58-96-8 Usage
Overview
Uridine is one of the key nucleotide that making RNA[1-3]. It is a glycosylated pyrimidine-analog containing uracil attached to a ribose ring[or more specifically, a ribofuranose] via a β-N1-glycosidic bond. It is one of the five standard nucleosides which make up nucleic acids[including both RNA and DNA] with the others four being adenosine, thymidine, cytidine and guanosine. The five nucleosides are commonly abbreviated to their one-letter codes U, A, T, C and G respectively. Thymidine is found in deoxyribonucleic acid[DNA] and not ribonucleic acid(RNA]. Conversely, uridine is found in RNA and not DNA[1, 3]. The remaining three nucleosides can be found in both RNA and DNA. In RNA, they would be represented as A, C and G whereas in DNA they would be represented as dA, dC and dG[1,3].
Biosynthesis and source
Uridine is widely produced in the form of uridine monophosphate[uridylate] through the decarboxylation of orotidylate, being catalyzed by orotidylate decarboxylase[4]. The orotidylate is produced from orotate, which is combined with 5-phosphoribosyl-1-pyrophosphate[PRPP] to form orotidylate by pyrimidine phosphoribosyltransferase. PRPP is created from ribose-5-phosphate by a further phosphorylation, serving as an energetic molecule to drive the reaction forward, while orotate is generated in several steps from carbamoyl phosphate and aspartate[4].
Diet is not an important source of uridine. Clinical studies and animal experimentation suggest that the
liver synthesizes and degrades uridine, and is likely to have a central role in maintaining plasma uridine. Blood platelets and storage organelles of various species are reported to contain UTP and may provide releasable pools of uridine after catabolism[5].
Applications
Uridine is phosphorylated to nucleotides, which are used for DNA and RNA synthesis as well as for the synthesis of membrane constituents and glycosylation[6-8]. Uridine plays a very important role in the glycolysis pathway of galactose. It can be used as a precursor in the production of CDP-choline. It is an important nutrient and widely used as a dietary supplement. It can improve the brain cholinergic functions and hepatic mitochondrial function in certain liver toxins. It plays a major role in pain physiology and brain energy utilization to maintain ATP production under restricted oxygen conditions[6, 8]. Uridine has many biological effects and, is thus can be used for the treatment of various kinds of diseases. In general, uridine can be used for the treatment for the following diseases such as cardiovascular disease and hypertension, respiratory dysfunction, liver disease, infertility, epilepsy, cancer & AIDS, Parkinsonism, anxiety, sleep dysfunction and Ischemia and hypoxia[7,8].
Effect on the central nerve system
Uridine plays a crucial role in the pyrimidine metabolism of the brain. It supplies nervous tissue with the pyrimidine ring, and in turn, participates in a number of important metabolic pathways. Uridine and its nucleotide derivatives may also have an additional role in the function of the central nervous system as signaling molecules. Uridine administration had sleep-promoting and anti-epileptic actions, improved memory function and affected neuronal plasticity. Uridine can exert various kinds of effects on the central nerve system[CNS][1, 8-10]?It was found to be an active component of sleep-promoting substances in our brain[11, 12, 2] Anti-epileptogenic and anti-convulsant effect[3, 9, 10] Thermoregulatory effect[4, 13] long-term exposure to uridine improve our memory[5, 14] involved in the regulation of neuronal plasticity through for example that it enhances neurite outgrowth[15]. Based on those above findings, it can be used for the treatment of various diseases such as developmental delay, seizures, ataxia, severe language deficit, age-related cognitive decline and even Alzheimer's disease and Parkinson's disease. Uridine might also be useful as a nutrition supplement during development. Uridine[as uridine monophosphate] is found in mother's milk and has been proposed to play a role in regulatory mechanism through which plasma composition influences brain development[16].
Cystic fibrosis
Cystic fibrosis is characterized by abnormal fluid transport across many epithelia including airways, pancreas, sweat glands and small intestine. This disease is associated with decreased Cl2 transport
and increased Na+ transport. The disease is caused by an absence or dysfunction of the cystic fibrosis transmembrane conductance regulator[CFTR], a Clchannel expressed by epithelial cells, and by an increase in active Na+ absorption[17, 18]. The uridine nucleotide can be used for the treatment of cystic fibrosis since UTP activates P2 purinoceptors, bypasses the defective Clsecretion to activate an alternative Ca2+ -dependent Clsecretory pathway, further stimulating Clsecretion in epithelial cells and decreased Na+ absorption[18].
