Muramyl pentapeptide

Formation of the three-dimensional network of bacterial peptidoglycan includes synthesis both of glycosidic and peptide linkages, but only the former type of reaction is discussed in this Section. The assembly of the carbohydrate chains of a peptidoglycan has been shown to occur through a block mechanism. The initial reaction consists in transfer of N-acetyl-muramyl-pentapeptide phosphate from the corresponding UDP derivative... 

The next stage in peptidoglycan synthesis results from poly- merization of A-acetylglucosamine and N-acetyl muramyl-pentapeptide containing residues into peptidoglycan [ strands. The relevant reactions take place on the inner sur-i face of the plasma membrane (fig. 16.17). f In step 1 (see fig. 16.17), UDP-N-acetyl muramyl-... 

The lactyl carboxyl group was unmasked by exposure of the phenylsulfonylethyl ester to DBU. Carboxyl group activation of muramic acid derivative 21 was achieved by conversion to the corresponding NHS ester (N-hydroxysuccinimide, EDCI, DMF). The pentapeptide fragment 10 was readily prepared in quantity using standard peptide synthesis protocols [Scheme 7]. Addition of a DMF solution of pentapeptide 10 to a solution of PrNEt2 and the NHS ester deriving from 21 provided the protected muramyl pentapeptide 9 in excellent overall yield. 

SCHEME 14.6 Synthesis of muramyl pentapeptide 48 with DAP residue by Boons et al. All, allyl Boc, fert-butoxycarbonyl HOBt, 1-hydroxybenzotriazole. 

The peptidoglycan layer confers mechanical stability to the cell wall of the bacteria. An important intermediate of the peptidoglycan biosynthesis is the GlcNAc- MurNAc-L-Ala-D-y-Gln-L-Lys-D-Ala-D-Ala peptide (muramyl-pentapeptide), which is in its lipid-carrrier bound form transglycosylated to a linear polysaccharide. The linear polysaccharide is then cross-linked to peptidoglycan by transpeptidation reactions. Perkins observed that vancomycin binds to the Lys-D-Ala-D-Ala peptide motif of bacterial cell wall intermediates. This observation was later investigated on a mole-cular level by NMR and by x-ray crystallographic studies. ... 

Binding at the D-ala-D-ala muramyl pentapeptide to sterically hinder the transgly-cosylation reactions involved in elongation of peptidoglycan chains... 

Enterococcal resistance involves change in the muramyl pentapeptide target, such that the terminal D-ala is replaced by D-lactate... 

When UDP-2-acetamido-2-deoxy-D-glucose and UDP-N-acetyl-muramyl-pentapeptide are together added to broken bacterial-cell preparations, a new product is formed that contains the sugar and sugar-peptide portions of the precursors. If cells broken by means of a sonic oscillator are used, it is necessary to carry out the incubations on a filter-paper support " the precise function played by the filter paper is not yet known. In contrast, if enzymes are prepared by grinding cells with alumina, filter-paper support is unnecessary and the product contains a linear glycan backbone in which the two sugar residues occur in the alternate sequence expected. ... 

It was found that the first reaction in synthesis of linear peptido-glycan involves the transfer of pentapeptidyl-N-acetylmuramyl 1-phosphate to an endogenous, lipid acceptor from UDP-N-acetyl-muramyl-pentapeptide, with concomitant production of UMP (see Reaction I of Scheme 3). " This reaction is fully reversible, and its kinetics have been studied in detail. Evidence was presented that the glycosyl phosphate is attached to the lipid through a pyrophosphate bridge. Strominger and coworkers found that the endogenous, lipid acceptor could be extracted from the lyophilized. 

Finally the dipeptide is added to the lysine residue of the UDPiV-acetyl-muramyl tripeptide by way of a specific enzyme, with characteristics similar to those of the other amino-acyl ligases described above. The UDPA-acetyl-muramyl pentapeptide so formed can now enter the next part of the biosynthetic pathway, in which the repeating unit of the polysaccharide of the peptidoglycan is formed by way of an undecaprenol-dependent cycle. 

The wild-type UDP-MurNAc-L-Ala-y-D-Glu-L-Lys-D-Ala-D-Ala (UDP-MurNAc-pentapeptide) was first isolated from S. aureus in 1952 by James Park [77], Nicolas Gisch et al. reported the synthesis of the biotinylated Lys-type and DAP-type muramyl tripeptides through their UDP derivatives [78], Both compounds activated Nod2 in a cell-based assay, although the required minimal motif for the activation of Nod2 is muramyl dipeptide [79], The chemical synthesis of the UDP-MurNAc-pentapeptide 7 (Scheme 14.1) [19] was followed by the chemoenzymatic synthesis by Chi-Huey Wong [80] and Michio Kurosu [81], Wong et al. also synthesized the vancomycin-resistant UDP-MurNAc-L-Ala-y-D-Glu-L-Lys-D-Ala-D-Lac... 

IV. Synthesis of N-acetyl-muramyl-tri-, tetra-, and -pentapeptides, and of Some... 

---