonstrated by diminished excretion of total urinary purine or by reduction of glycine-14C incorporation into hypoxanthine, xanthine, and uric acid to less than one-half of control values. A boy with the Lesch-Nyhan syndrome was resistant to this effect of allopurinol while a patient with 12.5% of normal enzyme activity had an equivocal response. Three patients with normal HG-PRTase activity had a mean molar ratio of hypoxanthine to xanthine in the urine of 0.28, whereas two subjects who were deficient in HG-PRTase had reversal of this ratio (1.01 and 1.04). The patterns of 14C-labeling observed in HG-PRTase deficiency reflected the role of hypoxanthine as precursor of xanthine. The data indicate that excessive uric acid in HG-PRTase deficiency is derived from hypoxanthine which is insufficiently reutilized and, as a consequence thereof, catabolized inordinately to uric acid. The data provide evidence for cyclic interconversion of adenine and hypoxanthine derivatives. Cleavage of inosinic acid to hypoxanthine via inosine does […] Find the latest version: https://jci.me/106316/pdf Mechanism of Excessive Purine Biosynthesis in Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency LEIF B. -
Nucleotide Metabolism II
Nucleotide Metabolism II • Biosynthesis of deoxynucleotides • Salvage Pathway • Catabolism: Purines • Catabolism: Pyrimidines • Feedback inhibition in purine nucleotide biosynthesis CPS II • Cytosolic CPS II uses glutamine as the nitrogen donor to carbamoyl phosphate Regulation of pyrimidine synthesis •CPSII is allosterically regulated: PRPP and IMP are activators Several pyrimidines are inhibitors • Aspartate transcarbamoylase (ATCase) Important regulatory point in prokaryotes Catalyzes the first committed pathway step Allosteric regulators: CTP (-), CTP + UTP (-), ATP (+) • Regulation of pyrimidine nucleotide synthesis in E. coli Biosynthesis of deoxynucleotides • Uses diphosphates (ribo) • Ribonucleotide reducatase • 2 sub-units • R1- reduces, active and two allosteric sites (activity and specificity site) • R2- tyrosine radical carries electrons • removes 2' OH to H Ribonucleotide reductase reaction • removes 2' OH to H • Thioredoxin and NADPH used to regenerate sulfhydryl groups Thymidylate synthesis • UDP ------> dUMP • dUMP --------> dTMP • required THF • methylates uracil Regulation THF • Mammals cannot conjugate rings or synthesize PABA. • So must get in diet. • Sulfonamides effective in bacteria due to competitive inhibition of the incorporation of PABA Cancer Drugs • fluorouracil-- suicide inhibitor of Thy synthase • aminopterin • Methotrexate -- inhibits DHF reductase Salvage of Purines and Pyrimidines • During cellular metabolism or digestion, nucleic acids are degraded to heterocyclic bases • These bases can be salvaged -
Effects of Salt Stress on Adenine and Uridine Nucleotide Pools, Sugar and Acid-Soluble Phosphate in Shoots of Pepper and Safflower
Journal of Experimental Botany, Vol. 39, No. 200, pp. 301-309, March 1988 Effects of Salt Stress on Adenine and Uridine Nucleotide Pools, Sugar and Acid-Soluble Phosphate in Shoots of Pepper and Safflower R. H. NIEMAN, R. A. CLARK, D. PAP, G. OGATA AND E. V. MAAS USDA, ARS, U.S. Salinity Laboratory, Riverside, California, U.S.A. Received 7 September 1987 ABSTRACT Nieman, R. H., Clark, R. A., Pap, D., Ogata, G. and Maas, E. V. 1988. Effects of salt stress on adenine and uridine nucleotide pools, sugar and acid-soluble phosphate in shoots of pepper and safflower.