Chemistry Reference
In-Depth Information
occur, the amino group of the amino acid in the A site
attacking the activated ester in the P site. The peptide
chain is thus initiated and has become attached to the
tRNA located in the A site. The tRNA at the P site is
no longer required and is released from the ribosome.
Then the peptidyl-tRNA at the A site is translo-
cated to the P site by the ribosome moving along
the mRNA a codon at a time, exposing the A site
for a new aminoacyl-tRNA appropriate for the par-
ticular codon, and a repeat of the elongation process
occurs. The cycles of elongation and
translocation
continue until a termination codon is reached, and
the peptide or protein is then hydrolysed and released
from the ribosome. Note that the protein is synthe-
sized from the
N
-terminus towards the
C
-terminus
(see Section 13.2).
Some special features of proteins are elaborated
by
secondary transformations
that are not part
of the translation process. The
N
-formylmethionine
initiator may be hydrolysed to methionine, or, as
we have already indicated, the methionine unit
may be removed altogether. Other
post-translational
changes
to individual amino acids may be seen, e.g.
the hydroxylation of proline to hydroxyproline (see
Section 13.1) or the generation of disulfide bridges
between cysteine residues (see Section 13.3).
Box 14.1
Antibiotics that interfere with ribosomal
peptide biosynthesis
Many of the antibiotics used clinically are active
by their ability to
inhibit protein biosynthesis
in
bacteria. The individual steps of protein biosynthesis
all seem susceptible to disruption by specific agents.
Some specific examples are listed below:
Inhibitors of transcription
Box 14.2
Nucleosides as antiviral agents
Viruses
are responsible for many human and ani-
mal diseases, with a variety of symptoms and levels
of severity. Common viral illnesses include colds,
influenza, cold-sores (herpes), and childhood infec-
tions such as chickenpox, measles, and mumps. More
serious conditions include meningitis, poliomyelitis,
and human immunodeficiency virus (HIV), the lat-
ter potentially leading to acquired immune deficiency
syndrome (AIDS).
Viruses are simpler than bacteria and consist
essentially of nucleic acid (either DNA or RNA)
enclosed in a protein coat. Those causing chickenpox,
smallpox, and herpes belong to the DNA virus
group, whereas those responsible for influenza,
measles, mumps, meningitis, poliomyelitis, and HIV
are classified as RNA viruses. Viruses have no
metabolic machinery of their own, and for their
very existence are intracellular parasites of other
organisms. To survive and reproduce, they have
to tap into the metabolic processes of the host
organism. For this reason, it is difficult to find drugs
that are selective towards viruses without damaging
the host. Most antiviral agents are only effective
whilst the virus is replicating, and viral replication
is very far advanced by the time the infection
is detectable. There are relatively few effective
antiviral drugs, and most of these are nucleoside
derivatives.
Aciclovir
(acyclovir) was one of the first effective
selective antiviral agents. It is a guanine derivative
of value in treating herpes viruses, though it does not
eradicate them, and is only useful if drug treatment
is started at the onset of infection.
rifampicin
(inhibits RNA polymerase)
Inhibitors of aminoacyl-tRNA binding to ribosome
tetracyclines
(bind to 30S subunit of ribosome and
prevent attachment of aminoacyl-tRNA)
Inhibitors of translation
streptomycin
(binds to 30S subunit of ribosome,
causes mRNA to be misread)
erythromycin
(binds to 50S subunit of ribosome,
inhibits translocation)
chloramphenicol
(binds to 50S subunit, inhibits
peptidyltransferase activity)
Naturally, if such materials are going to be useful
as antibiotic drugs, we require a selective action. We
need to be able to inhibit protein biosynthesis in
bacteria, whilst producing no untoward effects in man
or animals. Although the mechanisms for protein
biosynthesis are essentially the same in prokaryotes
and eukaryotes, there are some subtle differences,
e.g. in the nature of the ribosome and how the process
is initiated. Without such differences, the agent would
be toxic to man as well as to bacteria.