Effects on the circulatory system
The effects of uridine and its nucleotides on isolated blood vessels are complex, sometimes acting directly on smooth muscle cells, at other times stimulating surrounding endothelial cells. Uridine and its nucleotides produce opposing effects in some tissues, which suggests that these ligands could act at distinct receptors or via intracellular messenger systems. Further studies are warranted, because many of these effects were observed at potentially physiological levels, and could aid the development of a novel series of antihypertensive agents based on uridine analogues[19].
Modulation of reproduction
An important function of uridine could be to promote sperm motility, as seminal plasma uridine concentrations are positively correlated to percentage sperm motility[20]. It is perhaps relevant, therefore, that regulation of uridine diphosphatase during spermatogenesis in the rat was reported to be under hormonal control. The predominance of uridine in seminal fluids must lead to questions about its role in the environment of fertilization and implantation, but as yet these remain unanswered[21].
Cancer and antiviral therapy
Uridine and UDP?glucose have been used to counter the unwanted toxicity of pyrimidine-based anticancer drugs. Uridine has been used as a rescue therapy for myelotoxicity and gastrointestinal toxicity produced by 5-fluorouracil[22]. Uridine and benzylacyclouridine protected mice against the neurotoxic side effects of pyrimidine-based drugs, such as azidothymidine used to treat HIV infection[23].
Reference
www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(99]01298-5.pdf
https://www.trc-canada.com/product-detail/?CatNum=U829919&CAS=&Chemical_Name=Uridine[1’-D]&Mol_Formula=C?DH??N?O?
www.technologynetworks.com/genomics/lists/what-are-the-key-differences-between-dna-and-rna-296719
Berg JM, Tymoczko JL, Stryer L.[2002]. "Section 25.1In de Novo Synthesis, the Pyrimidine Ring Is Assembled from Bicarbonate, Aspartate, and Glutamine". Biochemistry[5th ed.]. W H Freeman.
Goetz, U, P. M. Da, and A. Pletscher. "Adenine-, guanineand uridine-5'-phosphonucleotides in blood platelets and storage organelles of various species. " Journal of Pharmacology & Experimental Therapeutics178.1(1971]:210-215.
L Ipata, P.; Pesi, R. Metabolic Regulation of Uridine in the Brain. Curr Metabolomics 2015, 3[1], 4-9.
Connolly, G. P., and J. A. Duley. "Uridine and its nucleotides: biological actions, therapeutic potentials. " Trends in Pharmacological Sciences20.5(1999]:218-25.
Dobolyi, and Arpad. Uridine Function in the Central Nervous System. Law, politics and the judicial system in Canada /. University of Calgary Press, 2011:743-751.
Yegutkin, G. G. Nucleotideand nucleoside-converting coenzymes: Important modulators of purinergic signalling cascade. Biochim. Biophys. Acta-Mol. Cell. Res., 2008, 1783, 673-694.?
Burnstock, G. Physiology and pathophysiology of purinergic neurotransmission. Physiol. Rev., 2007, 87, 659-797.?
Borbely, A. A.; Tobler, I. Endogenous sleep-promoting substances and sleep regulation. Physiol. Rev., 1989, 69, 605-670.?
Inoue, S. Sleep and sleep substances. Brain Dev., 1986, 8, 469-473.?
Peters, G. J.; van Groeningen, C. J.; Laurensse, E. J.; Lankelma, J.; Leyva, A.; Pinedo, H. M. Uridine-induced hypothermia in mice and rats in relation to plasma and tissue levels of uridine and its metabolites. Cancer Chemother. Pharmacol., 1987, 20, 101-108.?
Teather, L. A.; Wurtman, R. J. Chronic administration of UMP ameliorates the impairment of hippocampal-dependent memory in impoverished rats. J. Nutr., 2006, 136, 2834-2837.?
Pooler, A. M.; Guez, D. H.; Benedictus, R.; Wurtman, R. J. Uridine enhances neurite outgrowth in nerve growth factor-differentiated PC12 [corrected]. Neuroscience, 2005, 134, 207-214.?
Wurtman, R. J. Synapse formation and cognitive brain development: effect of docosahexaenoic acid and other dietary constituents. Metabol. Clin. Exp., 2008, 57, S6-S10.?
Knowles, Michael R, L. L. Clarke, and R. C. Boucher. "Activation by Extracellular Nucleotides of Chloride Secretion in the Airway Epithelia of Patients with Cystic Fibrosis." N Engl J Med 325.8(1991]:533-538.
