Addition of Amino Acids and Related Substances to Nucleic Acids by Nucleophilic Catalysis

  • Robert Shapiro


Little attention has been paid to nucleophilic reactants when considering the biologically important transformations of nucleic acids. The role of free radical processes in the radiation chemistry and photochemistry of nucleic acids is well appreciated (Smith, 1975). In the case of chemical carcinogenesis, it has been suggested that the ultimate carcinogens are often, or perhaps always, strong electrophilic reagents (Miller, 1970; Heidelberger, This Volume). Nucleic acids, do, however, contain a number of sites susceptible to nucleophilic attack, and there is no obvious reason why alterations at these positions should be of less significance then changes produced at other locations by other mechanisms. In fact, nucleophilic reactions on nucleic acid are involved in a number of biologically important processes.


Adduct Formation Sodium Bisulfite Nucleophilic Reagent Nucleophilic Catalysis Ultimate Carcinogen 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Andronikova, M.L., Velikodvorskaya, G.A., Tkhruni, F., and Tikhonenko, T.O., 1974, Biological effects associated with the modification of intraphage DNA with 0-methylhydroxylamine, Molecular Biology 8: 3–11.Google Scholar
  2. Banks, G.R., Brown, D.M., Streeter, D.G., and Grossman, L., 1971, Mutagenic analogues of cytosine: RNA polymerase template and substrate studies, J. Mol. Biol. 60: 425–439.PubMedCrossRefGoogle Scholar
  3. Baron, F., and Brown, D.M., 1955, Nucleotides. XXXIII. The structure of cytidylic acids a and b, J. Chem. Soc. 1955: 2855–2860.CrossRefGoogle Scholar
  4. Boni, I.V., and Budowsky, E.I., 1973, Transformation of non-covalent interactions in nucleoproteins into covalent bonds induced by nucleophilic reagents. I. The preparation and properties of the products of bisulfite ion-catalyzed reaction of amino acids and peptides with cytosine derivatives, J. Biochim. (Tokyo) 73: 821–830.Google Scholar
  5. Brandie, R., and Erismann, K.M., 1973, Bee influssung der DNS-Synthese durch sulfit im wurzelmeristem der puffbohne (vicia faba), Experienta 29: 586–587.CrossRefGoogle Scholar
  6. Brown, D.M., and Hewlins, M.J.E., 1968a, The reaction between hydroxylamine and cytosine derivatives, J. Chem. Soc. (C) 1968: 1922–1924.Google Scholar
  7. Brown, D.M., and Hewlins, M.J.E., 1968b, Dihydrocytosine and related compounds, J. Chem. Soc. (C) 1968: 2050–2055.Google Scholar
  8. Brown, D.M., Hewlins, M.J.E., and Schell, P., 1968, The tautomeric state of N(4)-hydroxy-and of N(4)-amino-cytosine derivatives, J. Chem. Soc. (C) 1968: 1925–1929.Google Scholar
  9. Budowsky, E.I., Sverdlov, E.D., Shibaeva, R.P., Monastyrskaya, G.S., and Kochetkov, N.K., 1971, Mechanism of the mutagenic action of hydroxylamine. III. Reaction of hydroxylamine and 0methylhydroxylamine with the cytosine nucleus, Biochim. Biophys. Acta 246: 300–319.PubMedCrossRefGoogle Scholar
  10. Budowsky, E.I., Sverdlov, E.D., and Monastyrskaya, G., 1972a, New method of selective and rapid modification of the cytidine residues, FEBS Lett. 25: 201–204.PubMedCrossRefGoogle Scholar
  11. Budowsky, E.I., Sverdlov, E.D., and Spasokukotskaya, T.N., 1972b, Mechanism of the mutagenic action of hydroxylamine. VII. Functional activity and specificity of cytidine triphosphate modified with hydroxylamine and 0-methylhydroxylamine, Biochim. Biophys. Acta 287: 195–210.PubMedCrossRefGoogle Scholar
