Vancomycin biosynthesis

An example of oxidative cross-linking takes place during vancomycin biosynthesis three cytochrome P450 enzymes—which use the same heme cofactor as the cytochromes from the primary metabolic electron transport chain—cross-link aromatic rings in its scaffold to form its rigid cup-like shape (29, 30). 

Zerbe, K., O. Pylypenko, F. Vitali, W. Zhang, S. Rouset, M. Heck et al. (2002). Crystal structure of OxyB, a cytochrome P450 implicated in an oxidative phenol coupling reaction during vancomycin biosynthesis. J. Biol. Chem. 211, 47476- 7485. 

CYP165B3 (OxyB) Amycolatopsis orientalis ILFK, 1LG9, ILGF Oxidative phenol coupling of CD-rings in vancomycin biosynthesis [248]... 

CYP165C4 (OxyC) Amycolatopsis orientalis lUED Biaryl cyclization of AB-rings in vancomycin biosynthesis [249]... 

CYP146A1 (OxyD) Amycolatopsis mediterranei 3MGX B-tyrosine hydroxylation in vancomycin biosynthesis [237]... 

Cryle MJ, Meinhart A, Schlichting I (2010) Structural characterization of OxyD, a cytochrome P450 involved in beta-hydroxytyrosine formation in vancomycin biosynthesis. J Biol Chem 285 24562-24574... 

Woithe K, Geib N, Zerbe K, Li DB, Heck M, Fournier-Rousset S, Meyer O, Vitali F, Matoba N, Abou-Hadeed K et al (2007) Oxidative phenol coupling reactions catalyzed by OxyB a cytochrome P450 from the vancomycin producing organism. Implications for vancomycin biosynthesis. J Am Chem Soc 129 6887-6895... 

Woithe K, Geib N, Meyer O, Woertz T, Zerbe K, Robinson JA (2008) Exploring the substrate specificity of OxyB, a phenol coupling P450 enzyme involved in vancomycin biosynthesis. Org Biomol Chem 6 2861-2867... 

FIGURE 4.21 The second glycosyltransferase in the vancomycin biosynthesis gene cluster GtfD can utilize both an unnatural donor (UDP- /)/-vancosamine) and unnatural acceptor (4-deoxy and 4-amino glucose). 

Biosynthesis. Biochemical studies on dalbaheptides have been reviewed (92,97). Experiments with and H have shown that in vancomycin (39), D-tyrosine is the precursor of D-/> -hydroxyphenyiglycine and P-hydroxy-y -chlorotyrosine, and acetate the precursor of the two y jy -dihydroxyphenyiglycines (98). Similar results using either or radioactively labeled material have been reported for avoparcin (Table 5) (23), ristocetin (Table 2) (99,100), ardacin (Table 3) (101), and A47934 (102). 

Thiostrepton (C72H85N19O18S5, molecular mass of 1663) has an unusual type of biological activity, in that it binds to ribosomal RNA and to one of its associated proteins, thus disabling protein biosynthesis. It was the first macrocyclic antibiotic evaluated as selector for the synthesis of HPLC CSPs, together with vancomycin... 

Figure 2 Summary of NRP natural product biosynthesis, exemplified by vancomycin.

For each structural class of antibacterial discussed, there are many members in chnical use. I have selected a few as representative examples of each class. There are several additional classes of antibacterials as well. Notable is vancomycin (Vancocin), like the p-lactam antibacterials an inhibitor of cell wall biosynthesis although the site... 

Glycopeptides Vancomycin Teicoplanin Reprogramming peptidoglycan biosynthesis... 

Pharmacology Vancomycin is a tricyclic glycopeptide antibiotic that inhibits cell-wall biosynthesis. It also alters bacterial-cell-membrane permeability and RNA synthesis. Pharmacokinetics ... 

The biosynthesis of cell wall peptidoglycan, showing the sites of action of five antibiotics (shaded bars 1 = fosfomycin, 2 = cycloserine, 3 = bacitracin, 4 = vancomycin, 5 = 3-lactam antibiotics). Bactoprenol (BP) is the lipid membrane carrier that transports building blocks across the cytoplasmic membrane M, N-acetylmuramic acid Glc, glucose NAcGIc or G, /V-acetylglucosamine. 

Mutasynthesis of New Antibiotics K. L. Rinehart, Pure Appl. Chem., 1977, 49,1361-1384. The Significance of D-Alanyl-D-Alanine Termini in the Biosynthesis of Bacterial Cell Walls and the Action of Penicillin, Vancomycin and Ristocetin H. R. Perkins and M. Nieto, Pure Appl. Chem., 1973, 35, 371-381. 

The poly (ribitol phosphate) synthetase and poly (glycerol phosphate) synthetase are inhibited by vancomycin, novobiocin, and Crystal Violet. Other antibiotic substances which interfere with cell-wall synthesis (such as bacitracin, ristocetin, and streptomycin) are almost without effect on the isolated synthetases, and penicillin is inhibitory at high concentrations only. Moreover, penicillin, vancomycin, and bacitracin do not markedly inhibit synthesis of cell-wall glycosaminopeptide in vitro, although the synthetical activity of extracts of cells which have been pretreated with these antibiotics is lowered.Convincing evidence that the primary site of inhibition by antibiotics is the biosynthesis of cell-wall material has been obtained only for the penicillins and cycloserine, and it appears that the action of even those antibiotics may be more complex than was originally supposed. 

Siissmuth RD, Pelzer S, Nicholson G, Walk T, Wohlleben W, Jung G (1999) New Advances in the Biosynthesis of Glycopeptide Antibiotics of the Vancomycin Type from Amycolatopsis mediterranei. Angew Chem Int Ed 38 1976... 

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