Summary
The mode and site of action of inhibitors of translation (initiation, elongation and termination of protein synthesis) in eukaryotic systems is reviewed. The isolation and characterization of a factor is described that binds Ac-Phe-tRNA to form a complex made up of binding factor, Ac-Phe-tRNA, and ribosome. The binding of Ac-Phe-tRNA probably occurs at the ribosomal site involved in the binding of the initiator substrate Met-tRNAF. The effect of inhibitors of the initiation phase of protein synthesis on the nonenzymic Ac-Phe-tRNA binding to ribosomes is investigated. The two sites translocation model for translation in eukaryotic cells is presented and the effects of inhibitors on the various steps of protein synthesis are determined empirically. The site of action of inhibitors of peptide bond formation at the ribosomal peptidyl transferase center is elucidated. The action of inhibitors of translocation is studied in model cell-free systems from human cells. In addition, a number of methylxanthines are shown to enhance the elongation phase in polypeptide synthesis by stimulating the enzymic binding of aminoacyl-tRNA. The effect of caffeine, theophylline and its derivatives are shown to be fairly specific and dependent on the ribosome concentration. Aminophylline is shown to have a similar effect but also enhances aminoacyl-tRNA synthetase activity at low Mg+ + concentrations, probably by displacing the optimal concentration of Mg+ + in the reaction. This second effect of aminophylline appears to be due to the ethylenediamine moiety of aminophylline since it is also observed in the presence of different polyamines but not in the presence of caffeine or theophylline.
Similar content being viewed by others
References
Vazquez, D. and Monro, R. E., Biochim. Biophys. Acta 142, 155–173 (1967).
Weisblum, B. and Davies, J., Bacteriol. Rev. 32, 493–528 (1968).
Pestka, S., Ann. Rev. Microbiol. 25, 487–562 (1971).
Cundliffe, E., in: The Molecular Basis of Antibiotic Action (Gale, E. F., Cundliffe, E., Reynolds, P. E., Richmond, M. H. and Waring, M. J., eds.), pp. 278–379, John Wiley and Sons, London (1972).
Kaji, A., in: Progress in Molecular and Subcellular Biology (Hahn, F. E., ed.), Vol. 3, pp. 85–158, Springer-Verlag, Berlin-Heidelberg-New York (1973).
Vazquez, D., FEBS Letters 40, S63-S84 (1974).
Wolf, H., FEBS Letters 36, 181–186 (1973).
Mizuno, S., Nitta, K. and Umezawa, H., J. Antibiotics 23, 581–588 (1970).
Khokhlov, A. S. and Blinov, N. O., FEBS Letters 11, 1–7 (1970).
Pirali, G., Somma, S. and Lancini, G. C., Biochim. Biophys. Acta 366, 310–318 (1974).
Sarasin, A. and Moulé, Y., FEBS Letters 32, 347–350 (1973).
Gonzalez-Cadavid, N. F. and Herrera, F., Biochem. J. 138, 129–141 (1974).
Reichman, M. and Penman, S., Biochim. Biophys. Acta 324, 282–289 (1973).
Carrasco, L., Fresno, M. and Vazquez, D., FEBS Letters, in the press52, 236–239 (1975).
Carrasco, L. and Vazquez, D., Biochim. Biophys. Acta 319, 209–217 (1973).
Vazquez, D., Barbacid, M. and Carrasco, L., in: Modern Trends in Human Leukemia: Biological, Biochemical and Virological Aspects (Neth, R., Galli, R. C. and Stohlman, F., eds.), pp. 327–340, Lehmans Verlag, Munich (1974).
Carrasco, L. and Vazquez, D., FEBS Letters 32, 152–156 (1973).
Carrasco, L., Barbacid, M. and Vazquez, D., Biochim. Biophys. Acta 312, 368–376 (1973).
Barbacid, M., Fresno, M. and Vazquez, D., J. Antibiotics, in the press (1975).
Carrasco, L. and Vazquez, D., J. Antibiotics 25, 732–737 (1972).
Schreier, M. H. and Staehelin, T., Nature New Biol. 242, 35–38 (1973).
Ragupathy, E., Peterson, N. A. and McKean, C. M., Biochem. Pharmacol. 20, 1901–1915 (1971).
Nishimura, S. and Weinstein, I. B., Biochemistry 8, 832–842 (1969).
Smith, A. E. and Marcker, K. A., Nature 226, 607–612 (1970).
Bermek, E. and Matthaei, H., Biochemistry 10, 4906–4912 (1971).
Carrasco, L. and Vazquez, D., Eur. J. Biochem. 50, 317–323 (1975).
Cabrer, B., Vazquez, D. and Modolell, J., Proc. Natl. Acad. Sci. U.S.A. 69, 733–736 (1972).
Mönkemeyer, H. and Bermek, E., Hoppe-Seyler's Z. Physiol. Chem. 355, 26–32 (1974).
Smith, A. E., Nature 251, 467–469 (1974).
Gupta, N. K., Woodley, C. L., Chen, Y. C. and Base, K. K., J. Biol. Chem. 248, 4500–4511 (1973).
Levin, D. H. M., Kyner, D. and Acs, G., Proc. Natl. Acad. Sci. U.S.A. 70, 41–45 (1973).
Dettman, G. L. and Stanley, W. M., Jr., Biochim. Biophys. Acta 287, 124–133 (1972).
Darnbrough, C., Legon, S., Hunt, T. and Jackson, R. J., J. Mol. Biol. 76, 379–403 (1973).
