Inhibition of translation in eukaryotic systems by harringtonine.

The Cephalotaxus alkaloids harringtonine, homoharringtonine and isoharringtonine inhibit protein synthesis in eukaryotic cells. The alkaloids do not inhibit, in model systems, any of the steps of the initiation process but block poly(U)-directed polyphenylalanine synthesis as well as peptide bond formation in the fragment reaction assay, the sparsomycin-induced binding of (C)U-A-C-C-A-[3H]Leu-Ac, and the enzymic and the non-enzymic binding of Phe-tRNA to ribosomes. These results suggest that the Cephalotaxus alkaloids inhibit the elongation phase of translation by preventing substrate binding to the acceptor site on the 60-S ribosome subunit and therefore block aminoacyl-tRNA binding and peptide bond formation. However, the Cephalotaxus alkaloids do not inhibit polypeptide synthesis and peptidyl[3H]puromycin formation in polysomes. Furthermore, these alkaloids strongly inhibit [14C]trichlodermin binding to free ribosomes but hardly affect the interaction of the antibiotic with yeast polysomot interact with polysomes and therefore only inhibit cycles of elongation. This explains the polysome run off that has been observed by some workers in the presence of harringtonine.

[1]  A. Jimenez,et al.  Competition between trichodermin and several other sesquiterpene antibiotics for binding to their receptor site(s) on eukaryotic ribosomes. , 1976, The Biochemical journal.

[2]  Luis Carrasco,et al.  Initiation of the polypeptide chain by reticulocyte cell-free systems. Survey of different inhibitors of translation. , 1976, European journal of biochemistry.

[3]  C. Carter,et al.  Prevention, by ribosome-bound nascent polyphenylalanine chains, of the functional interaction of t-2 toxin with its receptor site. , 1976, The Biochemical journal.

[4]  A. Kaji,et al.  Mode of action of bottromycin A2. Release of aminoacyl- or peptidyl-tRNA from ribosomes. , 1976, The Journal of biological chemistry.

[5]  A. Jimenez,et al.  Yeast ribosomal sensitivity and resistance to the Amaryllidaceae alkaloids , 1975, FEBS letters.

[6]  S. Pestka,et al.  Inhibition of Protein Synthesis in Intact HeLa Cells , 1975, Antimicrobial Agents and Chemotherapy.

[7]  M. Huang,et al.  Harringtonine, an inhibitor of initiation of protein biosynthesis. , 1975, Molecular pharmacology.

[8]  A. Jimenez,et al.  Quantitative binding of antibiotics to ribosomes from a yeast mutant altered on the peptidyl-transferase center. , 1975, European journal of biochemistry.

[9]  A. Jimenez,et al.  Simultaneous ribosomal resistance to trichodermin and anisomycin in Saccharomyces cerevisiae mutants. , 1975, Biochimica et biophysica acta.

[10]  S. Mizuno Mechanism of inhbition of protein systhesis initiation by diacetoxyscirpenol and fusarenon X in the reticulocyte lysate system. , 1975, Biochimica et biophysica acta.

[11]  E. Cundliffe,et al.  Inhibition at the initiation level of eukaryotic protein synthesis by T‐2 toxin , 1975, FEBS letters.

[12]  M. Barbacid,et al.  Binding of (acetyl-14C)trichodermin to the peptidyl transferase centre of eukaryotic ribosomes. , 1974, European journal of biochemistry.

[13]  M. Barbacid,et al.  (3H)anisomycin binding to eukaryotic ribosomes. , 1974, Journal of molecular biology.

[14]  C. McLaughlin,et al.  Structure-function relationship in the 12,13-epoxytrichothecenes. Novel inhibitors of protein synthesis. , 1974, Biochemical and biophysical research communications.

[15]  J. Davies,et al.  Mechanism of inhibition of eukaryotic protein synthesis by trichothecene fungal toxins. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[16]  M. Barbacid,et al.  The trichodermin group of antibiotics, inhibitors of peptide bond formation by eukaryotic ribosomes. , 1973, Biochimica et Biophysica Acta.

[17]  E. Battaner,et al.  Inhibitors of protein synthesis by ribosomes of the 80-S type. , 1971, Biochimica et biophysica acta.

[18]  D. Weisleder,et al.  Structure of cephalotaxine and related alkaloids , 1969 .

[19]  J. Matthaei,et al.  Human gene expression. I. An aminoacyl-RNA binding system from human placenta. , 1967, Biochemical and biophysical research communications.