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.
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.
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.
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