Peptidoglycans

Peptidoglycans are components of bacterial cell walls and consist of heteropolysaccharide chains cross-linked by short peptide chains. These cell walls bear the antigenic determinants when exposed to them, humans (and other mammalian species) develop specific antibodies to defend against bacteria. Bacterial virulence is also related to substances associated with the cell wall. Cell wall synthesis is the target for the action of the penicillins and cephalosporins. 

Bacterial cell walls are rigid and complex, enable the cells to withstand severe osmotic shock, and survive in a 

Number Eponym Clinical Manifestations Enzyme Deficiency Glycosaminoglycan Affected 

MPS IH Hurler Corneal clouding, dysostosis multiplex, organomegaly, heart disease, mental retardation, death in childhood a-L-Iduronidase Dermatan sulfate, heparan sulfate 

The biological activities of bacterial peptidoglycans have been reviewed, and the immunoadjuvant activities of a number of S3oithetic iV-acetylmuramyl-peptides and of derivatives and analogues of iV-acetylmuramyldipeptide (A -acetylmuramyl-L-alanyl-D-isoglutamine) have been reported. 

A radioimmunoassay based on binding a I-labelled hapten (n-Ala-y-D-Glu-L-Lys-D-Ala-D-Ala) has been developed for measuring antibodies to peptidoglycans in human sera.  

spectra of a number of peptidoglycans of bacterial cell walls have been reported the carbohydrate portion of the peptidoglycans is arranged similarly to chitin, and the peptide moiety does not occur in the j3-structure.  

The synthesis of peptidoglycans by Agmenellum quadruplicatum is stimulated during the formation of the cross-walls. There is no correlation between septum formation or cell separation and the rate of turnover of the peptide portion of the peptidoglycan. The peptidoglycans of a new strain of Arthrobacter 

Tamura, T. Sasaki, M. Matsuhashi, A. Takatsuki, and M. Yamasaki, Agric. and Biol. 

Pepddoglycans.—A range of helical conformations for the glycan chains of bacterial peptidoglycans has been proposed on the basis of X-T y diffraction studies of cell walls and peptidoglycans from several bacterial species. These studies support the view that the peptide conformation has proportions of the residues in the helical and hydrogen-bonded 5-sheet conformations. The balance between the two conformations is presumably related to the mean separation of the glycan chains, which varies with the water content by a factor of approximately two. 

The pentapeptide chains of peptidoglycans have a sequence of amino-acids terminated with o-Ala-o-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, o-Val-o-Ala, and o-Ala-o-Val have been analyzed 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. 

Possible conformations of the disaccharide-peptlde sub-units of the peptido-glycans of Staphylococcus aureus and Micrococcus luteus have been studied by an energy-minimization procedure. Contrary to earlier reports the favoured conformation of the disaccharide 2-acetamido-2-deoxy-/8-D-glucosyl-(l- 4)-.A -acetylmuramic acid is different from that of cellulose or chitin. Three types of conformation, two compact and one extended, are postulated with all three being stabilized by intramolecular hydrogen bonds. Two different models were proposed for the three-dimensional arrangement of peptidoglycan in the cell wall. 

A Ray crystallographic studies of the binding of the trisaccharide (1) to sub-sites B, C, and D of lysozyme indicate no distortion of sugar residues at sub-site D.  

Lipopolysaccharides.—From studies of the interactions between lipopoly-saccharide and phosphatidyl-ethanolamine in molecular monolayers at air-water interfaces, it has been concluded that each lipopolysaccharide molecule is surrounded by approximately sixteen phosphatidyl-ethanolamine molecules. The hydrocarbon chains of lipopolysaccharides can undergo a reversible thermal order-disorder transition, as shown by thermal phase-transition studies. The ordered conformation of lipopolysaccharides interpreted from wide-angle X-ray studies is considered less developed than that in normal phospholipid bilayers. 

A radioimmunoassay using a synthetic pentapeptide hapten has been developed for measurement of the pentapeptide determinant of peptidoglycans.  

The chemistry and immunochemistry of bacterial lipopolysaccharides have been reviewed.  

Electrodialysis has been used to remove a large proportion of the metal ions and amines that frequently contaminate preparations of lipopolysaccharides.  

UDP-D-galactose to the terminal, non-reducing D-glucosyl residues of these oligosaccharides. The tetrasaccharide repeating unit (8) of the O-specific side-chains of the cell-wall lipopolysaccharide from E. colt 075 has been established by methylation analysis and Smith degradation.  

Sugiyama, P. F. Smith, T. A. Langworthy, and W. R. Mayberry, Infection and Immunity, 

In Micrococcus varians all three glycerol phosphate residues in the linkage unit are derived from CDP-glycerol and are therefore not transferred from a lipoteichoic acid carried.  

Possible conformations of the disaccharide-peptide sub-units of the peptidoglycans of Staphylococcus aureus and Micrococcus luteus have been studied using an energy-minimization procedure. Contrary to earlier reports the favoured conformation of the disaccharide 2-acetamido-2-deoxy-/3-D-glucosyl- 

Exhaustive digestion of B. megaterium cells with lysozyme yielded a teichuronic acid containing a small amount of peptidoglycan. Degradative studies indicated that the teichuronic acid is glycosidically linked to a tetrasaccharide unit of the peptidoglycan the tetrasaccharide unit does not contain cross-linked peptide chains. 