  12. Cashmore, A.R., Brown, D.M., and Smith, J.D., 1971, Selective reaction of methoxyamine with cytosine bases in transfer ribonucleic acid, J. Mol. Biol. 59: 359–371.PubMedCrossRefGoogle Scholar
  13. Cashmore, A.R., and Petersen, G.B., 1969, The degradation of DNA by hydrazine: a critical study of the suitability of the reaction for the quantitative determination of purine nucleotide sequences, Biochim. Biophys. Acta 174: 591–603.PubMedCrossRefGoogle Scholar
  14. Chu, B.F.C., Brown, D.M., and Burdon, M.G., 1973, Effect of nitrogen and of catalase on hydroxylamine and hydrazine mutagenesis, Mutat. Res. 20: 265–270.PubMedCrossRefGoogle Scholar
  15. Das, G., and Runeckles, V.C., 1974, Effects of bisulfite on metabolic development in synchronous chlorella pyrenoidosa, Environ. Res. 7: 473–483.CrossRefGoogle Scholar
  16. Dorange, J.-L., and Dupuy, P., 1972, Mise en evidence d’une action mutagene du sulfite de sodium sur la levure, C.R. Acad. Sci. Paris, Ser. D. 274: 2798–2800.Google Scholar
  17. Drake, J.W., 1970, “The Molecular Basis of Mutation,” Holden-Day, San Francisco.Google Scholar
  18. Filipowicz, W., Wodnar, A., Zagorska, L., and Szafranski, P., 1972, f2 RNA structure and peptide chain initiation: fMet-tRNA binding directed by methoxyamine-modified unfolded or native-like f2 RNA’s, Biochim. Biophys. Res. Commun. 49: 1272–1279.Google Scholar
  19. Fishbein, L., Flamm, W.G., and Falk, H.L., 1970, “Chemical Mutagens, Environmental Effects on Biological Systems,” Academic Press, New York.Google Scholar
  20. Flavell, R.A., Sako, D.L., Bandle, E.F., and Weissman, C., 1974, Site-directed mutagenesis: generation of an extracistronic mutation in bacteriophage OR RNA, J. Mol. Biol. 89: 255–272.PubMedCrossRefGoogle Scholar
  21. Fraenkel-Conrat, H., and Singer, B., 1972, The chemical basis for the mutagenicity of hydroxylamine and methoxyamine, Biochim. Biophys. Acta 262: 264–268.PubMedCrossRefGoogle Scholar
  22. Freese, A., 1971, Molecular mechanisms of mutations, in “Chemical Mutagens, Principles and Methods for Their Detection,” (A. Hollaender, ed.), Vol. 1, pp. 1–56, Plenum Press, New York.Google Scholar
  23. Gal-Or, L., Mellema, J.E., Moudrianakis, N., and Beer, M., 1967, Electron microscopy study of base sequence in nucleic acids. VII. Cytosine-specific addition of acyl hydrazides, Biochemistry 6: 1909–1915.PubMedCrossRefGoogle Scholar
  24. Garrett, E.R., and Tsau, J., 1972, Solvolyses of cytosine and cytidine, J. Pharm. Sci. 61: 1052–1060.PubMedCrossRefGoogle Scholar
  25. Havelaar, K.J., and de Waard, A., 1973, Isolation of purine oligo-nucleotides after hydrazinolysis of deoxyribonucleic acid, Rec. Tray. Chim. Pays-Bas 92: 132–144.CrossRefGoogle Scholar
  26. Hayatsu, H., 1975, Bisulfite modification of nucleic acids and their constituents, Progr. Nucleic Acid Res. Mol. Biol. 16 (in press).Google Scholar
  27. Hayatsu, H., and Miura, M., 1970, The mutagenic action of sodium bisulfite, Biochem. Biophys. Res. Commun. 39: 156–160.PubMedCrossRefGoogle Scholar
  28. Hayatsu, H., Takeisha, K.-I., and Ukita, T., 1966, The modification of nucleosides and nucleotides. III. A selective modification of cytidine with semicarbazide, Biochim. Biophys. Acta 123: 445–457.PubMedCrossRefGoogle Scholar
  29. Hayatsu, H., and Ukita, T., 1964, Selective modification of cytidine residue in ribonucleic acid by semicarbazide, Biochem. Biophys. Res. Commun. 14: 198–203.PubMedCrossRefGoogle Scholar
