Transpeptidation is a fundamental biochemical reaction involving the formation of new peptide bonds. It is a type of chemical reaction where a peptide chain, a sequence of amino acids, is transferred from one molecule to another. This enzymatic activity is widespread in living organisms, playing a part in various biological processes.
The Process of Transpeptidation
Transpeptidation involves the transfer of a peptide chain from a donor to an acceptor molecule, forming a new peptide bond. Transpeptidases, the enzymes that catalyze this reaction, facilitate the creation of this new bond. In bacteria, these enzymes are often called Penicillin-Binding Proteins (PBPs) due to their interaction with certain antibiotics. The process begins with the donor peptide binding to the enzyme’s active site.
The enzyme then forms a temporary covalent bond with the donor peptide, releasing the initial part of the donor molecule. An amino group from the acceptor molecule then attacks the enzyme-peptide complex. This attack forms a new peptide bond between the transferred peptide chain and the acceptor molecule, completing the transfer and releasing the enzyme. This enzymatic reaction is important for various biological syntheses.
Transpeptidation in Bacterial Survival
Transpeptidation plays an important role in the synthesis and maintenance of the bacterial cell wall, specifically the peptidoglycan layer. Peptidoglycan is a net-like polymer that provides structural rigidity and support to bacteria, acting like a protective external skeleton. Transpeptidases facilitate the cross-linking of adjacent peptidoglycan strands, which are composed of sugar chains with attached peptides, creating a strong, three-dimensional meshwork.
A robust cell wall is essential for bacterial survival, particularly because bacteria often live in environments where internal solute concentration is much higher than outside. This difference creates osmotic pressure, causing water to constantly move into the cell. Without a strong, intact cell wall, the internal pressure would cause the bacterial cell to swell and burst, a process known as osmotic lysis. The continuous cross-linking mediated by transpeptidases ensures the cell wall remains strong enough to counteract this pressure and protect the bacterium.
Targeting Transpeptidation with Antibiotics
The important role of transpeptidation in bacterial cell wall synthesis makes it an effective target for antibiotics. Beta-lactam antibiotics, a widely used class including penicillins and cephalosporins, specifically interfere with this process. These antibiotics structurally resemble the D-alanyl-D-alanine portion of bacterial peptidoglycan precursors, which is the natural substrate for transpeptidases (PBPs).
When a beta-lactam antibiotic enters a bacterium, it binds irreversibly to the active site of the transpeptidase enzyme. This binding prevents the enzyme from catalyzing the necessary cross-linking of peptidoglycan strands, effectively inactivating it. Without proper cross-linking, the bacterial cell wall becomes weakened and structurally compromised. The compromised cell wall can no longer withstand internal osmotic pressure, leading to water influx, cell swelling, and ultimately, cell lysis and death.
Bacterial Resistance and Future Strategies
Despite the effectiveness of antibiotics targeting transpeptidation, bacteria have evolved various mechanisms to develop resistance. One common strategy is the production of enzymes called beta-lactamases. These enzymes break down the beta-lactam ring structure of the antibiotic, rendering it inactive before it can bind to the transpeptidases. Another significant resistance mechanism involves modifications to the transpeptidase enzymes (PBPs) themselves.
Bacteria can acquire mutations in their PBP genes, leading to changes in the enzyme’s structure that reduce its binding affinity for beta-lactam antibiotics. This means the antibiotic can no longer effectively inhibit the transpeptidation process, allowing the bacteria to continue building their cell walls. To combat this evolving resistance, researchers are exploring new strategies, such as developing novel antibiotics that can evade beta-lactamase degradation or bind to modified PBPs. Combination therapies, where a beta-lactam is paired with a beta-lactamase inhibitor, are also being used to overcome some forms of resistance.