Peptidoglycan, bacterial cell walls cross-linking

Several drugs in current medical use are mechanism-based enzyme inactivators. Eor example, the antibiotic penicillin exerts its effects by covalently reacting with an essential serine residue in the active site of glycoprotein peptidase, an enzyme that acts to cross-link the peptidoglycan chains during synthesis of bacterial cell walls (Eigure 14.17). Once cell wall synthesis is blocked, the bacterial cells are very susceptible to rupture by osmotic lysis, and bacterial growth is halted. 

The peptidoglycan structure of bacterial cell walls. The shaded areas represent points of attachment of this macromolecule to the rest of the cell wall. The amino sugar units are joined end to end to form long, straight chains. The peptides form cross-links when the amino group of a meso-diaminopimelic acid in one chain replaces the terminal alanine in another chain. Source ... 

The pathway from simple molecules to the peptidoglycan of the bacterial cell wall is lengthy and complex. Many of the details are well known but need not concern us here. Suffice it to say that long carbohydrate chains are synthesized, subsequently decorated with shorter amino acid chains, and these are finally cross-linked to provide a strong strnctnre. It is this final cross-linking step that is inhibited by the p-lactam antibiotics. The consequence is that cell wall biosynthesis cannot be completed and cell death ensnes. Again, the mammalian host carries out no similar reactions so that similar consequences do not ensne for the host orgaiusm. 

Peptidoglycans (14,16) are the primary component of bacterial cell walls. They consist of a heteropolysaccharide called murein cross-linked with short peptide chains. 

Biosynthesis of bacterial cell wall is remarkable in two respects (1) It entails the synthesis of a regularly cross-linked polymer and (2) Part of the synthesis takes place inside the cell and part outside the cell. The synthesis of cell wall is divided into three stages, which occur at different locations (1) synthesis of UDP-/V-acetylmuramyl-penta-peptide, (2) polymerization of IV-acetylglucosamine and N-acetylmuramyl-pentapeptide to form linear peptidoglycan strands, and (3) cross-linking of the peptidoglycan strands. 

The major problem in the synthesis of complex carbohydrates outside the cell is the lack of an external energy source such as ATP. The biosynthesis of a bacterial cell wall such as the peptidoglycan occurs mainly inside the cell, the final step being the cross-linking of the peptidoglycan strands outside the cell. This reaction is a transpeptidation, which does not require any energy source. 

Peptidoglycan. The main component of the bacterial cell wall, consisting of a two-dimensional network of heteropolysaccharides running in one direction, cross-linked with polypeptides running in the perpendicular direction. 

Peptidoglycan cross-linked polysaccharide in a bacterial cell wall—also known as murein. 

The peptidoglycan layer confers mechanical stability to the cell wall of the bacteria. An important intermediate of the peptidoglycan biosynthesis is the GlcNAc- MurNAc-L-Ala-D-y-Gln-L-Lys-D-Ala-D-Ala peptide (muramyl-pentapeptide), which is in its lipid-carrrier bound form transglycosylated to a linear polysaccharide. The linear polysaccharide is then cross-linked to peptidoglycan by transpeptidation reactions. Perkins observed that vancomycin binds to the Lys-D-Ala-D-Ala peptide motif of bacterial cell wall intermediates. This observation was later investigated on a mole-cular level by NMR and by x-ray crystallographic studies. ... 

Penicillins and cephalosporins have similar mechanisms of action. They both interfere with the terminal step in bacterial cell wall formation by preventing proper cross-linking of the peptidoglycan. 

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