The 23S ribosomal RNA (rRNA) is a large, complex molecule of ribonucleic acid found in the cellular machinery of bacteria and archaea. It plays an indispensable role in protein synthesis, a process central to all forms of life. Its foundational role makes it a significant target in medicine, particularly for antibiotics.
Where 23S rRNA Resides and Its Structure
The 23S rRNA is a major constituent of the large ribosomal subunit, known as the 50S subunit, in prokaryotic cells like bacteria and archaea. Ribosomes are complex molecular machines responsible for synthesizing proteins, composed of a smaller and a larger subunit. In prokaryotes, the large 50S subunit contains the 23S rRNA, a smaller 5S rRNA, and numerous ribosomal proteins.
The 23S rRNA molecule, approximately 2,904 nucleotides long in E. coli, folds into a precise three-dimensional shape. This complex folding forms a network of interactions, organized into six distinct structural domains (I through VI). While ribosomal proteins are also part of the 50S subunit, the intricate folding of the 23S rRNA forms the core architecture, providing the framework for the ribosome’s function.
The Central Role in Protein Production
The primary function of 23S rRNA is its catalytic activity during protein synthesis. It acts as a ribozyme, an RNA molecule with enzymatic capabilities, specifically catalyzing peptide bond formation. This activity, known as peptidyl transferase activity, occurs within the peptidyl transferase center (PTC), located predominantly in domain V of the 23S rRNA.
During protein synthesis, messenger RNA (mRNA) carries genetic instructions, and transfer RNA (tRNA) molecules bring amino acids to the ribosome. The ribosome has three binding sites for tRNA: the A (aminoacyl) site, P (peptidyl) site, and E (exit) site. As a new aminoacyl-tRNA enters the A site, the 23S rRNA facilitates the transfer of the growing polypeptide chain from the P site tRNA to the amino acid on the A site tRNA. This reaction forms a new peptide bond, elongating the protein chain.
This process is fundamental because it connects individual amino acids into long chains, which then fold into functional proteins. Studies have shown that the peptidyl transferase center itself is composed almost entirely of RNA, with no proteins directly at the active site where the peptide bond is formed. This highlights the direct and central role of 23S rRNA as the catalyst for one of the most basic and universal biochemical reactions in living organisms.
A Key Target for Antibiotics
The 23S rRNA is a significant target for antibiotics due to distinct structural and functional differences between prokaryotic and eukaryotic ribosomes. Bacterial ribosomes, which contain 23S rRNA, are structurally different from human ribosomes. This difference allows antibiotics to selectively interfere with bacterial protein synthesis without harming human cells. Targeting bacterial protein production effectively stops bacterial growth and reproduction.
Several classes of antibiotics bind to the 23S rRNA to exert their antibacterial effects. Macrolides, such as erythromycin and azithromycin, bind to the 23S rRNA within the large ribosomal subunit, often at the entrance of the peptide exit tunnel. This binding blocks the passage of nascent peptides, preventing the elongation of the protein chain and leading to premature dissociation of the peptidyl-tRNA from the ribosome. Chloramphenicol, another antibiotic, also targets the 23S rRNA in the peptidyl transferase center. It directly competes with the incoming aminoacyl-tRNA at the A-site cleft, thereby inhibiting peptide bond formation and halting protein synthesis.
Clindamycin, a lincosamide antibiotic, interferes with protein synthesis by binding to the 23S rRNA, specifically within the peptidyl transferase loop. Its mechanism involves preventing the growth of the polypeptide chain. Bacterial resistance to these antibiotics often arises from genetic alterations in the 23S rRNA, such as nucleotide mutations or modifications by rRNA methylases, which prevent the drugs from binding effectively to their target site. These modifications can reduce the affinity of the antibiotic for the ribosome, rendering the bacteria insensitive to the drug’s action.