—J. exp. Bot. 39: 301-309. Pepper (Capsicum annuum cv. Yolo wonder) and safflower (Carthamus tmctonus L. cv. Gila) were 3 3 grown hydroponically and subjected to a salt stress (51 mol m" NaCl plus 25-5 mol m" CaCl2). Mature photosynthetic source leaves and shoot meristematic sinks (young pepper leaves and safflower buds) were analyzed for nucleotides by high performance liquid chromatography and for hexose and acid-soluble P—pepper was still vegetative whereas safflower had switched to flower bud formation—the salt stress reduced the fresh shoot yield of pepper by nearly two-thirds and of safflower by half. It reduced the ATP pool and ATP/ADP ratio in the source leaves of both species and also in the young pepper leaves. It had little or no effect on ATP or other nucleotide pools in safflower buds. The UDPG pool was not affected in source leaves or safflower buds, but in the young pepper leaves it was reduced by half, along with UTP. -
Natural Health Products As Modulators of Adenosine and ATP
s Chemis ct try u d & Kolathuru and Yeung, Nat Prod Chem Res 2014, 2:5 o r R P e s l e a r a DOI: 10.4172/2329-6836.1000e109 r u t c h a N Natural Products Chemistry & Research ISSN: 2329-6836 Editorial Open Access Natural Health Products as Modulators of Adenosine and ATP Metabolism for Cardiovascular Protection Shyam Sundar Kolathuru and Pollen K Yeung* College of Pharmacy and Department of Medicine, Dalhousie University, Halifax, NS, Canada Introduction Adenosine Receptors and Cardiovascular Protection Adenosine is an important endogenous purine nucleoside and Adenosine is a key mediator in ischemia preconditioning which an essential component of the molecular energy generated from is an important factor responsible for cardiovascular protection [20]. adenosine 5’-triphosphate (ATP). It acts as both a precursor and Adenosine modulates its actions via membrane bound adenosine metabolite of adenine nucleotides. As every cell utilizes the energy receptors which are coupled to G-protein and subdivided into 4 generated from catabolism of ATP, adenosine is found ubiquitously in different subtypes: 1A , A2a, A2b and A3 [21-23]. Cross-talks between the body. It is also a signaling molecule in the cardiovascular system, the receptors are known to occur which self regulates and provokes a and its role for cardioprotection and cardiovascular homeostasis has specific cardiovascular response. For example activation of A1 receptor been studied for over 80 years [1-3]. Adenosine is also known as a induces vasoconstriction which counteracts the A2 mediated dilating “homeostatic metabolite in cardiac energy metabolism” [4] owing to effect on vascular tone [24]. -
Shaping Rolling Circle Amplification Products Into DNA Nanoparticles by Incorporation of Modified Nucleotides and Their Applicat
molecules Communication Shaping Rolling Circle Amplification Products into DNA Nanoparticles by Incorporation of Modified Nucleotides and Their Application to In Vitro and In Vivo Delivery of a Photosensitizer Kyoung-Ran Kim 1, Pascal Röthlisberger 2, Seong Jae Kang 1, Kihwan Nam 3, Sangyoup Lee 3, Marcel Hollenstein 2 ID and Dae-Ro Ahn 1,4,* ID 1 Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Korea; [email protected] (K.-R.K.); [email protected] (S.J.K.) 2 Department of Structural Biology and Chemistry, Laboratory for Bioorganic Chemistry of Nucleic Acids, Institut Pasteur, CNRS UMR3523, 28, rue du Docteur Roux, 75724 Paris CEDEX 15, France; [email protected] (P.R.); [email protected] (M.H.) 3 Center for Bionics, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Korea; [email protected] (K.N.); [email protected] (S.L.) 4 Division of Biomedical Science and Technology, KIST School, Korea University of Science and Technology (UST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Korea * Correspondence: [email protected] Academic Editor: Shigeki Sasaki Received: 10 June 2018; Accepted: 20 July 2018; Published: 23 July 2018 Abstract: Rolling circle amplification (RCA) is a robust way to generate DNA constructs, which are promising materials for biomedical applications including drug delivery because of their high biocompatibility. To be employed as a drug delivery platform, however, the DNA materials produced by RCA need to be shaped into nanoparticles that display both high cellular uptake efficiency and nuclease resistance. -
