AssessmentsProtein synthesis inhibitors: Tetracyclines
Protein synthesis inhibitors: Tetracyclines
Content Reviewers:Yifan Xiao, MD
Tetracyclines are antimicrobial antibiotics that inhibit bacterial ribosomes which are the organelles that make proteins.
During transcription, a specific gene on the DNA is “read” and a copy is made called a messenger RNA, which is like a blueprint with instructions on what protein to build.
Translation is also known as protein synthesis, and it’s when organelles called ribosomes assemble the protein from amino acids within the cytoplasm.
Now, prokaryotic cells, like bacteria, have smaller ribosomes than eukaryotic cells, like those found in humans.
Bacterial ribosomes are made up of a 50S subunit and a 30S subunit which combine to form a 70S ribosome.
Eukaryotic ribosomes are made up of a 60S and a 40S subunits that form an 80S ribosome.
Since these proteins are different, we can created medications that selectively interfere with the bacterial ones.
In both eukaryotic and prokaryotic cells, protein synthesis involves initiation, elongation, and termination.
In bacteria, initiation occurs when the 50S and 30S subunits bind to the mRNA sequence to form a ribosome-mRNA complex.
The mRNA serves as a blueprint for the protein that will be synthesized. It’s made up of three nucleotide long sequences, called codons.
Transport RNA, or tRNA, carrying different amino acids can bind to these codons with their matching anticodons.
The complete ribosome-mRNA complex has 3 sites where tRNA can enter and bind.
These are called the A, or aminoacyl site, the P, or peptidyl site, and the E, or exit site.
Elongation starts when the first tRNA, carrying a formylmethionine amino acid, enters the P site and binds to the start codon.
This causes a conformational change in the ribosome which unlocks the A site for the next tRNA.
A process called proofreading occurs here where only tRNAs with the matching anticodon can bind to corresponding mRNA codon.
After the next tRNA binds at the A site, the amino acid detaches from the tRNA in the P site and gets attached to the amino acid in the A site by the enzyme peptidyl transferase. This step is called transpeptidation because the peptide chain is transferred from the P site tRNA to the A site tRNA.
Now, the A site has the newly formed peptide chain dangling from it, while the P site has an empty tRNA with no amino acids.
In the final stage of elongation, the ribosome slides across the mRNA, and the A site sits above a new codon, the tRNAs that was in the A site slides over to the P site, and the tRNA in the P site slides over to the E site.
Now, a new tRNA with the matching anticodon binds, and the process repeats until a long peptide chain, called a protein, is synthesized.
Finally, termination happens when the ribosome comes across a termination codon on the mRNA.
There are no tRNA anticodons that can bind to these, so they signal the end of protein synthesis.
Tetracyclines were originally derived from soil-dwelling Streptomyces bacteria. They get their name from their structure, which involves four rings bound together, so “tetra” for four, and “cyclins” for rings.
Tetracyclines bind to the A-site on the 30s subunit of the ribosome which inhibits the binding of tRNAs to the mRNA-ribosome complex, and shuts down protein synthesis before it even begins.
Tetracyclines are divided according to their duration of action.
Now, some bacteria developed enzymes that can break down tetracyclines, or they have proteins on their membrane that could pump the medication out.
Tetracyclines are a class of antibiotics that inhibit bacterial protein synthesis by binding to the 30s subunit of their ribosomes and preventing tRNA from binding. Tetracyclines are broad-spectrum antibiotics, effective against many common gram-positive and gram-negative bacteria, as well as certain types of anaerobic and atypical bacteria. They are often used to treat respiratory and urinary tract infections, skin and soft tissue infections, and sexually transmitted diseases. Common side effects of tetracyclines include phototoxicity, tinnitus, teeth staining, bone growth delay, nephrotoxicity, and hepatotoxicity.
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