MurG enzyme

The second stage of this cascade takes place at the cytoplasmic surface of the bacterial cell membrane. In the first reaction, MraY catalyzes a pyrophosphate exchange reaction wherein the UDP-MurNAc-pentapeptide precursor is coupled to a membrane-anchored C55 lipid carrier with ejection of UMP to provide undecaprenylpyrophosphoryl-MurNAc-pentapeptide 4, also know as lipid I. In the second reaction, the MurG enzyme catalyzes the transfer of GlcNAc from a UDP-GlcNAc precursor to the C(4)-hydroxyl group of the lipid-linked MurNAc-pentapeptide. The product of this enzymatic reaction, lipid II5, is the... 

By 2001, mechanistic characterization had been completed for MurA-G from E. coli, and crystal structures had been obtained for all of these enzymes except MurC [41,42,43,44,45,46, 47,48]. For a detailed discussion of the work completed on this pathway prior to 2000, see the review by van Heijenoort [37]. Since then, E. coli MurC and MurG have been crystallized [47,48,49], and homologues of the Mur enz)mes from other bacteria have been purified and characterized as well. MraY has also now been purified and characterized [50], a significant accomplishment because this enzyme is an integral membrane protein with many hydrophobic segments, making it particularly hard to purify in significant quantities. However, there is still no crystal structure for this enz)mie. 

One potential drawback to multi-target screens is that they are unable to distinguish between different modes of inhibition, so are equally likely to identify substrate binders and enzyme binders. The latter are specifically needed to help unravel enzymatic mechanism. Affinity screens can be used to identify compounds that bind to the enzyme. This type of screen has been successfully used to identify inhibitors of MurF that were subsequently used to obtain a crystal structure to aid in drug design [180,181]. A slightly different approach is a displacement screen, which selects for inhibitors that compete with the substrate for binding. This method has been used successfully to identify small-molecule inhibitors of MurG [182,183]. 

An enzymatic method has been developed for the synthesis of the lipid n (57) by using the MraY, MurG, and undecaprenol kinase (UK) enzymes. Activity of lipid II analogues (57) for bacterial transglycolase has also been evaluated. ... 

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