Subsystem: Peptidoglycan Biosynthesis

This subsystem's description is:

In both gram-positive and gram-negative bacteria, the scaffold of the cell wall consists of the cross-linked polymer peptidoglycan.
Peptidoglycan consists of linear glycan chains interlinked by short peptides. The glycan chains are composed of alternating units of N-acetylglucosamine and N-acetylmuramic acid. Muramyl residues bear short pentapeptides, a proportion of which are cross-linked either directly or through a second short peptide. It is this cross-linkage that joins the glycan chains into a macromolecular network of high tensile strength and rigidity.

=====Mur enzymes========

The biosynthetic pathway of peptidoglycan is a complex two-stage process. The first stage, which occurs in the cytoplasm, is the formation of the monomeric building block N-acetylglucosamineľN-acetylmuramyl pentapeptide. The first committed step in the pathway is the transfer of an enolpyruvate residue from phosphoenolpyruvate (PEP) to position 3 of UDP-N-acetylglucosamine. This reaction is catalysed by MurA. This is followed by a MurB-catalysed reduction of the enolpyruvate moiety to d-lactate, yielding UDP-N-acetylmuramate.
A series of ATP-dependent amino acid ligases (MurC, MurD, MurE and MurF) catalyse the stepwise addition of the pentapeptide side-chain on the newly reduced d-lactyl group, resulting in the formation of UDP-N-acetylmuramyl pentapeptide.

======Mur enzymes as potential antibacterial targets=============

The machinery for peptidoglycan biosynthesis is a rich source of crucial targets for antibacterial chemotherapy. The cytoplasmic steps of the biosynthesis of peptidoglycan precursor, catalysed by a series of Mur enzymes, are excellent candidates for drug development.
Only MurA is inhibited by a known antibiotic, fosfomycin. Several attempts made to develop novel inhibitors of this pathway are discussed in this review. Three novel inhibitors of MurA were identified recently. 4-Thiazolidinone compounds were designed as MurB inhibitors. Many phosphinic acid derivatives and substrate analogues were identified as inhibitors of the MurC to MurF amino acid ligases.


=======REFERENCES:=======================

1. Scheffers DJ, Pinho MG. Bacterial cell wall synthesis: new insights from localization studies. Microbiol Mol Biol Rev. 2005 Dec;69(4):585-607. Review. PMID: 16339737.

2. El Zoeiby A, Sanschagrin F, Levesque RC. Structure and function of the Mur enzymes: development of novel inhibitors. Mol Microbiol. 2003 Jan;47(1):1-12. Review. PMID: 12492849.

3. Olsen LR, Tian Y, Roderick SL. Purification, crystallization and preliminary X-ray data for Escherichia coli GlmU: a bifunctional acetyltransferase/uridyltransferase. Acta Crystallogr D Biol Crystallogr. 2001 Feb;57(Pt 2):296-7. PMID: 11173485.

4. Griffiths E, Gupta RS. Protein signatures distinctive of chlamydial species: horizontal transfers of cell wall biosynthesis genes glmU from archaea to chlamydiae and murA between chlamydiae and Streptomyces. Microbiology. 2002 Aug;148(Pt 8):2541-9.
PMID: 12177347

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