In peptidoglycan biosynthesis

Fosfomycin is an antibiotic produced by several Streptomyces species [95, 96] as well as by the Gram-negative Pseudomonas syringiae and Pseudomonas viridiflava. dl, 98] As an analogue of phosphoenolpyruvate, it irreversibly inhibits UDP-N-acetylglu-cosamine-3-O-enolpymvyltransferase (MurA), the enzyme that catalyzes the first step in peptidoglycan biosynthesis [99]. 

J. M. Frere, B. Joris, Penicillin-Sensitive Enzymes in Peptidoglycan Biosynthesis , Crit. Rev. Microbiol. 1985,1, 299-396. 

Our studies of the bacterial enzymes utilized in peptidoglycan biosynthesis required an ample supply of both lipid I and lipid II. Isolation of these precursors from bacterial sources presented significant challenges. First, each of these intermediates is present in very low copy numbers. For example, in E. coli, the copy numbers for lipid I and lipid II are estimated to be approximately 700 and 1000-2000 molecules per cell, respectively.9 Second, separation of miniscule amounts of the cell wall precursors from the comparatively large amounts of cellular lipid and membrane components is technically challenging and further compromises the ability to isolate sufficient quantities of the enzyme substrates to enable detailed mechanistic studies.10... 

Frere JM, Joris B. Penicillin-sensitive enzymes in peptidoglycan biosynthesis. Crit Rev Microbiol 1985 ll(4) 299-396. 

Figure 11 Structures of key molecules In peptidoglycan biosynthesis (a) MurNAc-pentapeptIde (b) Lipid I and Lipid II (GIcNAc residue added by MurG Is shown In red) (c) Lipid IV and the cross-linked peptidoglycan structure.

Over the last fifteen years, a large number of terminal phosphonopeptides [162-165] have been synthesised and tested as potential inhibitors of the early stages in peptidoglycan biosynthesis. For instance, alophosphin (313) inhibits alanine racemase, and has emerged as an excellent antibacterial agent [163]. 

The pentapeptide chains of peptidoglycans have a sequence of amino-acids terminated with D-Ala-D-Ala at positions 4 and 5. Possible conformations of D-Ala-D-Ala and its analogues L-Ala-D-Ala, D-Ala-L-Ala, D-butyryl-L-Ala, D-Ala-D-butyric acid, D-Val-D-Ala, and D-Ala-D-Val have been analysed by theoretical methods.From theoretical studies it is predicted that L-Ala or D-Val at the 4 or 5 position of the pentapeptide group of the peptidoglycan will reduce the cross-linking in peptidoglycan biosynthesis, whereas the effect of D-butyric acid will be marked at the 4 position and moderate at the 5 position. This is in agreement with experimental results. 

Sauvage, E., Kerff, R, Terrak, M., Ayala, J. A., and Charlier, R, "The penicillin-binding proteins structure and role in peptidoglycan biosynthesis." FEMS Microbiol. Rev., 32,234-258 (2008). 

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