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Chemical Compound Review

uracil     1H-pyrimidine-2,4-dione

Synonyms: Urazil, Pirod, Pyrod, Hybar X, Uracil-5-d, ...
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Disease relevance of uracil


High impact information on uracil

  • Recently, a biochemically distinct family of DNA repair enzymes has been identified, which excises both uracil and thymine, but only from mispairs with guanine [6].
  • Uracil is removed in a base-excision repair pathway by uracil DNA-glycosylase (UDG), which excises uracil from both single- and double-stranded DNA [6].
  • The high levels of dUTPase as well as the presence of RNA primers on most nascent DNA pieces (Tseng and Goulian, 1977) suggest that repair of uracil-containing DNA does not contribute to the generation of the small, nascent DNA pieces found during DNA synthesis in this in vitro system [7].
  • Addition of uracil, a known inhibitor of the enzyme uracil-DNA glycosidase (Lindahl et al., 1977), increased total synthesis and shifted the incorporation to longer progeny strands [1].
  • We have examined the virulence of T. gondii mutants that lack carbamoyl phosphate synthetase II (uracil auxotrophs) to determine whether de novo pyrimidine biosynthesis is required in vivo [4].

Chemical compound and disease context of uracil


Biological context of uracil


Anatomical context of uracil

  • Extracts from these cell lines were found to be defective in uracil-initiated base-excision repair [17].
  • Together with the finding that nuclear UNG expression was induced in activated B cells, these data support a model of CSR and SHM in which AID deaminates cytosine into uracil in targeted DNA (immunoglobulin switch or variable regions), followed by uracil removal by UNG [18].
  • However, when exposed to a nitric oxide donor, Ung(-/-) fibroblasts show an increase in the uracil/cytosine ratio in the genome and augmented cell death [19].
  • In addition to its role in selective protein degradation, the conjugation of ubiquitin to proteins has also been implicated in the internalization of plasma membrane proteins, including the alpha-factor receptor Ste2p, uracil permease Fur4p, epithelial sodium channel ENaC and the growth hormone receptor (GHR) [20].
  • Cell lines inoculated with "convalescent" cerebrospinal fluid showed slightly increased uracil uptake, slightly decreased uptake ratios, and persistent FA staining of approximately 5% of cells, indicating incomplete clearance of M. pneumoniae [21].

Associations of uracil with other chemical compounds


Gene context of uracil

  • Therefore, HIV-1 prevents incorporation of dUTP in viral cDNA by UNG2-mediated uracil excision followed by a dNTP-dependent, reverse transcriptase-mediated endonucleolytic cleavage and finally by strand-displacement polymerization [28].
  • Ung knockout mice display no increase in mutation frequency due to a second UDG activity, SMUG1, which is specialized for antimutational uracil excision in mammalian cells [29].
  • Moreover, the UNG mutations lead to increased accumulation of genomic uracil [30].
  • Analyses with isogenic uracil-DNA-glycosylase (UNG1) deficient or proficient strains indicate that in the absence of dUTPase, cell death results from the incorporation of uracil into DNA and the attempted repair of this damage by UNG1-mediated excision repair [31].
  • The Ung and Smug1 enzymes excise uracil from DNA to effect repair in mammalian cells, and gene-targeted Ung(-/-) mice exhibit a moderate increase in genome-wide spontaneous mutagenesis [32].

