Pharmacological targets: 30S and 50S
The bacterial translation apparatus is fundamentally different from the human one, making it an excellent target for selective drug toxicity. Protein synthesis inhibitors are divided into two major groups depending on which part of the ribosome they bind to.
Drugs acting on the 30S (small subunit):
- Aminoglycosides;
- Aminocyclitols;
- Tetracyclines;
- Glycylcyclines.
Drugs acting on the 50S (large subunit):
- Macrolides;
- Ketolides;
- Lincosamides;
- Chloramphenicol;
- Linezolid.
Translation initiation
The synthesis process begins with the assembly of the working complex. First, messenger RNA (mRNA) binds to the small 30S subunit.
The starting amino acid plays a key role at this stage. In prokaryotic organisms, this function is performed by formylmethionine (fMet). Transfer RNA carrying fMet locates the start codon (AUG) on the mRNA and attaches to it.
After this, the large 50S subunit joins the structure, completing the formation of the functional 70S ribosome.
Inside the assembled ribosome, the fMet-tRNA molecule is located in the P site (peptidyl site). The neighboring A site (aminoacyl site) remains completely vacant at this moment—it is ready to accept the next transfer RNA to continue synthesis.
Elongation: peptide chain extension
During the elongation phase, the ribosome moves sequentially along the mRNA in the 5’ to 3’ direction, attaching new amino acids. This cycle consists of several strict steps:
- Binding. A new aminoacyl-tRNA enters the empty A site. It carries a specific amino acid and binds to the mRNA via complementary base pairing.
- Peptidyl transferase reaction. The enzyme peptidyl transferase links two amino acids together. A peptide bond forms between the formylmethionine located in the P site and the newly arrived amino acid in the A site.
- Transpeptidation. As a result of this linking, the tRNA from the A site takes over the fMet. Now this tRNA holds a dipeptide (a chain of two amino acids).
- Translocation. The ribosome moves forward by exactly three nucleotides toward the 3’ end. The enzyme translocase assists in this process by shifting the mRNA.
During the shift, tRNA rearrangement occurs: the molecule that gave up its fMet and became "empty" leaves the P site. The tRNA carrying the dipeptide, previously located in the A site, moves into its place (the vacated P site).
Cycle outcome: The A site is vacant once again. The system is ready to accept the next aminoacyl-tRNA, and the entire elongation cycle repeats.
Briefly: answers to topical questions
What is the exact mechanism of action of tetracyclines on the 30S subunit?
Tetracyclines reversibly block the binding of new aminoacyl-tRNA to the A site (acceptor site) on the 30S subunit of the bacterial ribosome. As a result, the transfer RNA carrying the specific amino acid cannot attach to the ribosome. This halts the elongation of the peptide chain by blocking the initiation phase of elongation. The inhibition is reversible, and protein synthesis resumes once the antibiotic is removed.
What is the mechanism of action of macrolides on the 50S subunit?
Macrolides bind to a specific ligand within the ribosomal tunnel of the 50S subunit and inhibit translocation. The ribosome loses its ability to move along the mRNA by a single triplet (codon). As a result, the movement of the formed peptide from the A site to the P site is blocked, and the release of synthesized peptides from the ribosome is impaired. This prevents the A site from freeing up for the next tRNA and blocks the release of the "empty" tRNA from the P site, thereby halting further protein synthesis.
Which protein factors are involved in the translation elongation stage in bacteria?
Specific protein elongation factors are involved in the translation elongation stage in prokaryotes (bacteria). They facilitate the addition of amino acids to the growing chain as the ribosome moves from the 5’ to the 3’ end of the mRNA. These include:
- EF-Tu — elongation factor.
- EF-Ts — elongation factor.
- EF-G — translocation factor.
Which antibiotics specifically inhibit the peptidyl transferase reaction?
The peptidyl transferase reaction is specifically inhibited by chloramphenicol (levomycetin). The drug binds to the catalytic center of the ribosomal 50S subunit and blocks the peptidyl transferase enzyme. Consequently, the transpeptidation reaction is inhibited: peptide bond formation is blocked, making it impossible to transfer the growing peptide chain from the tRNA in the P site to the amino acid in the A site.
Antibiotic classes that inhibit the 30S subunit are easy to remember using the mnemonic "Two A's, two T/C's": Aminoglycosides, Aminocyclitols, Tetracyclines, Glycylcyclines. The rest from the list act on the 50S subunit.
Class and exam questions
Which subunit binds to mRNA at the very beginning of initiation?
Initially, messenger RNA binds to the small (30S) ribosomal subunit, and only after the fMet-tRNA attaches does the complex close with the large 50S subunit.
In which direction does the ribosome read mRNA?
Ribosomal movement (and translocase enzyme activity) always proceeds from the 5’ end to the 3’ end of the messenger RNA.
Where is the transfer RNA carrying the starting amino acid located after 70S ribosome assembly?
The fMet-tRNA molecule is located in the peptidyl P site, leaving the neighboring aminoacyl A site vacant for the next step.
What else to study on this topic
- The role of the translocase enzyme during ribosomal stepping
- Mechanism of the peptidyl transferase reaction
- Spatial distribution of the P and A ribosomal sites
- Function of the AUG start codon in translation
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