Inhibitors of Protein Synthesis

Many compounds have been identified which inhibit different steps in protein synthesis, either by mimicking translational substrates, blocking movement within the ribosome, or otherwise interfering with essential interactions (Table III). Some of these inhibitors are clinically relevant antibiotics and others have facilitated functional studies of the ribosome as described earlier. For example aminoglycosides such as streptomycin and gentamycin interfere with the decoding center on the 30S subunit. At low concentrations these antibiotics affect translational accuracy, while at increased doses they prevent formation of the 30S initiation complex, leading to cell death. Despite the increasing incidence of antibiotic resistance, the aminoglycosides remain useful therapeutic agents against gram-negative bacteria.

Puromycin is an antibiotic that mimics tyrosyl–or phenylalanyl–tRNA and binds in the ribosomal A-site (Fig. 13). The ribosome will even use puromycin as a substrate in one round of elongation, forming a peptide bond between the antibiotic and the P-site peptidyl–tRNA. This transpeptidation step terminates synthesis of the polypeptide and releases the abortive peptidyl–puromycin product.

Figure 13 Puromycin—an AA–tRNA mimic. Puromycin (right) inhibits protein synthesis by binding in the ribosomal A-site as a mimic of tyrosyl–tRNA (left). Translation is terminated because puromycin does not have a free carboxyl group available for further elongation steps.

TABLE III Inhibitors of Protein Synthesis

Antibiotic	Activity
Chloramphenicol	Blocks peptidyl transferase function
Erythromycin	Blocks translocation of peptidyl–tRNA
Gentamycin	Prevents formation of 30S initiation complex
Kirromycin	Blocks release of EF-Tu:GDP from ribosome
Pseudomonic acid	Inhibits isoleucyl–tRNA synthetase
Puromycin	Mimics tyrosyl–tRNA, terminates elongation
Spectinomycin	Inhibits EF-G function
Streptomycin	Prevents transition from initiation to elongation
Tetracycline	Inhibits binding of aminoacyl–tRNAs to small subunit