  30. Hayatsu, H., Wataya, Y., and Kai, K., 1970a, The addition of sodium bisulfite to uracil and to cytosine, J. Amer. Chem. Soc. 92: 724–726.CrossRefGoogle Scholar
  31. Hayatsu, H., Wataya, Y., Kai, K., and Iida, S., 1970b, Reaction of sodium bisulfite with uracil, cytosine, and their derivatives, Biochemistry 9: 2858–2865.PubMedCrossRefGoogle Scholar
  32. Hayes, D.H., and Baron, F.H., 1967, Hydrazinolysis of some purines and pyrimidines and their related nucleosides and nucleotides, J. Chem. Soc. (C) 1967: 1528–1533.Google Scholar
  33. Janion, C., and Shugar, D., 1967, Reaction of amines with dihydro- cytosine analogs and formation of amino acid and peptidyl derivatives of dihydropyrimidines, Acta Biochim. Polon. 14: 293–302.Google Scholar
  34. Janion, C., and Shugar, D., 1971, Chemical mutagenesis: reaction of N-methylhydroxylamine with cytosine analogues, Acta Biochim. Polon. 18: 403–418.PubMedGoogle Scholar
  35. Johns, H.E., LeBlanc, J.C., and Freeman, K.B., 1965, Reversal and deamination rates of the main ultraviolet photoproduct of cytidylic acid, J. Mol. Biol. 13: 849–861.CrossRefGoogle Scholar
  36. Kai, K., Tsuruo, T., and Hayatsu, H., 1974, The effect of bisulfite modification on the template activity of DNA for DNA polymerase I, Nucleic Acids Res. 1: 889–899.PubMedCrossRefGoogle Scholar
  37. Kikugawa, K., Hayatsu, H., and Utika, T., 1967, Modification of nucleosides and nucleotides. V. A selective modification of cytidylic acids with Girard-P reagent, Biochim. Biophys. Acta 134: 221–231.CrossRefGoogle Scholar
  38. Lawley, P.D., 1967, Reaction of hydroxylamine at high concentration with deoxycytidine or with polycytidylic acid: evidence that substitution of amino groups in cytosine residues by hydroxy-lamine is a primary reaction, and the possible relevance to hydroxylamine mutagenesis, J. Mol. Biol. 24: 75–81.CrossRefGoogle Scholar
  39. Levine, A.F., Fink, L.M., Weinstein, I.B., and Grunberger, D., 1974, Effect of N-2-acetylaminofluorene modification on the conformation of nucleic acids, Cancer Res. 34: 319–327.PubMedGoogle Scholar
  40. Lingens, F., and Schneider-Bernlöhr, H., 1966, Uber die unsetzung naturlich vorkommender pyrimidinbasen mith hydrazin und methylsubstituierten hydrazinen, Justus Liebigs Ann. Chem. 686: 134–144.CrossRefGoogle Scholar
  41. Linney, E.A., Hayashi, M.N., and Hayashi, M., 1972, Gene A of 0174. I. Isolation and identification of its products, Virology 50: 381–387.PubMedCrossRefGoogle Scholar
  42. Ma, T.-H., Isbandi, D., Khan, S.H., and Tseng, Y.-S., 1973, Low level of SO2 enhanced and chromatid aberrations in tradescantia pollen tubes and seasonal variation of the aberration rates, Mutat. Res. 21: 93–100.CrossRefGoogle Scholar
  43. Miller, J.A., 1970, Carcinogenesis by chemicals: an overview, Cancer Res. 30: 559–575.PubMedGoogle Scholar
  44. Mukai, F., Hawryluk, I., and Shapiro, R., 1970, The mutagenic specificity of sodium bisulfite, Biochem. Biophys. Res. Commun. 39: 983–988.PubMedCrossRefGoogle Scholar
  45. Nelson, J.H., Grunberger, D., Cantor, C.R., and Weinstein, I.B., 1971, Modification of ribonucleic acid by chemical carcinogens. IV. Circular dichroism and proton magnetic resonance studies of oligonucleotides modified with N-2-acetylaminofluorene, J. Mol. Biol. 62: 331–346.PubMedCrossRefGoogle Scholar
  46. Notari, R.E., 1967, A mechanism for the hydrolytic deamination of cytosine arabinoside in aqueous buffer, J. Pharm. Sci. 56: 804–809.PubMedCrossRefGoogle Scholar
