Penicillin-binding protein 4 and low-molecular-weight penicillin-binding protein (PBP4; LMW PBP)

Penicillin-binding protein 4 (PBP4) and other low-molecular-weight (LMW) penicillin-binding proteins are a group of bacterial enzymes, typically classified as Class C PBPs, that play essential roles in the maturation and remodeling of the peptidoglycan cell wall [1.1.1, 1.3.1]. Unlike high-molecular-weight PBPs that primarily function as transpeptidases and transglycosylases, LMW PBPs generally act as DD-carboxypeptidases or DD-endopeptidases, regulating the degree of peptidoglycan cross-linking by removing terminal D-alanine residues or cleaving existing cross-links [1.1.2, 1.3.3]. In certain pathogens like Staphylococcus aureus, PBP4 is unique among LMW PBPs for its significant transpeptidase activity, which contributes to high-level beta-lactam resistance and the ability of the bacteria to invade specialized tissues like bone [1.1.3, 1.2.1]. These proteins are the primary targets of beta-lactam antibiotics, which act as pseudo-substrates that covalently acylate the active site serine, forming a stable and inactive acyl-enzyme complex [1.4.3, 1.4.5]. Inhibition of these enzymes disrupts cell wall homeostasis, leading to morphological abnormalities, cell wall weakening, and eventual osmotic lysis of the bacterium [1.1.2, 1.3.2].

Other names

D-alanyl-D-alanine carboxypeptidaseDD-carboxypeptidaseDD-endopeptidaseClass C penicillin-binding proteinDacBDacADacCPBP 4PBP 5PBP 6Low-molecular-mass penicillin-binding proteinLMM PBP

Beta-lactam antibiotics act as structural analogs of the D-alanyl-D-alanine terminus of peptidoglycan precursors. They covalently bind to the active site serine of PBP4 and LMW PBPs, forming a stable acyl-enzyme intermediate that irreversibly inhibits the enzyme's DD-carboxypeptidase, DD-endopeptidase, or transpeptidase activity [1.4.3, 1.4.5]. This inhibition prevents proper peptidoglycan cross-linking and remodeling, leading to cell wall instability and bacterial death [1.1.2, 1.3.2].