transpeptidases

Transpeptidases are enzymes that catalyze transpeptidation reactions during peptidoglycan synthesis. In bacteria, the peptidoglycan mesh provides structural strength to the cell wall, and cross-linking between peptide stems is essential for maintaining integrity under osmotic pressure. Transpeptidases operate in the periplasmic space in Gram-negative species or in the cell wall surrounding Gram-positive bacteria, connecting stem peptides of adjacent glycan strands.

Two main classes exist: D,D-transpeptidases and L,D-transpeptidases. D,D-transpeptidases, commonly called penicillin-binding proteins (PBPs), form 4-3 cross-links by linking the fourth amino acid (the terminal D-alanine) of one stem to the third amino acid of another. L,D-transpeptidases form 3-3 cross-links between the third residues of stem peptides. D,D-transpeptidases typically use a serine-based catalytic mechanism, generating an acyl-enzyme intermediate that is resolved by the incoming stem peptide, while L,D-transpeptidases use a different catalytic machinery, often involving a cysteine residue as the nucleophile.

Clinical relevance is high. PBPs are principal targets of beta-lactam antibiotics (such as penicillins and cephalosporins). Inhibition of transpeptidation weakens the cell wall and can lead to bacterial lysis. Resistance can arise through alterations that reduce antibiotic affinity for PBPs or through beta-lactamases that hydrolyze the drugs. Some bacteria also rely on L,D-transpeptidases for cross-linking, particularly when D,D-transpeptidases are inhibited, which can contribute to beta-lactam resistance. Carbapenems can inhibit both classes in some contexts and are used to treat infections where alternative cross-linking pathways predominate.

Transpeptidases are widespread among bacteria and are central to cell-wall remodeling during growth and division, making them key targets and mediators of antibiotic action and resistance.