Bennett, W D, et al. "Effect of uridine 5'-triphosphate plus amiloride on mucociliary clearance in adult cystic fibrosis. " American Journal of Respiratory & Critical Care Medicine 153.6 Pt 1(1996]:1796.
Seifert, R, and G. Schultz. "Involvement of pyrimidinoceptors in the regulation of cell functions by uridine and by uracil nucleotides. " Trends in Pharmacological Sciences 10.9(1989]:365-369.
Ronquist, G., B. Stegmayr, and F. Niklasson. "Sperm Motility and Interactions Among Seminal Uridine, Xanthine, Urate, and Atpase in Fertile and Infertile Men." Archives of Andrology 15.1(1985]:21-27.
Xuma, M, and R. W. Turkington. "Hormonal regulation of uridine diphosphatase during spermatogenesis in the rat." Endocrinology91.2(1972]:415.
Leyva, A, et al. "Phase I and pharmacokinetic studies of high-dose uridine intended for rescue from 5-fluorouracil toxicity. " Cancer Research 44.12 Pt 1(1984]:5928-5933.
Calabresi, P, et al. "Benzylacyclouridine reverses azidothymidine-induced marrow suppression without impairment of anti-human immunodeficiency virus activity." Blood 76.11(1990]:2210-5.
Description
Uridine is one of the four basic components of ribonucleic acid (RNA).
Chemical Properties
White powder; odorless; slightly acrid
and faintly sweet taste. Soluble in water;
slightly soluble in dilute alcohol; insoluble in strong
alcohol.
Uses
Different sources of media describe the Uses of 58-96-8 differently. You can refer to the following data:
1. Uridine is a nucleoside, contains a uracil attached to a ribose ring via a β-N1-glycosidic bond
2. Uridine is a nucleoside; widely distributed in nature. Uridine is one of the four basic components of ribonucleic acid (RNA)
3. A nucleoside and one of main component in RNA.
Definition
Different sources of media describe the Definition of 58-96-8 differently. You can refer to the following data:
1. The nucleoside
formed when uracil is linked to D-ribose by
a β-glycosidic bond.
2. A nucleoside consistingof one uracil molecule linked to a dribosesugar molecule. The derivedmucleotide uridine diphosphate(UDP) is important in carbohydratemetabolism.
General Description
Uridine is a pyrimidine nucleoside which is crucial for the synthesis of RNA and membranes. It helps in normal cell function and growth by forming pyrimidine nucleotide -lipid conjugates.
Biochem/physiol Actions
Uridine monophosphate is essential for protein glycosylation, polysaccharide biosynthesis and lipid metabolism. Oral administration of uridine is suggested for anisopoikilocytosis and epileptic encephalopathy disorders. Uridine has numerous biological functions like treating dry eye syndrome, regulating nervous system and favors reproduction. High levels of uridine are implicated in insulin resistance.
Purification Methods
Crystallise -uridine from aqueous 75% MeOH or EtOH (m 165-166o). [Beilstein 24 III/IV 1202.]
Check Digit Verification of cas no
The CAS Registry Mumber 58-96-8 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 8 respectively; the second part has 2 digits, 9 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 58-96:
(4*5)+(3*8)+(2*9)+(1*6)=68
68 % 10 = 8
So 58-96-8 is a valid CAS Registry Number.
InChI:InChI=1/C9H12N2O6/c12-3-4-6(14)7(15)8(17-4)11-2-1-5(13)10-9(11)16/h1-2,4,6-8,12,14-15H,3H2,(H,10,13,16)/t4-,6+,7-,8-/m0/s1
58-96-8Relevant articles and documents
Mechanistic studies relevant to bromouridine-enhanced nucleoprotein photocrosslinking: Possible involvement of an excited tyrosine residue of the protein
Norris, Christopher L.,Meisenheimer, Kristen M.,Koch, Tad H.
, p. 201 - 207 (1997)
The results of mechanistic studies on formation of uridine (U) and N-acetyl-m-(5-uridinyl)tyrosine N-ethylamide (2) from irradiation of aqueous, pH 7 solutions of bromouridine (BrU) and N-acetyltyrosine N-ethylamide (1) are reported. Solutions were irradiated with monochromatic laser emission at 266, 308 and 325 nm. Quantum yield measurements as a function of excitation wave-length suggest that both products result from excitation of the tyrosine derivative followed by electron transfer to BrU, possibly with intermediacy of the hydrated electron. The BrU radical anion ejects bromide to form the uridinyl radical, which then abstracts a hydrogen atom from 1 or adds to the aromatic ring of 1. Formation of adduct 2 is a model for photocrosslinking of nucleic acids bearing the bromouracil chromophore to adjacent tyrosine residues of proteins in nucleoprotein complexes. The value of 325 nm excitation in photocrosslinking, where the tyrosine chromophore is more competitive for photons, was demonstrated with an RNA bound to the MS2 bacteriophage coat protein; more than a 60% increase in the yield of photocrosslinking relative to that obtained with 308 nm excitation was achieved.
