Many Antibiotics work by Selectively Inhibiting Protein Synthesis in Bacteria
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p417-418
2025-10-04
205
Ribosomes in bacteria and in the mitochondria of higher eukaryotic cells differ from the mammalian ribosome described in Chapter 34. The bacterial ribosome is smaller (70S vs 80S) and has a different, somewhat simpler complement of RNA and protein molecules. This difference can be exploited for clinical purposes because many effective antibiotics interact specifically with the proteins and RNAs of prokaryotic ribosomes and thus only inhibit bacterial protein synthesis. This results in growth arrest (ie, bacteriostatic action) or death (ie, bactericidal action) of the bacterium. The most useful members of this class of antibiotics (eg, tetracyclines, lincomycin, erythromycin, and chloramphenicol) do not interact with components of eukaryotic ribosomes and thus are not toxic to eukaryotes. Tetracycline prevents the binding of aminoacyl-tRNAs to the bacterial ribosome A site. Chloramphenicol works by binding to 23S rRNA, which is interesting in view of the newly appreciated role of rRNA in peptide bond formation through its peptidyl transferase activity. It should be mentioned that the close similarity between prokaryotic and mitochondrial ribosomes can lead to complications in the use of some antibiotics.
Other antibiotics inhibit protein synthesis on all ribosomes (puromycin) or only on those of eukaryotic cells (cycloheximide). Puromycin (Figure 1) is a structural analog of tyrosinyl-tRNA. Puromycin is incorporated via the A site on the ribosome into the carboxyl terminal position of a peptide but causes the premature release of the polypeptide. Puromycin, as a tyrosinyl-tRNA analog, effectively inhibits protein synthesis in both prokaryotes and eukaryotes. Cycloheximide inhibits peptidyl transferase in the 60S ribosomal subunit in eukaryotes, presumably by binding to an rRNA component.
Fig1. The comparative structures of the antibiotic puromycin (top) and the 3′ terminal portion of tyrosinyl-tRNA (bottom).
Diphtheria toxin, an exotoxin of Corynebacterium diphtheriae infected with a specific lysogenic phage, catalyzes the ADP-ribosylation of EF-2 on the unique amino acid diphthamide (a posttranslationally modified version of histidine) in mammalian cells. This modification inactivates EF-2 and thereby specifically inhibits mammalian protein synthesis. Many animals (eg, mice) are resistant to diphtheria toxin. This resistance is due to inability of diphtheria toxin to cross the cell membrane rather than to insensitivity of mouse EF-2 to diphtheria toxin-catalyzed ADP-ribosylation by NAD.
Ricin, an extremely toxic molecule isolated from the castor bean, inactivates eukaryotic 28S ribosomal RNA by catalyzing the N-glycolytic cleavage or removal of a single adenine.
Many of these compounds—puromycin and cycloheximide in particular—are not clinically useful but have been important in the laboratory as a tool to elucidate the role of protein synthesis in the regulation of metabolic processes, particularly enzyme induction by hormones.
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