Peptidoglycan Peptides

Definition
Peptidoglycans are glycoconjugates found in the rigid layer of bacterial cell walls, composed of alternating sugar units, N-acetyl glucosamine and muramic acid, cross-linked by short peptides.

Structural Characteristics
The primary chemical structures of peptidoglycans of both Gram-positive and Gram-negative bacteria have been established; they consist of a glycan backbone of repeating groups of ß1, 4-linked disaccharides of ß1, 4-N-acetylmuramyl-N-acetylglucosamine. Tetrapeptides of L-alanine-D-isoglutamic acid-L-lysine (or diaminopimelic acid)-n-alanine are linked through the carboxyl group by amide linkage of muramic acid residues of the glycan chains; the D-alanine residues are directly cross-linked to the amino group of lysine or diaminopimelic acid on a neighboring tetrapeptide, or they are linked by a peptide bridge. A peptidoglycan with a chemical structure substantially different from that of all eubacteria has been discovered in certain archaebacteria. Instead of muramic acid, this peptidoglycan contains talosaminuronic acid and lacks the D-amino acids found in the eubacterial peptidoglycans. Interestingly, organisms containing this wall polymer (referred to as pseudomurein) are insensitive to penicillin, an inhibitor of the transpeptidases involved in peptidoglycan biosynthesis in eubacteria1.

Synthesis
Unique features of almost all prokaryotic cells (except for Halobacterium halobium and mycoplasmas) are cell wall peptidoglycan and the specific enzymes involved in its biosynthesis.

Synthesis of peptidoglycan is a complex process. The first is the formation of a peptidoglycan subunit, disaccharide pentapeptide, in the cytoplasm. In many organisms, including Bacillus subtilis and Escherichia coli, the pentapeptide consists of L-Ala-D-Glu-L-meso-diaminopimelic acid-D-Ala-D-Ala. The second is the polymerization, which occurs on the outer surface of the cytoplasmic membrane. Polymerization of peptidoglycan requires two enzymatic activities, a transglycosylase that polymerizes the glycan strands and a transpeptidase that cross-links these strands by means of the peptide side chains2. During the transpeptidation reaction the terminal D-alanine is removed from one of the peptide chains (donor), while it’s penultimate D-alanine becomes linked to the e-amino group of diaminopimelic acid (A2pm) in another peptide chain (acceptor) 3.

Functions
The key role of peptidoglycan in the opsonization of Staphylococcus aureus: A study was conducted to determine the staphylococcal cell surface component(s) of importance in opsonization, cell walls (peptidoglycan and teichoic acid) and peptidoglycan were isolated from Staphylococcus aureus strain H grown in [3H] glycine-containing broth. After incubation of the cell walls and peptidoglycan with various opsonic sources, uptake by human polymorphonuclear leukocytes was measured. It was found that the opsonic requirements for phagocytosis of cell walls and peptidoglycan were similar to those of intact bacteria. Furthermore the removal of teichoic acid from the cell wall did not affect opsonization. Likewise, a teichoic acid-deficient mutant strain of S. aureus H was opsonized in a manner similar to that of the parent strain. Immunoglobulin G functioned as the major heat-stable opsonic factor and both the classical and alternative pathways participated in opsonization. Kinetic studies revealed that opsonization of peptidoglycan, as well as C3-C9 consumption by peptidoglycan, proceeded at a slower rate via the alternative pathway (C2-deficient serum) than when the classical pathway was present (normal serum). The ability of peptidoglycan to activate C3-C9 was significantly reduced when normal and C2-deficient sera were preabsorbed with peptidoglycan at 2 degrees C suggesting that antibodies to peptidoglycan may be involved in activation of both the classical and alternative complement pathways. Thus, peptidoglycan appears to be the key cell wall component involved in staphylococcal opsonization, and it is suggested that host response to peptidoglycan, a major cell wall component of most gram-positive bacteria, may be related to the development of "natural immunity" to this group of microorganisms4.

The role of peptidoglycan in pathogenesis: Bacterial pathogens rely on a variety of virulence factors to establish the colonization of a new niche. Peptidoglycan and its muropeptide derivatives have been known to possess potent biological properties. With the identification of the cytosolic surveillance mechanism mediated by the nucleotide-binding oligomerization domain (Nod) 1 and (Nod) 2 proteins, which detect unique peptidoglycan-derived muropeptides, these muropeptides are considered as potential virulence factors. Recent research shows the role of peptidoglycan in the pathogenesis of different human pathogens such as Streptococcus pneumoniae, Listeria monocytogenes or Helicobacter pylori 5.

References
1.Book: Salton MRJ, Kim KS, Baron's Medical Microbiology By. (4th ed.). Univ of Texas Medical Branch (1996).
2.Heijenoort JV (2007). Lipid Intermediates in the Biosynthesis of the bacterial peptidoglycan. Microbiology and molecular biology reviews., 71(4):620-635.
3.Gally DL , IC Hancock, CR. Harwood, and AR Archibald (1991). Cell wall assembly in Bacillus megaterium: incorporation of new peptidoglycan by a monomer addition process. J. Bacteriol., 173(8):2548-2555.
4.Peterson PK, Wilkinson BJ, Kim Y, Schmeling D, Douglas SD, Quie PG, Verhoef J (1978). The key role of peptidoglycan in the opsonization of Staphylococcus aureus. J Clin Invest., 61(3):597-609.
5.Boneca IG. (2005). The role of peptidoglycan in pathogenesis. Curr Opin Microbiol., 8(1):46-53.

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