Bacterial cell wall pentapeptide

Cycloserine (Fig- 4) is produced by several species of Streptomyces. One of the basic glycosyl components of the bacterial cell wall, n-acetyl-muramic acid (the product of Mur A and MurB), is modified by the addition of the first three amino acids sequentially by MurC, MurD and MurE enzymes. A dipeptide, D-alanyl-D-alanine is then added to make the pentapeptide. In bacteria, L-alanine is the native form and it is converted to D-alanine form by alanine racemase (Air). Two D-alanines are joined by D-ala-D-ala ligase (DdlA) to synthesize the dipeptide. Cycloserine resembles the substrate for Air and Ddl and inhibits their respective reactions in stage I of the peptidoglycan biosynthesis (Fig. 2). 

Biosynthesis of bacterial cell wall is remarkable in two respects (1) It entails the synthesis of a regularly cross-linked polymer and (2) Part of the synthesis takes place inside the cell and part outside the cell. The synthesis of cell wall is divided into three stages, which occur at different locations (1) synthesis of UDP-/V-acetylmuramyl-penta-peptide, (2) polymerization of IV-acetylglucosamine and N-acetylmuramyl-pentapeptide to form linear peptidoglycan strands, and (3) cross-linking of the peptidoglycan strands. 

SA Hitchcock, CN Eid, JA Aikins, M Zia-Ebrahimi, LC Blaszczak. The first total synthesis of bacterial cell wall precursor UDP-N-acetylmuramyl-pentapeptide (park nucleotide). J Am Chem Soc 120 1916-1917, 1998. 

A Lilly group21"3 devised a synthesis of the bacterial cell wall precursor UDP-N-acetylmuramyl-pentapeptide (Park nucleotide) in which deprotection of a 2-(phenylsulfonyl)ethyl ester using a catalytic amount of DBU in dichloro-methane220,221 was an important step in the release of a carboxyl group [Scheme 6,99]. 2-(Methylsulfonyl)ethyl esters have also been cleaved under basic conditions to release a protected carboxylic acid. Scheme 6.100 shows an example from the closing stages of a synthesis of Surugatoxin.222... 

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. ... 

There have been a number of hypotheses regarding the mode of action of /8-lactam antibiotics [237,238]. That most widely used at present is the structural analogue hypothesis [183,215], based on the structural similarity between penicillins and a possible conformation of the acyl-D-alanyl-D-alanine end of the N-acetylmuramyl-pentapeptide strand of the bacterial cell wall. A number of experimental data support this hypothesis (for recent reviews see [237] and [238]) and the model attractively explains the mechanism of action of /3-lactam antibiotics, especially penicillins. Nevertheless, certain more recent data contradict the structural analogue model [239-241] and a conformational response model has been set up [242,243]. It must be emphasized, however, that the contradictions are sometimes only apparent, and a one-sided interpretation of the structure-activity data may lead to false conclusions, e.g. the problem of the 6(7)a-substitution in penicillins and cephalosporins. 

The bacterial cell wall is a cross-linked polymer of polysaccharides and pentapeptides. Penicillins interact with cytoplasmic membrane-binding proteins (PBPs) to inhibit transpeptidation reactions involved in cross-linking, the final steps in cell wall synthesis. 

Bacterial cell wall is cross-linked polymer of polysaccharides and pentapeptides... 

Ribosylation of isopropylideneuridine and subsequent manipulations led to the synthesis of 170 (R = H), which constitutes a part-structure of the liposidomycin class of antibiotics. The two isomers of 170 (R = CH2OH) were also prepared in synthetic sequences that involved ribosylation of D-allofuranose and L-talofuranose derivatives at 0-5, with introduction of uracil at a late stage. Molecular modelling was carried out of both liposidomycins and tunicamycin with the UDP-iV-acetylmuramic acid-pentapeptide that is the substrate for the enzyme (translocase) in bacterial cell wall biosynthesis that the antibiotics inhibit, and, in accordance with the predictions, only the 5-isomer of 170 (R = CH2OH) was a good inhibitor. ... 

Pacidamycins, napsamycins, mureidomycins, and sansanmycins are uridyl peptide antibiotics isolated from Streptomyces sp. strains and show potent inhibitory activity against phosphoMurVAc-pentapeptide translocase (MraY), an essential enzyme in bacterial cell wall peptidoglycan biosynthesis [269, 270]. 

Arendt, a., a. Kolodziejezyk, and T. Sokolowska Synthesis of mucopeptide fragments of bacterial cell walls containing diaminopimelic add. Part IX. Synthesis of pentapeptide related to bacterial mureine fragment. Roczniki Chem. Ann. Soc. Chim. Polonorum. 48, 1921 (1974). 

A-acetylglucosamine, providing the necessary carboxylate anchor for attachment of the pentapeptide required for bacterial peptidoglycan (cell wall) formation. Bacteria that encode a MurA orthologue where the susceptible Cys is replaced by an Asp (e.g., Mycobacteria) are intrinsically genetically resistant to fosfomycin (Fig. 1) (11, 12). 

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