Analytical, diagnostic and therapeutic context of uracil


  1. Formation of Okazaki fragments in polyoma DNA synthesis caused by misincorporation of uracil. Brynolf, K., Eliasson, R., Reichard, P. Cell (1978) [Pubmed]
  2. Crystal structure of human uracil-DNA glycosylase in complex with a protein inhibitor: protein mimicry of DNA. Mol, C.D., Arvai, A.S., Sanderson, R.J., Slupphaug, G., Kavli, B., Krokan, H.E., Mosbaugh, D.W., Tainer, J.A. Cell (1995) [Pubmed]
  3. Uracil in DNA in megaloblastic anemia. Luzzatto, L., Falusi, A.O., Joju, E.A. N. Engl. J. Med. (1981) [Pubmed]
  4. De novo pyrimidine biosynthesis is required for virulence of Toxoplasma gondii. Fox, B.A., Bzik, D.J. Nature (2002) [Pubmed]
  5. Uracil mustard in the treatment of thrombocytosis. Shamasunder, H.K., Gregory, S.A., Knospe, W.H. JAMA (1980) [Pubmed]
  6. Crystal structure of a G:T/U mismatch-specific DNA glycosylase: mismatch recognition by complementary-strand interactions. Barrett, T.E., Savva, R., Panayotou, G., Barlow, T., Brown, T., Jiricny, J., Pearl, L.H. Cell (1998) [Pubmed]
  7. The incorporation of uracil into animal cell DNA in vitro. Grafstrom, R.H., Tseng, B.Y., Goulian, M. Cell (1978) [Pubmed]
  8. In vivo synthesis and properties of uracil-containing DNA. Warner, H.R., Duncan, B.K. Nature (1978) [Pubmed]
  9. Crystal structure of a dUTPase. Cedergren-Zeppezauer, E.S., Larsson, G., Nyman, P.O., Dauter, Z., Wilson, K.S. Nature (1992) [Pubmed]
  10. Transcriptional mutagenesis induced by uracil and 8-oxoguanine in Escherichia coli. Brégeon, D., Doddridge, Z.A., You, H.J., Weiss, B., Doetsch, P.W. Mol. Cell (2003) [Pubmed]
  11. Adjuvant mitomycin and fluorouracil followed by oral uracil plus tegafur in serosa-negative gastric cancer: a randomised trial. Gastric Cancer Surgical Study Group. Nakajima, T., Nashimoto, A., Kitamura, M., Kito, T., Iwanaga, T., Okabayashi, K., Goto, M. Lancet (1999) [Pubmed]
  12. Codon choice and gene expression: synonymous codons differ in their ability to direct aminoacylated-transfer RNA binding to ribosomes in vitro. Thomas, L.K., Dix, D.B., Thompson, R.C. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  13. A new class of uracil-DNA glycosylases related to human thymine-DNA glycosylase. Gallinari, P., Jiricny, J. Nature (1996) [Pubmed]
  14. Escape of DNA from mitochondria to the nucleus in Saccharomyces cerevisiae. Thorsness, P.E., Fox, T.D. Nature (1990) [Pubmed]
  15. A covalent adduct between the uracil ring and the active site of an aminoacyl tRNA synthetase. Starzyk, R.M., Koontz, S.W., Schimmel, P. Nature (1982) [Pubmed]
  16. Suppressible four-base glycine and proline codons in yeast. Donahue, T.F., Farabaugh, P.J., Fink, G.R. Science (1981) [Pubmed]
  17. Requirement of mammalian DNA polymerase-beta in base-excision repair. Sobol, R.W., Horton, J.K., Kühn, R., Gu, H., Singhal, R.K., Prasad, R., Rajewsky, K., Wilson, S.H. Nature (1996) [Pubmed]
  18. Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Imai, K., Slupphaug, G., Lee, W.I., Revy, P., Nonoyama, S., Catalan, N., Yel, L., Forveille, M., Kavli, B., Krokan, H.E., Ochs, H.D., Fischer, A., Durandy, A. Nat. Immunol. (2003) [Pubmed]
  19. Increased postischemic brain injury in mice deficient in uracil-DNA glycosylase. Endres, M., Biniszkiewicz, D., Sobol, R.W., Harms, C., Ahmadi, M., Lipski, A., Katchanov, J., Mergenthaler, P., Dirnagl, U., Wilson, S.H., Meisel, A., Jaenisch, R. J. Clin. Invest. (2004) [Pubmed]
