Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

FROM RNA TO PROTEIN
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Inhibitors of Prokaryotic Protein Synthesis Are Useful as Antibiotics
Many of the most effective antibiotics used in modern medicine are compounds
made by fungi that inhibit bacterial protein synthesis. Fungi and bacteria compete
for many of the same environmental niches, and millions of years of coevolution
have resulted in fungi producing potent bacterial inhibitors. Some of these
drugs exploit the structural and functional differences between bacterial and
eukaryotic ribosomes so as to interfere preferentially with the function of bacterial
ribosomes. Thus, humans can take high dosages of some of these compounds
without undue toxicity. Many antibiotics lodge in pockets in the ribosomal RNAs
and simply interfere with the smooth operation of the ribosome; others block
specific parts of the ribosome such as the exit channel (Figure 6–75). Table 6–4
lists some common antibiotics of this kind along with several other inhibitors of
protein synthesis, some of which act on eukaryotic cells and therefore cannot be
used as antibiotics.
Because they block specific steps in the processes that lead from DNA to
protein, many of the compounds listed in Table 6–4 are useful for cell biological
studies. Among the most commonly used drugs in such investigations are chloramphenicol,
cycloheximide, and puromycin, all of which specifically inhibit protein
synthesis. In a eukaryotic cell, for example, chloramphenicol inhibits protein
synthesis on ribosomes only in mitochondria (and in chloroplasts in plants), presumably
reflecting the prokaryotic origins of these organelles (discussed in Chapter
14). Cycloheximide, in contrast, affects only ribosomes in the cytosol. Puromycin
is especially interesting because it is a structural analog of a tRNA molecule
linked to an amino acid and is therefore another example of molecular mimicry;
the ribosome mistakes it for an authentic amino acid and covalently incorporates
it at the C-terminus of the growing peptide chain, thereby causing the premature
termination and release of the polypeptide. As might be expected, puromycin
inhibits protein synthesis in both prokaryotes and eukaryotes.
Quality Control Mechanisms Act to Prevent Translation of
Damaged mRNAs
In eukaryotes, mRNA production involves both transcription and a series of elaborate
RNA processing steps; as we have seen, these take place in the nucleus,
segregated from ribosomes, and only when the processing is complete are the
mRNAs transported to the cytosol to be translated (see Figure 6–38). However,
this scheme is not foolproof, and some incorrectly processed mRNAs are inadvertently
sent to the cytosol. In addition, mRNAs that were flawless when they left the
nucleus can become broken or otherwise damaged in the cytosol. The danger of
tetracycline
chloramphenicol
spectinomycin
hygromycin B
streptomycin
erythromycin
streptogramin B
small ribosomal subunit
large ribosomal subunit
Figure 6–75 Binding sites for antibiotics
on the bacterial ribosome. The small (left)
and large (right) subunits of the ribosome
are arranged as though the ribosome has
been opened like a book. Antibiotic binding
sites are marked with colored spheres,
and the bound tRNA molecules are shown
in purple (see Figure 6–62). Most of the
antibiotics shown bind directly to pockets
formed by the ribosomal RNA molecules.
Hygromycin B induces errors in translation,
spectinomycin blocks the translocation
of the peptidyl-tRNA from the A site to
the P site, and streptogramin B prevents
elongation of nascent peptides. Table 6–4
lists the inhibitory mechanisms of the other
antibiotics shown in the figure. (Adapted
from J. Poehlsgaard and S. Douthwaite,
Nat. Rev. Microbiol. 3:870–881, 2005. With
permission from Macmillan Publishers Ltd.)