A peptidoglycan biosynthetic pathway is a pathway involved in the production of the peptidoglycan layer, which makes up the cell wall in bacterial cells. The peptidoglycan layer is made up of glycan chains, which are cross-linked peptide substituents. As a main pathway for the production of this layer, the disruption in this pathway causes a weakened cell wall, or may even lead to bacterial lysis. Recent research has improved our understanding of peptidoglycan biosynthesis, which may potentially lead to the development of peptidoglycan-based therapeutics. The first step in peptidoglycan synthesis occurs in the cytoplasm with the murA-catalyzed transfer of enolpyruvyl moeitry from phosphoenolpyruvate(PEP) to uridine diphosphate-N-acetylglucosamine(UDP-GlcNAc). This transfer process is catalyzed by murA, and gram-negative bacteria only have one copy of this gene; therefore, its deletion is often lethal. Gram-positive bacteria, on the other hand, have two murA genes. The crystal structure of murA, in aoenzyme form and in complex with ligands, has been determined from several species of bacteria including E.coli. The structures contain two globular domains made up of four beta sheets and two parallel helices, and between these two domains is an active site, which is rearranged and brought closer together when substrates are attached. Fosfomycin, a naturally occurring antibiotic, inactivates murA by mimicking PEP and modifying the active site. The next step involves MurB catalyzing the NADPH-dependent conversion of enolpyruvyl UDP-GlcNAc to UDP-MurNAc in the cytoplasm. Following this production, a series of ATP-dependent amino acid ligases catalyze the addition of penetapeptide side chain onto this UDP-MurNAc complex. There are four additional Mur Ligases (Mur C, D, E, and F), and the structures of these enzymes have been determined. They all contain three structural domains that are involved in the peptide bond formation dependent on ATP hydrolysis. These domains include an N-terminal domain for binding the substrate, a centra ATPase domain, and a C-terminal domain to bind the amino acid. MurC catalyzes the first addition of L-Alanine onto UDP-MurNAc, to which MurD adds the D-Glutamine. In the addition of L-Alanine, the C-terminal of the UDP-MurNAc substrate is activated by phosphorylation that requires ATP, and the intermediate that results from this is attacked by the animo group of the incoming L-Alanine. The intermediate is an acyl phosphate, and this acyl phosphate mechanism is also used by MurE in the addition of mesodiaminopimelic acid. MurF then adds D-Ala-D-Ala to the UDP-MurNAc-L-Ala-D-Glu-mesoA2pm, which is the product of MurE. In the first membrane-associated step, an integral membrane protein named MraY transfers the MurNAc pentapeptide from the cytoplasm to a phosphate carrier. This results in a product known as lipid I. MraY is a type of a prenyl sugar transferase. Through the use of a thin-layer chromatography, the production of the lipid I product was able to be analyzed. It has been found that MurG, the final cytoplasmic component of the pathway, interacts with MraY to convert lipid I to lipid II via glycosyl transfer. High-resolution X-ray was used to show the structure of MurG and its domains. Lovering, Andrew L., Susan S. Safadi, and Natalie CJ Strynadka. "Structural perspective of peptidoglycan biosynthesis and assembly." Annual Review of Biochemistry 81 (2012): 451-478.
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