Shafritz, D. A. and Anderson, W. F., J. Biol. Chem. 245, 5553–5559 (1970).
Shafritz, D. A., Prichard, P. M. and Anderson, W. F., in: Methods in Molecular Biology (Last, J. A. and Laskin, A. I., eds.), Vol. 2, pp. 265–294, Marcel-Dekker Inc., New York (1972).
Cashion, L. M. and Stanley, W. M., Jr., Proc. Natl. Acad. Sci. U.S.A. 71, 436–440 (1974).
Heywood, S. M., Kennedy, D. S. and Bester, A. J., Proc. Natl. Acad. Sci. U.S.A. 71, 2428–2431 (1974).
Haselkorn, R. and Rothman-Denes, L. B., Ann. Rev. Biochem. 42, 397–438 (1973).
Robertus, J. D., Ladner, J. E., Finch, J. T., Rhodes, O., Brown, R. S., Clark, B. F. C. and Klug, A., Nucleics Acids Research 1, 927–932 (1974).
Lucas-Lenard, J. and Lipmann, F., Ann. Rev. Biochem. 40, 409–448 (1971).
Kappen, L. S. and Goldberg, I. H., Biochem. Biophys. Res. Commun. 54, 1083–1091 (1973).
Cheung, C. P., Stewart, M. L. and Gupta, N. K., Biochem. Biophys. Res. Commun. 54, 1092–1101 (1973).
Yamaki, H., Nishimura, T., Kubota, K., Kinoshita, T. and Tanaka, N., Biochem. Biophys. Res. Commun. 59, 482–488 (1974).
Olsnes, S. and Pihl, A., Biochemistry 12, 3121–3126 (1973).
Olsnes, S. and Pihl, A., Eur. J. Biochem. 35, 179–185 (1973).
Olsnes, S., Heiberg, R. and Pihl, A., Mol. Biol. Reports 1, 15–20 (1973).
Montanaro, L., Sperti, S. and Stirpe, F., Biochem. J. 136, 677–683 (1973).
Carrasco, L. Fernandez-Puentes, C. and Vazquez, D., Eur. J. Biochem., in the press (1975).
Vazquez, D., Battaner, E., Neth, R., Heller, G. and Monro, R. E., Cold Spring Harbor Symp. Quant. Biol. 34, 369–375 (1969).
Neth, R., Monro, R. E., Heller, C., Battaner, E. and Vazquez, D., FEBS Letters 6, 198–202 (1970).
Skogerson, L. and Moldave, K., Arch. Biochem. Biophys. 125, 497–505 (1968).
Carrasco, L., Battaner, E. and Vazquez, D., Methods Enzymol. 30, 283–289 (1974).
Battaner, E. and Vazquez, D., Biochim. Biophys. Acta 154, 316–330 (1971).
Barbacid, M. and Vazquez, D., J. Mol. Biol. 84, 603–623 (1974).
Barbacid, M. and Vazquez, D., J. Mol. Biol.93, 449–463 (1975).
Barbacid, M. and Vazquez, D., Eur. J. Biochem. 44, 437–444 (1974).
Jimenez, A., Sanchez, L. and Vazquez, D., Biochim. Biophys. Acta,383, 427–434 (1975).
Jimenez, A. and Vazquez, D., Eur. J. Biochem., in the press (1975).
Barbacid, M. and Vazquez, D., Eur. J. Biochem. 44, 445–453 (1974).
Huang, M. T. and Grollman, P., Mol. Pharmacol. 8, 538–550 (1972).
Bermek, E., FEBS Letters 23, 95–99 (1972).
Tiboni, O., Parisi, B. and Ciferri, O., Giornale Botanico Italiano 102, 337–345 (1968).
Pestka, S., Rosenfeld, H., Harris, R. and Hintikka, H., J. Biol. Chem. 247, 6895–6900 (1972).
Grant, P., Sanchez, L. and Jimenez, A., J. Bact. 120, 1308–1314 (1974).
Hirashima, A. and Kaji, A., Biochemistry 11, 4037–4044 (1972).
Hirashima, A. and Kaji, A., J. Mol. Biol. 65, 43–58 (1972).
Fernandez-Puentes, C., Carrasco, L. and Vazquez, D., FEBS Letters 45, 132–135 (1974).
Igarashi, K., Takahashi, K. and Hirose, S., Biochem. Biophys. Res. Commun. 60, 234–240 (1974).
Young, D. and Oliver, I. T., Biochemistry 7, 3231–3239 (1968).
Robison, G. A., Butcher, R. W. and Sutherland, E. W., Cyclic AMP, Academic Press, New York-London (1971).
Richter, D., J. Biol. Chem. 248, 2853–2857 (1973).
McKeehan, W. L. and Hardesty, B., J. Biol. Chem. 224, 4330–4339 (1969).
Girgis, G. R. and Nichols, D. M., Biochim. Biophys. Acta 269, 465–474 (1972).
Legon, S., Brayley, A., Hunt, T. and Jackson, R. J., Biochem. Biophys. Res. Commun. 56, 745–752 (1974).
Author information
Authors and Affiliations
Additional information
An invited article.
Rights and permissions
About this article
Cite this article
Carrasco, L., Fernandez-Puentes, C. & Vazquez, D. Antibiotics and compounds affecting translation by eukaryotic ribosomes. Specific enhancement of aminoacyl-tRNA binding by methylxanthines. Mol Cell Biochem 10, 97–122 (1976). https://doi.org/10.1007/BF01742203
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF01742203