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There were several reports on the inhibitory effect of tetracyclines on the eukaryotic protein synthesis. They were based on the in vitro experiments where high concentrations of the antibiotic were added into eukaryotic cell-free systems. However, tetracycline is a strong Mg2+-chelating agent, so that the inhibition could be the result of the depletion of Mg2+ in the system, rather than due to a specific action on eukaryotic ribosomes. Indeed, no inhibition of the eukaryotic cell-free systems by tetracyclines was observed at increased Mg2+ concentrations.

10.3.2.Aminoglycosides

Another group of antibiotics also affects the binding of the aminoacyl-tRNA to the ribosomal A site, but the action is of a completely different nature. These antibiotics are the so-called aminoglycoside antibiotics, the principal members of which are streptomycin (Fig. 10.9), neomycin kanamycin, and gentamicin (Fig. 10.10). Antibiotics in this group contribute to the ribosomal retention of non-cognate aminoacyl-tRNAs, i.e., the aminoacyl-tRNAs which do not correspond to the codon positioned in the ribosomal A site (Davies et al., 1964, 1965; Gorini, 1974). Such a miscoding results in synthesis of incorrect polypeptides characterized by a large number of errors, with a consequent cytotoxic or bactericidal effect on cells. Streptomycin specifically affects bacterial 70S ribosomes, and kanamycin and neomycin are known to induce miscoding with eukaryotic 80S ribosomes as well. The main site of the antibiotic binding to the ribosome appears to occur on the small (30S or 40S) ribosomal subunit, although the effect depends on the interaction of both subunits and is manifested only with the complete 70S or 80S ribosome.

Ribosomal protein mutations are known that confer to ribosomes the resistance against streptomycin or other aminoglycosides. Most typically, streptomycin resistance of bacterial ribosomes is acquired as a result of mutations in protein S12. Mutations of the same protein, as well as proteins S4 and S5, are responsible also for streptomycin-dependent phenotypes.

Generally, proteins S4, S5, S12 and S17, or their eukaryotic analogs, in the small ribosomal subunit seem to form a protein group that modulates the response of the ribosome to the aminoglycosides.

At the same time the aminoglycosides bind specifically to the ribosomal RNA of the small subunit, rather than to the proteins. When bound, they protect from chemical modification the residues at the regions of the ribosomal RNA that are involved in the formation of the A-site part of the decoding center on the small subunit (see section 9.3). In the bacterial (E. coli) ribosome these are positions 1405, 1408 and 1494 at the base of the long, penultimate hairpin of the 16S rRNA (see Figs. 6.1 and 9.3) in the case of

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