  47. Notari, R.E., Chin, M.L., and Cardoni, A., 1970, Intermolecular and intramolecular catalysis in deamination of cytosine nucleosides, J. Pharm. Sci. 59: 28–32.CrossRefGoogle Scholar
  48. Phillips, J.H., and Brown, D.M., 1967, The mutagenic action of hydroxylamine, Progr. Nucleic Acid Res. Mol. Biol. 7: 349–367.CrossRefGoogle Scholar
  49. Robertus, J.D., Ladner, J.E., Finch, J.T., Rhodes, D., Brown, R.S., Clark, B.F.C., and Klug, A., 1974, Correlation between three-dimensional structure and chemical reactivity of transfer RNA, Nucleic Acids Res. 1: 927–932.PubMedCrossRefGoogle Scholar
  50. Schneider, L.K., and Calkins, C.A., 1970, Sulfur-dioxide-induced lymphocyte defects in human peripheral blood cultures, Environ. Res. 3: 473–483.CrossRefGoogle Scholar
  51. Schulman, L.H., and Her, M.O., 1973, Reaction of altered E. coli formylmethionine transfer RNA by bacterial T factor, Biochem. Biophys. Res. Commun. 51: 275–283.PubMedCrossRefGoogle Scholar
  52. Schulman, L.H., Shapiro, R., Law, D.C.F., and Louis, J.B., 1974, A simplified method for study of RNA conformation-reaction of formylmethionine transfer RNA with [14C]methylamine-bisulfite, Nucleic Acids Res. 1: 1305–1316.PubMedCrossRefGoogle Scholar
  53. Shapiro, R., and Braverman, B., 1972, Modification of polyuridylic acid by bisulfite: effect on double helix formation and coding properties, Biochem. Biophys. Res. Commun. 47: 554–550.CrossRefGoogle Scholar
  54. Shapiro, R., Braverman, B., Louis, J.B., and Servis, R.E., 1973, Nucleic acid reactivity and conformation. II. Reaction of cytosine and uracil with sodium bisulfite, J. Biol. Chem. 248: 4060–4064.PubMedGoogle Scholar
  55. Shapiro, R., DiFate, V., and Welcher, M., 1974, Deamination of cytosine derivatives by bisulfite. Mechanism of the reaction, J. Amer. Chem. Soc. 96:906–912..Google Scholar
  56. Shapiro, R., and Klein, R.S., 1966, The deamination of cytidine and cytosine by acidic buffer solutions. Mutagenic implications, Biochemistry 6: 2358–2362.CrossRefGoogle Scholar
  57. Shapiro, R., and Klein, R.S., 1967, Reactions of cytosine derivatives with acidic buffer solutions. II. Studies on transamination, deamination, and deuterium exchange, Biochemistry 7: 3576–3582.CrossRefGoogle Scholar
  58. Shapiro, R., Law, D.C.F., and Weisgras, J.M., 1972, A new chemical probe for single-stranded RNA, Biochem. Biophys. Res. Commun. 49: 358–366.PubMedCrossRefGoogle Scholar
  59. Shapiro, R., Servis, R.E., and Welcher, M., 1970, Reactions of uracil and cytosine derivatives with sodium bisulfite. A specific deamination method, J. Amer. Chem. Soc. 92: 422–424.CrossRefGoogle Scholar
  60. Shapiro, R., and Weisgras, J.M., 1970, Bisulfite-catalyzed trans-amination of cytosine and cytidine, Biochem. Biophys. Res. Commun. 40: 839–843.PubMedCrossRefGoogle Scholar
  61. Simukova, N.A., and Budowsky, E.I., 1974, Conversion of non-covalent interactions in nucleoproteins into covalent bonds: UV-induced formation of polynucleotide-protein crosslinks in bacteriophage Sd virions, FEBS Lett. 38: 299–303.PubMedCrossRefGoogle Scholar
  62. Simukova, N.A., Turchinsky, M.F., Boni, I.V., Skoblov, Yu. M., and Budowsky, E.I., 1975, UV-induced cytosine involved poly-nucleotide-protein cross-linking. Abstr. Int. Symp. “Protein and Other Adducts to DNA: Their Significance to Aging, Carcinogenesis and Radiation Biology,” Williamsburg, Virginia, May 2–6, 1975.Google Scholar