  20. Identification of a novel ubiquitin conjugation motif, required for ligand-induced internalization of the growth hormone receptor. Govers, R., ten Broeke, T., van Kerkhof, P., Schwartz, A.L., Strous, G.J. EMBO J. (1999) [Pubmed]
  21. Neurological disease associated with Mycoplasma pneumoniae pneumonitis: demonstration of viable Mycoplasma pneumoniae in cerebrospinal fluid and blood by radioisotopic and immunofluorescent tissue culture techniques. Bayer, A.S., Galpin, J.E., Theofilopoulos, A.N., Guze, L.B. Ann. Intern. Med. (1981) [Pubmed]
  22. The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites. Hendrich, B., Hardeland, U., Ng, H.H., Jiricny, J., Bird, A. Nature (1999) [Pubmed]
  23. Mutagenic deamination of cytosine residues in DNA. Duncan, B.K., Miller, J.H. Nature (1980) [Pubmed]
  24. A ribozyme composed of only two different nucleotides. Reader, J.S., Joyce, G.F. Nature (2002) [Pubmed]
  25. Chemical evolution from hydrogen cyanide: photochemical decarboxylation of orotic acid and orotate derivatives. Ferris, J.P., Joshi, P.C. Science (1978) [Pubmed]
  26. Pyrimidine metabolism in Tritrichomonas foetus. Wang, C.C., Verham, R., Tzeng, S.F., Aldritt, S., Cheng, H.W. Proc. Natl. Acad. Sci. U.S.A. (1983) [Pubmed]
  27. Opposite effects of uracil and adenine nucleotides on the survival of murine cardiomyocytes. Mazzola, A., Amoruso, E., Beltrami, E., Lecca, D., Ferrario, S., Cosentino, S., Tremoli, E., Ceruti, S., Abbracchio, M.P. J. Cell. Mol. Med. (2008) [Pubmed]
  28. HIV-1-associated uracil DNA glycosylase activity controls dUTP misincorporation in viral DNA and is essential to the HIV-1 life cycle. Priet, S., Gros, N., Navarro, J.M., Boretto, J., Canard, B., Quérat, G., Sire, J. Mol. Cell (2005) [Pubmed]
  29. Structure and specificity of the vertebrate anti-mutator uracil-DNA glycosylase SMUG1. Wibley, J.E., Waters, T.R., Haushalter, K., Verdine, G.L., Pearl, L.H. Mol. Cell (2003) [Pubmed]
  30. B cells from hyper-IgM patients carrying UNG mutations lack ability to remove uracil from ssDNA and have elevated genomic uracil. Kavli, B., Andersen, S., Otterlei, M., Liabakk, N.B., Imai, K., Fischer, A., Durandy, A., Krokan, H.E., Slupphaug, G. J. Exp. Med. (2005) [Pubmed]
  31. dUTP pyrophosphatase is an essential enzyme in Saccharomyces cerevisiae. Gadsden, M.H., McIntosh, E.M., Game, J.C., Wilson, P.J., Haynes, R.H. EMBO J. (1993) [Pubmed]
  32. C --> T mutagenesis and gamma-radiation sensitivity due to deficiency in the Smug1 and Ung DNA glycosylases. An, Q., Robins, P., Lindahl, T., Barnes, D.E. EMBO J. (2005) [Pubmed]
  33. Pyrimidine salvage in Giardia lamblia. Aldritt, S.M., Tien, P., Wang, C.C. J. Exp. Med. (1985) [Pubmed]
  34. Biosynthetic labeling of RNA with uracil phosphoribosyltransferase allows cell-specific microarray analysis of mRNA synthesis and decay. Cleary, M.D., Meiering, C.D., Jan, E., Guymon, R., Boothroyd, J.C. Nat. Biotechnol. (2005) [Pubmed]
  35. Characterization of genetic miscoding lesions caused by postmortem damage. Gilbert, M.T., Hansen, A.J., Willerslev, E., Rudbeck, L., Barnes, I., Lynnerup, N., Cooper, A. Am. J. Hum. Genet. (2003) [Pubmed]
  36. Cytotoxicity of 5-fluoro-2'-deoxyuridine: requirement for reduced folate cofactors and antagonism by methotrexate. Ullman, B., Lee, M., Martin, D.W., Santi, D.V. Proc. Natl. Acad. Sci. U.S.A. (1978) [Pubmed]
  37. Nucleic acid composition of bone marrow mononuclear cells in cobalamin deficiency. Ramsahoye, B.H., Burnett, A.K., Taylor, C. Blood (1996) [Pubmed]
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