Peptidoglycans.—The biosynthesis of the peptidoglycans of bacterial cell walls and the action of penicillin on the biosynthesis of peptidoglycans have been re-viewed. Other reviews have discussed the effects of endogenous and exogenous factors on the primary structures of bacterial peptidoglycans and the com- 

Inhibition of the synthesis of peptidoglycans by B. megaterium with amphomycin resulted in an accumulation of UDP-A-acetylmuramylpeptides.  

Tanaka, Y. Iwai, R. Oiwa, S. Shinohara, S. Shimizu, T. Oka, and S. Omura, Biochim. Biophys. Acta. 1977, 497, 633. 

Electron microscopic studies have indicated that in wild-type cells, lipopoly-saccharide-protein complexes are stabilized by either divalent cations or poly-amines. The binding of the cationic polypeptide polymyxin B to the lipid A portion of bacterial lipopolysaccharides has resulted in the generation of higher molecular weight aggregates with decreased isopycnic density.  

Fredriksen and T. Hofstad, Acta Path. Microbiol. Scand., 1978, 86B, 41. 

Isopycnic density gradient centrifugation has been used in the characterization of the lipopolysaccharide from Pasturella multocida. Cerulenin, an inhibitor of fatty acid biosynthesis, has been used to induce changes in the fatty acid composition of the lipopolysaccharide of Proteus mirabilis.  

Lindberg, K. Petersson, E. Katzenellenbogen, and E. Romanowska, European 

Hurlbert, J. Weckesser, R. N. Tharanathan, and H. Mayer, European J. Biochem., 

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D,D-endopeptidase acting on maturing peptidoglycan D, D - c arb o xyp ep tidase transpeptidation is absent none apparent... 

Glycoconjugates. Another class of carbohydrates are the glycoconjugates (14), composed of glycoproteins, proteoglycans, peptidoglycans, and glycohpids. 

IV-Acetylglucosamine and IV-Acetylmuraniic acid Sugar derivatives in the peptidoglycan layer of bacterial cell walls. 

Cell wall Peptidoglycan a rigid framework of polysaccharide cross-linked by short peptide chains. Some bacteria possess a lipopolysaccharide- and protein-rich outer membrane. Mechanical support, shape, and protection against swelling in hypotonic media. The cell wall is a porous nonselective barrier that allows most small molecules to pass. 

FIGURE 8.18 Dolichol phosphate is an initiation point for the synthesis of carbohydrate polymers in animals. The analogous alcohol in bacterial systems, undecaprenol, also known as bactoprenol, consists of 11 isoprene units. Undecaprenyl phosphate delivers sugars from the cytoplasm for the synthesis of cell wall components such as peptidoglycans, lipopolysaccharides, and glycoproteins. Polyprenyl compounds also serve as the side chains of vitamin K, the ubiquinones, plastoquinones, and tocopherols (such as vitamin E). 

FIGURE 9.25 Teichoic acids are covalently linked to the peptidoglycan of Grampositive bacteria. These polymers of (a, b) glycerol phosphate or (c) ribitol phosphate are linked by phosphodiester bonds. 

Several drugs in current medical use are mechanism-based enzyme inactivators. Eor example, the antibiotic penicillin exerts its effects by covalently reacting with an essential serine residue in the active site of glycoprotein peptidase, an enzyme that acts to cross-link the peptidoglycan chains during synthesis of bacterial cell walls (Eigure 14.17). Once cell wall synthesis is blocked, the bacterial cells are very susceptible to rupture by osmotic lysis, and bacterial growth is halted. 

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]. 

Figure 6.7 Formation of cross-linkage between individual peptide chains in the peptidoglycan layer of S. aureus.

Many different types of carbohydrate-containing molecules are located on the surface of microbial cells. Some of these are components of die microbial cell wall and are limited to certain types of micro-organisms such as bacterial peptidoglycan, lipopolysaccharides, techoic adds and yeast mannans. Other polysaccharides are not... 

Penicillin has an interesting mode of action it prevents the cross-linking of small peptide chains in peptidoglycan, the main cell wall polymer of bacteria. Pre-existing cells are unaffected, but all newly produced cells are abnormally grown. The newborn cells are unable to maintain their wall rigidity, and they are susceptible to osmotic lysis. 

Gram-positive (whole organisms peptidoglycans [e.g., muramyl dipeptide] lipoteichoic acids exotoxins enterotoxins erythrogenic toxins group B polysaccharides)... 

Gram-negative (whole organisms peptidoglycans lipopolysaccharides [lipid A])... 

Lactam antibiotics are bicyclic or monocyclic azetidinone ring-containing compounds (Fig. 1). They kill bacteria by preventing the assembly of (4-3) peptidoglycans. These covalently closed net-like polymers form the matrix of the cell wall by which the bacteria can divide and multiply, despite their high internal osmotic pressure. 

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