Many Antibiotics Work Because They Selectively Inhibit Protein Synthesis In Bacteria

Ribosomes in bacteria and in the mitochondria of higher eukaryotic cells differ from the mammalian ribo-some described in Chapter 35. The bacterial ribosome is smaller (70S rather than 80S) and has a different, somewhat simpler complement of RNA and protein molecules. This difference is exploited for clinical purposes because many effective antibiotics interact specifically with the proteins and RNAs of prokaryotic ribo-somes and thus inhibit protein synthesis. This results in growth arrest or death 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 ribosomal particles and thus are not toxic to eukaryotes. Tetracycline prevents the binding of aminoacyl-tRNAs to the A site. Chloramphenicol and the macrolide class of antibiotics work 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.

hoch2 o.

hoch2 o.

OCH3

OCH3

Figure 38-11. The comparative structures of the antibiotic puromycin (top) and the 3' terminal portion of tyrosinyl-tRNA (bottom).

Figure 38-11. The comparative structures of the antibiotic puromycin (top) and the 3' terminal portion of tyrosinyl-tRNA (bottom).

Other antibiotics inhibit protein synthesis on all ri-bosomes (puromycin) or only on those of eukaryotic cells (cycloheximide). Puromycin (Figure 38-11) is a structural analog of tyrosinyl-tRNA. Puromycin is incorporated via the A site on the ribosome into the car-boxyl 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. Cyclohex-imide inhibits peptidyltransferase in the 60S ribosomal subunit in eukaryotes, presumably by binding to an rRNA component.

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 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 providing 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 elucidating the role of protein synthesis in the regulation of metabolic processes, particularly enzyme induction by hormones.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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