EM2487, a novel anti-HIV-1 antibiotic, produced by Streptomyces sp. Mer-2487: Taxonomy, fermentation, biological properties, isolation and structure elucidation
Takeuchi, Hitoshi,Asai, Naoki,Tanabe, Kazunori,Kozaki, Teruya,Fujita, Masanori,Sakai, Takashi,Okuda, Akifumi,Naruse, Nobuaki,Yamamoto, Satoshi,Sameshima, Tomohiro,Heida, Naohiko,Dobashi, Kazuyuki,Baba, Masanori
, p. 971 - 982 (1999)
For the purpose of discovering novel agents that inhibit HIV-1 replication at the transcriptional level, we have established cell lines reflecting the HIV-1 long terminal repeat-driven gene expression. Using these cell lines, we have screened approximately 10,000 microorganism products and found that the culture supernatant of Streptomyces sp. Mer-2487 suppresses the HIV-1 Tat-induced gene expression without affecting the basal or tumor necrosis factor-α-induced transcription. The purified active component has a unique structure. This compound has an inhibitory effect on HIV-1 replication in chronically infected cells as well as acutely infected cells, suggesting that the inhibition occurs at a postintegration step of HIV-1 proviral DNA in the HIV-1 replication cycle.
Hydrolytic stability of a phosphate-branched oligonucleotide incorporating a ribonucleoside 3′-phosphotriester unit
Loennberg, Tuomas
, p. 315 - 323 (2006)
A phosphate-branched oligonucleotide has been prepared by using an appropriately protected trinucleoside phosphotriester building block in conventional solid-phase synthesis. Hydrolysis of the branched oligonucleotide has been followed over a wide pH range. Comparison of the present results with those previously obtained for simpler analogues indicates that a trinucleoside 3′,3′,5′-monophosphate, when embedded in an oligonucleotide structure, is stabilized toward hydroxide-ion catalyzed cleavage by more than one order of magnitude, lending some support to the feasibility of existence of phosphate-branched RNA X in biological systems. Copyright Taylor & Francis Group, LLC.
The effective molarity of the substrate phosphoryl group in the transition state for yeast OMP decarboxylase
Sievers, Annette,Wolfenden, Richard
, p. 45 - 52 (2005)
The second order rate constant (kcat/Km) for decarboxylation of orotidine by yeast OMP decarboxylase (ODCase), measured by trapping 14CO2 released during the reaction, is 2 × 10-4 M-1 s-1. This very low activity may be compared with a value of 3 × 107 M-1 s-1 for the action of yeast OMP decarboxylase on the normal substrate OMP. Both activities are strongly inhibited by 6-hydroxy UMP (BMP), and abrogated by mutation of Asp-96 to alanine. These results, in conjunction with the binding affinity of inorganic phosphate as a competitive inhibitor (Ki = 7 × 10-4 M), imply an effective concentration of 1.1 × 109 M for the substrate phosphoryl group in stabilizing the transition state for enzymatic decarboxylation of OMP. The observed difference in rate (1.5 × 1011-fold) is the largest effect of a simple substituent that appears to have been reported for an enzyme reaction.
-
Cushley et al.
, p. 5393 (1968)
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Mechanistic studies of the 5-iodouracil chromophore relevant to its use in nucleoprotein photo-cross-linking
Norris, Christopher L.,Meisenheimer, Poncho L.,Koch, Tad H.