  63. Smith, K.C., 1975, The radiation-induced addition of protein and other molecules to nucleic acids, in “Photochemistry and Photobiology of Nucleic Acids” (S.Y. Wang, ed.), Academic Press, New York (in press).Google Scholar
  64. Small, G.D., and Gordon, M.P., 1968, Reaction of hydroxylamine and methoxyamine with the ultraviolet-induced hydrate of cytidine, J. Mol. Biol. 34: 281–291.PubMedCrossRefGoogle Scholar
  65. Sono, M., Wataya, W., and Hayatsu, H., 1973, Role of bisulfite in the deamination and the hydrogen isotype exchange of cytidylic acid, J. Amer. Chem. Soc. 95: 4745–4749.CrossRefGoogle Scholar
  66. Summers, G., and Drake, J.W., 1971, Bisulfite mutagenesis in bacteriophage T4, Genetics 68: 603–607.PubMedGoogle Scholar
  67. Sverdlov, E.D., Krapivko, A.P., and Budowsky, E.I., 1971, Tautomeric equilibrium of 1-D-ribofuranosyl-2-keto-4-(N-methoxyamino) pyrimidine, Khim. Geterotsikl. Soedin 9: 1264–1267.Google Scholar
  68. Sverdlov, E.D., Monastyrskaya, G.S., and Budowsky, E.I., 1972a, Determination of the number of cytidine residues in oligonucleotides, FEBS Lett. 28: 236–238.PubMedCrossRefGoogle Scholar
  69. Sverdlov, E.D., Monastryrskaya, G.S., Budowsky, E.I., and Grachev, M.A., 1972b, A novel approach to structural analysis of oligonucleotides, FEBS Lett. 28: 231–235.PubMedCrossRefGoogle Scholar
  70. Temperli, A., Turler, H., Rust, P., Danon, A., and Chargaff, E., 1964, Studies in the nucleotide arrangement in deoxyribonucleic acid. IX. Selective degradation of pyrimidine deoxyribonucleotides, Biochim. Biophys. Acta 91: 462–476.PubMedGoogle Scholar
  71. Tikchonenko, T.I., Budowsky, E.I., Sklyadneva, V.B., and Khromov, I.S., 1971, The secondary structure of bacteriophage DNA in situ. III. Reaction of Sd phage with 0-methylhydroxylamine J. Mol. Biol. 55: 535–547.PubMedCrossRefGoogle Scholar
  72. Tikchonenko, T.I., Kisseleva, N.P., Zintshenko, A.I., Ulanov, B.P., and Budowsky, E.I., 1973, Peculiarities of the secondary structure of bacteriophage DNA in situ. IV. Covalent cross-links between DNA and protein that arise in the reaction of Sd phage with 0-methylhydroxylamine, J. Mol. Biol. 73: 109–119.PubMedCrossRefGoogle Scholar
  73. Turchinsky, M.F., Boni, I.V., and Budowsky, E.I., 1975, Bisulfite-induced cytosine involved polynucleotide-protein crosslinking. Abstr. Int. Symp. “Protein and Other Adducts to DNA: Their Significance to Aging, Carcinogenesis and Radiation Biology,” Williamsburg, Virginia, May 2–6, 1975.Google Scholar
  74. Turchinsky, M.F., Kusova, K.S., and Budowsky, E.I., 1974, Conver- sion of non-covalent interactions in nucleoproteins into covalent bonds: bisulfite-induced formation of polynucleotide-protein crosslinks in MS2 bacteriophage virions, FEBS Lett. 38: 304–307.PubMedCrossRefGoogle Scholar
  75. Verdlov, E.D., Monastyrskaya, G.S., Guskova, L.I., Levitan, T.L., Sheichenko, V.I., and Budowsky, E.I., 1974, Modification of cytidine residues with a bisulfite-O-methylhydroxylamine mixture, Biochim. Biophys. Acta 340: 153–165.PubMedCrossRefGoogle Scholar
  76. U.S. Department of Health, Education, and Welfare, 1969, “Air Quality Criteria for Sulfur Oxides,” National Air Pollution Control Administration Publication No. AP-50, Washington, D.C.Google Scholar
  77. Wechter, W.J., and Kelly, R.C., 1970, The mechanism of the deamination of cytidine, Collect Czech. Chem. Commun. 35: 1991–2002.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1976

Authors and Affiliations

  • Robert Shapiro
    • 1
  1. 1.Department of ChemistryNew York UniversityNew YorkUSA

Personalised recommendations