Protein Synthesis: Protein Synthesis Is Inhibited by Many Antibiotics and Toxins
Protein synthesis is a central function in cellular physiology and is the primary target of many naturally occurring antibiotics and toxins. Except as noted, these antibiotics inhibit protein synthesis in bacteria. The differences between bacterial and eukaryotic protein syn thesis, though in some cases subtle, are sufficient that most of the compounds discussed below are relatively harmless to eukaryotic cells. Natural selection has favored the evolution of compounds that exploit minor differences in order to affect bacterial systems selectively, such that these biochemical weapons are synthesized by some microorganisms and are extremely toxic to others. Because nearly every step in protein synthesis can be specifically inhibited by one antibiotic or another, antibiotics have become valuable tools in the study of protein biosynthesis.
FIGURE 1 Disruption of peptide bond formation by puromycin. (a)The antibiotic puromycin resembles the aminoacyl end of a charged tRNA, and it can bind to the ribosomal A site and participate in pep tide bond formation. The product of this reaction, instead of being translocated to the P site, dissociates from the ribosome, causing pre mature chain termination. (b) Peptidyl puromycin.
Puromycin, made by the mold Streptomyces alboniger, is one of the best-understood inhibitory antibiotics. Its structure is very similar to the 3end of an aminoacyl-tRNA, enabling it to bind to the ribosomal A site and participate in peptide bond formation, producing peptidyl-puromycin (Fig. 1). However, because puromycin resembles only the 3end of the tRNA, it does not engage in translocation and dissociates from the ribosome shortly after it is linked to the carboxyl terminus of the peptide. This prematurely terminates polypeptide synthesis. Tetracyclines inhibit protein synthesis in bacteria by blocking the A site on the ribosome, preventing the binding of aminoacyl-tRNAs. Chloramphenicol inhibits protein synthesis by bacterial (and mitochondrial and chloroplast) ribosomes by blocking peptidyl trans fer; it does not affect cytosolic protein synthesis in eukaryotes. Conversely, cycloheximide blocks the peptidyl transferase of 80S eukaryotic ribosomes but not that of 70S bacterial (and mitochondrial and chloroplast) ribosomes. Streptomycin, a basic trisaccharide, causes misreading of the genetic code (in bacteria) at relatively low concentrations and inhibits initiation at higher concentrations.
Several other inhibitors of protein synthesis are notable because of their toxicity to humans and other mammals. Diphtheria toxin (Mr58,330) catalyzes the ADP-ribosylation of a diphthamide (a modified histidine) residue of eukaryotic elongation factor eEF2, thereby inactivating it. Ricin (Mr29,895), an extremely toxic protein of the castor bean, inactivates the 60S sub unit of eukaryotic ribosomes by depurinating a specific adenosine in 23S rRNA.
