Cell wall synthesis of bacteria

In Gram-Positive bacteria, the peptidoglycan is essential for the structure, replication, and survival in the normally hostile conditions in which bacteria grow.

The peptidoglycan is a rigid mesh made up of bristle-like linear polysaccharide chains, cross-linked by peptides.

The polysaccharide is made up of repeating disaccharides of N-acetylglucosamine (GlcNAc, NAG, G) and N-acetylmuramic acid (MurNAc, NAM, M).

The synthesis occurs in four phases.

First, the precursors are synthesized and activated inside the cell.

Glucosamine is enzymatically converted into NAM and then energetically activated by a reaction with uridine triphosphate (UTP) to produce uridine diphosphate-N-acetylmuramic acid (UDP-NAM).

Next, the uridine diphosphate-N-acetylmuramic acid-pentapeptide is assembled in a series of enzymatic steps.

In the second phase, this complex(UDP-NAM-pentapeptide) is attached to the bactoprenol in the cytoplasmic membrane through a pyrophosphate link, with the release of uridine monophosphate (UMP).

N-acetylglucosamine is added to make the disaccharide building block of the peptidoglycan.

Some bacteria (e.g. S. aureus) add a pentaglycine or another chain to the diamino amino acid at the third position of the peptide chain to lengthen the cross-link.

In the third phase, the bactoprenol molecule translocates the disaccharide: peptide precursor to the outside of the cell.

Lastly, the peptidoglycan is extended at the outside surface of the plasma membrane.

The N-acetylglucosamine -N-acetylmuramic acid disaccharide is attached to a peptidoglycan chain, using the pyrophosphate link between itself and the bactoprenol as energy to drive the reaction by enzymes called transglycosylases.

The pyrophosphobactoprenol is converted back to phospho-bactoprenol and recycled.

The cross-linking reaction is catalyzed by membrane-bound transpeptidases.

The peptide cross-link is formed between the free amine of the amino acid in the third position of the peptide chain or the N-terminus of the attached pentaglycine chain, and the D-alanine at the fourth position of the other peptide chain.

The precursor form of the peptide has an extra D-alanine, which is released during the cross-linking step.

D-carboxypeptidase, removes unreacted terminal D-alanine to limit the extent of cross-linking.

The number and length of cross-links determine the rigidity of the peptidoglycan mesh.

An understanding of the biosynthesis of peptidoglycan is essential in medicine because these reactions are unique to bacterial cells and

hence can be inhibited with little or no adverse effect on host (human) cells.

The transpeptidases and carboxypeptidases are called penicillin-binding proteins (PBPs) because they are targeted by penicillin and other β-lactam antibiotics.

Penicillin and related β-lactam antibiotics resemble the “transition state” conformation of the D-Ala-D-Ala substrate when bound to these enzymes. Then, It stops the cross-link.

Bacitracin blocks the recycling of bactoprenol by interfering with the activity of phosphorylase in the second step of peptidoglycan biosynthesis.

Vancomycin binds to the D-Ala-D-Ala structure to block this biosynthesis.