, p. 5796 - 5803 (1996)
The photoreactivity of the 5-iodouracil chromophore was investigated toward understanding photo-cross-linking of nucleic acids bearing the chromophore to functionality in associated proteins. Irradiation of 5-iodouridine (IU) in the presence of a 10-fold excess of N-acetyltyrosine N-ethylamide (1) at 308 nm with a XeCl excimer laser or at 325 nm with a HeCd laser yields uridine (U) and N-acetyl-m-(5-uridinyl)tyrosine N-ethylamide (2) in a 1:2 mole ratio. In the presence of N-acetylphenylalanine N-ethylamide, uridine and analogous ortho, meta, and para regioisomeric adducts (3o, 3m, and 3p) were formed in a similar U to adduct mole ratio. The primary photochemical process leading to products was established as carbon-iodine bond homolysis in the first excited singlet state from a deuterium labeling experiment, photoacoustic calorimetry, and quantum yield measurements. Photoreduction of IU in 2-propanol-d solvent gave U with no deuterium incorporation. Photoacoustic calorimetric measurements established that triplet benzophenone transferred energy to IU with a rate constant of 2 x 109 M-1 s-1. Further, the reaction of IU with 1 to form 2 was sensitized by benzophenone; however, comparison of quantum yields upon direct and sensitized excitation indicated that, at most, only a small portion of the reactions occurred via the triplet state. With direct excitation of IU, quantum yields as a function of the concentration of 1 showed that U and adduct 2 resulted from a common intermediate proposed to be the 5-uridinyl radical. Uridine formation was enhanced by the presence of hydrogen atom donors at the expense of formation of 2. Quantum yields were independent of excitation wavelength in the region 310-330 nm but not the reaction medium. The quantum yield of uridine formation but not adduct formation was approximately an order of magnitude higher in 90% acetonitrile - 10% water than in pH 7 water. The results are discussed in terms of high-yield cross-linking of nucleic acids bearing the 5-iodouracil chromophore to associated proteins in light of cocrystal X-ray structural data.
Pyrimidine nucleotidases/phosphotransferases from human erythrocyte
Amici,Emanuelli,Raffaelli,Ruggieri,Magni
, p. 853 - 855 (1999)
Two cytoplasmic pyrimidine 5'-nucleotidase have been purified from human erythrocytes to homogeneity and partially characterized. The two enzymes, indicated as PN-I and PN-II, preferentially hydrolyse pyrimidine 5'- monophosphates and 3'-monophosphates, respectively. The kinetic analysis demonstrate that pyrimidine 5'-nucleotidases, in the presence of suitable nucleoside substrates, can operate as phosphotransferases by transferring phosphate to various nucleoside acceptors, including nucleoside analogues known as important drugs widely used in chemotherapy.
Development of a Robust Manufacturing Route for Molnupiravir, an Antiviral for the Treatment of COVID-19
Bade, Rachel,Bernardoni, Frank,Bothe, Jameson,Brito, Gilmar,Castro, Steve,Chang, Darryl,Diaz-Santana, Anthony,Diribe, Ike,Emerson, Khateeta M.,Fier, Patrick S.,Humphrey, Guy R.,Krishnamurthi, Bharath,Morris, William J.,Ouyand, Honggui,Poirier, Marc,Sirk, Kevin M.,Sirota, Eric,Stone, Kevin,Tan, Lushi,Taylor, Jerry,Ward, Michael,Xiao, Chengqian,Xu, Yingju,Zhan, Jianfeng,Zhang, Yongqian,Zhao, Ralph,Zheng, Michelle,Zompa, Michael A.
, p. 2806 - 2815 (2021/12/30)
Herein is described the development of a large-scale manufacturing process for molnupiravir, an orally dosed antiviral that was recently demonstrated to be efficacious for the treatment of patients with COVID-19. The yield, robustness, and efficiency of each of the five steps were improved, ultimately culminating in a 1.6-fold improvement in overall yield and a dramatic increase in the overall throughput compared to the baseline process.
The Peculiar Case of the Hyper-thermostable Pyrimidine Nucleoside Phosphorylase from Thermus thermophilus**
Kaspar, Felix,Neubauer, Peter,Kurreck, Anke
, p. 1385 - 1390 (2021/01/29)
The poor solubility of many nucleosides and nucleobases in aqueous solution demands harsh reaction conditions (base, heat, cosolvent) in nucleoside phosphorylase-catalyzed processes to facilitate substrate loading beyond the low millimolar range. This, in turn, requires enzymes that can withstand these conditions. Herein, we report that the pyrimidine nucleoside phosphorylase from Thermus thermophilus is active over an exceptionally broad pH (4–10), temperature (up to 100 °C) and cosolvent space (up to 80 % (v/v) nonaqueous medium), and displays tremendous stability under harsh reaction conditions with predicted total turnover numbers of more than 106 for various pyrimidine nucleosides. However, its use as a biocatalyst for preparative applications is critically limited due to its inhibition by nucleobases at low concentrations, which is unprecedented among nonspecific pyrimidine nucleoside phosphorylases.