Overview of the Synthesis of Nucleoside Phosphates and Polyphosphates 13.1.6
Overview of the Synthesis of Nucleoside UNIT 13.1 Phosphates and Polyphosphates Phosphorylated nucleosides play a domi- ity to the synthesis. Side reactions can occur, nant role in biochemistry. Primary metabolism, such as depurination of the nucleoside, phos- DNA replication and repair, RNA synthesis, phorylation of the nucleobase, as well as chemi- protein synthesis, signal transduction, polysac- cal alteration of nucleobase analogs. Due to charide biosynthesis, and enzyme regulation their intrinsic reactivity, the synthesis of phos- are just a handful of processes involving these phoanhydride bonds is also synthetically chal- molecules. Literally thousands of enzymes use lenging. Phosphate anhydrides are phosphory- these compounds as substrates and/or regula- lating reagents that are readily degraded under tors. The need to obtain such compounds in acidic conditions. Finally, purification of syn- both labeled and unlabeled forms, as well as a thetic nucleotides can be problematic. Ionic burgeoning need for analogs, has driven the reagents, starting materials, and mixtures of development of a myriad of chemical and en- regioisomers (2′-, 3′-, 5′-phosphates) can be zymatic synthetic approaches. As chemical en- particularly difficult to separate from the de- tities, few molecules possess the wide array of sired product. densely packed functionality present in phos- In spite of the many potential difficulties phorylated nucleosides. This poses a formida- associated with nucleoside phosphorylation ble challenge to the synthetic chemist, one that and polyphosphorylation, a certain amount of has not yet been fully overcome. This overview success has been achieved in these areas. Given will address some common methods (synthetic the wealth of phosphorylating reagents avail- and enzymatic) used to construct phosphory- able, simple phosphorylation of nucleosides at lated nucleosides. -
Metabolite Standards Detected by UHPLC-HRMS
Metabolite standards detected by UHPLC-HRMS #ID NAME 1 - 1,2-DIDECANOYL-SN-GLYCERO-3-PHOSPHOCHOLINE 2 - 10-HYDROXYDECANOATE 3 - 1-HYDROXY-2-NAPHTHOATE 4 - 2,4-DIHYDROXYPTERIDINE 5 - 2,6-DIHYDROXYPYRIDINE 6 - 2-Sulfoaniline 7 - 3-AMINO-4-HYDROXYBENZOATE 8 - 3-AMINO-5-HYDROXYBENZOATE 9 - 3-Hydroxyphenyl acetate 10 - 3-METHYL-2-OXINDOLE 11 - 3-NITRO-L-TYROSINE 12 - 4-QUINOLINECARBOXYLATE 13 - 4-QUINOLINECARBOXYLIC ACID 14 - ANILINE-2-SULFONATE (2-SULFOANILINE) 15 - BIS(2-ETHYLHEXYL)PHTHALATE 16 - CORTISOL 21-ACETATE 17 - delta-Valerolactone 18 - DEOXYCORTICOSTERONE ACETATE 19 - DIDECANOYL-GLYCEROPHOSPHOCHOLINE 20 - D-MANNOSAMINE 21 - ETHYL 3-INDOLEACETATE 22 - GALACTOSAMINE 23 - GLUCOSAMINATE 24 - Hydrocortisone acetate 25 - Hydrocortisone acetate (CORTISOL 21-ACETATE) 26- LUMICHROME 27 - Methyl vallinic acid 28 - N6-(DELTA2-ISOPENTENYL)-ADENINE 29 - N-ACETYLPROLINE 30 - N-METHYLGLUTAMATE 31- PALATINOSE 32 - S-HEXYL-GLUTATHIONE 33 - SN-GLYCERO-3-PHOSPHOCHOLINE 34 - URACIL 5-CARBOXYLATE 35 HMDB0000001 1-METHYL-L-HISTIDINE 36 HMDB0000012 DEOXYURIDINE 37 HMDB0000014 DEOXYCYTIDINE 38 HMDB0000015 CORTEXOLONE 39 HMDB0000017 4-pyridoxic acid 40 HMDB0000020 p-hydroxyphenylacetic acid 41 HMDB0000022 3-METHOXYTYRAMINE 42 HMDB0000026 ureidopropionic acid 43 HMDB0000030 BIOTIN 44 HMDB0000033 CARNOSINE 45 HMDB0000034 ADENINE 46 HMDB0000036 Taurocholic acid (TCA) 47 HMDB0000038 DIHYDROBIOPTERIN 48 HMDB0000043 BETAINE 49 HMDB0000045 ADENOSINE MONOPHOSPHATE (AMP) Inselspital Printed on 30.05.2018 University Institute of Clinical Chemistry Page 1/9 Bern,