Sandbox Reserved 1488: Difference between revisions
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==Function == | ==Function == | ||
The bacterial cell wall is essential for cell survival. It is composed of layers of peptidoglycan modified with proteins and polymers. In bacteria, this peptidoglycan layer is formed by the coordinated action of multiple proteins, including penicillin-binding proteins (PBPs). PBPs are transpeptidases, carboxypeptidases and endopeptidases that synthesize new and remodel existing peptidoglycan<ref>doi: 10.1074/jbc.RA118.006052</ref> . | The bacterial cell wall is essential for cell survival. It is composed of layers of peptidoglycan modified with proteins and polymers. In bacteria, this peptidoglycan layer is formed by the coordinated action of multiple proteins, including penicillin-binding proteins (PBPs). PBPs are transpeptidases, carboxypeptidases and endopeptidases that synthesize new and remodel existing peptidoglycan<ref name="tsop">doi: 10.1074/jbc.RA118.006052</ref> . | ||
PBPs are classified by their enzymatic activity: | PBPs are classified by their enzymatic activity: | ||
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In class B PBP transpeptidases, the catalytic serine attacks the carbonyl of the penultimate D-Ala residue of a ‘donor’ stem peptide, releasing the C-terminal D-Ala and forming a covalent acyl-enzyme adduct with the donor peptide. In a second step, the carbonyl of D-Ala adduct undergoes nucleophilic attack from a primary amine located at the extremity of a side chain of an acceptor stem peptide. This creates a bridge between the peptides and, in turn, links the glycan strands to one another. | In class B PBP transpeptidases, the catalytic serine attacks the carbonyl of the penultimate D-Ala residue of a ‘donor’ stem peptide, releasing the C-terminal D-Ala and forming a covalent acyl-enzyme adduct with the donor peptide. In a second step, the carbonyl of D-Ala adduct undergoes nucleophilic attack from a primary amine located at the extremity of a side chain of an acceptor stem peptide. This creates a bridge between the peptides and, in turn, links the glycan strands to one another. | ||
== Structural insights into β-lactam resistance <ref | == Structural insights into β-lactam resistance <ref name="tsop"/> == | ||
Penicillins, carbapenems and cephalosporins mimic the D-Ala-D-Ala sequence in the donor substrate and function as suicide inhibitors. Due to the fact that these PBPs have unusually low affinities for β-lactams, the β-lactam acylation rates are negligible compared with bacterial generation times, allowing the pathogens to survive antibiotic treatment. Of greater concern is the observation that prolonged β-lactam therapy can lead to the emergence of highly resistant strains. β-lactam resistance of PBP4 has also been shown to be due to the inefficient formation of the acyl-PBP intermediate. The molecular basis of PBP4 resistance to β-lactams are related to domain movements about the active site and changes in the structures of the active site motifs. However, they depend upon the particular acyl-adduct formed. | Penicillins, carbapenems and cephalosporins mimic the D-Ala-D-Ala sequence in the donor substrate and function as suicide inhibitors. Due to the fact that these PBPs have unusually low affinities for β-lactams, the β-lactam acylation rates are negligible compared with bacterial generation times, allowing the pathogens to survive antibiotic treatment. Of greater concern is the observation that prolonged β-lactam therapy can lead to the emergence of highly resistant strains. β-lactam resistance of PBP4 has also been shown to be due to the inefficient formation of the acyl-PBP intermediate. The molecular basis of PBP4 resistance to β-lactams are related to domain movements about the active site and changes in the structures of the active site motifs. However, they depend upon the particular acyl-adduct formed. | ||
