Gramicidines biosynthesis

In contrast to these results, the process of tyrocidine and gramicidin biosynthesis has been compared to protein synthesis, but this evidence was obtained in cell-free systems of B. brevis . Yet a difference in the mechanism of protein and antibiotic synthesis has also been reported for gramicidin polymyxin and mycobacillin and seems now to be... 

Tyrocidine [8011-61-8] is a mixture of three closely related components. Tyrocidine studies on mechanism of action (98), biosynthesis on multien2yme complexes (93,99,100), and chemistry (101) are available, and tyrothricin production is discussed (102). Although the mechanism of action of linear gramicidins has been well researched, such work on tyrocidine is more limited it appears that tyrocidine damages membranes (103,104). 

Several characterized NRPSs utilize alternative methods for chain termination. In some synthetases, the TE domain of the final module is replaced by an NAD(P)H-dependent reductase domain. Reduction of a peptidyl-S-PCP substrate through a two-electron reaction leads to the formation of a transient aldehyde, which is subsequently converted into a cyclic imine or hemiaminal through intramolecular cyclization. This two-electron reaction is utilized in the biosynthesis of nostocyclopeptides, the saframycins, ° and anthramycin. Alternatively, a four-electron reduction to the primary alcohol is observed in the biosynthesis of mycobacterial peptidolipids, linear gramicidin," " the myxalamides, lyngbyatoxin, " and myxochelin A 75,76 alternative four-electron reduction pathway involving aldehyde formation, transamination, and reduction to a primary amine occurs in the biosynthesis of myxochelin B. ... 

A non-ribosomal biosynthetic pathway is clearly indicated for cyclosporin A, considering the uncommon structural elements MeBmt, L-a-aminobutyric acid and D-alanine as well as the plethora of isolated congeners [20,21]. Non-ribosomal biosynthesis directed by multienzyme thiotemplates have been reported for other small peptides of microbial origin, for example, gramicidin S [22] and enniatin [23]. Experimental data for cyclosporin A were obtained by feeding appropriate labelled precursors to cultures of T. inflation strains. The distribution profile of the labelled atoms in cyclosporin A was determined by 3H- or 13C-NMR spectroscopy. In preliminary trials with several tritium and carbon-14 labelled precursors, [met/y>/-3H]methionine proved to be the most suitable marker for the biosynthetic preparation of radiolabelled cyclosporin A for pharmacokinetic and metabolic studies [24],... 

F Leenders, J Vater, T Stein, P Franke. Characterization of the binding site of the tripeptide intermediate D-phenylalanyl L-prolyl-L-valine in gramicidin S biosynthesis. J Biol Chem 273 18011-18014, 1998. 

R Kittelberger, M Pavela-Vrancic, El von Dohren. Active site titration of gramicidin S synthetase 2 evidence for misactivation and editing in nonribosomal peptide biosynthesis. FEBS Lett 461 145-148, 1999. 

E Conti, T Stachelhaus, MA Marahiel, P Brick. Structural basis for the activation of phenylalanine in the non-ribosomal biosynthesis of gramicidin S. EMBO J 16 4174-4183, 1997. 

F. Lipmann (1971). Gramicidin S and tyrocidine biosynthesis primitive process of sequential addition of amino acids on polyenzymes . In R. Buvet and C. Ponnamperuma (Eds), Molecular Evolution, Vol. 1, Chemical Evolution and the Origin of Life, North-Holland, Amsterdam, The Netherlands, p. 381. 

Schoenafinger G, Schracke N, Linne U, Marahiel MA. Formy- 29. lation domain an essential modifying enzyme for the nonribosomal biosynthesis of linear gramicidin. J. Am. Chem. Soc. 2006 128 7406-7407. 

Some antibiotics that have been derived from peptides were mentioned in Chapter l. The biosynthesis of penicillins was discussed in Chapter 8. Many peptide antibiotics are known. Some find clinical applications but others such as gramicidin S (9.7), tyrocidine A (9.8) and polymyxins (9.9) are too toxic for use in humans. Cyclosporin A (Figure 1.4), however, has immunosuppressive properties and it has been used in transplant surgery for this reason rather than for its antibiotic properties. Peptide antibiotics have some non-standard structural features and these may explain in part their antibiotic properties. First, cyclic peptides are not found in animal cells. Secondly, peptide antibiotics usually contain some unusual amino acids they may have the d configuration, be A-methylated or have other non-standard structural features. Clearly, these features are not compatible with direct ribo-somal synthesis. 

An enzyme has been isolated from the FK520 producer which is believed to be the key one responsible for inserting pipecolic acid into the macrocycle [114]. It is reported to be dimeric and activates pipecohc acid and several structural analogues in an ATP-dependent reaction to give an enzyme-bound amino-acyl adenylate. There is evidence that this then reacts to form a thioester linkage to the enzyme. This mechanism of activation is the same as that found in the non-ribosomal biosynthesis of peptide natural products such as gramicidin [112]. 

Even in the case it should be possible to separate ribozyme activity from the ribosome or to isolate an in vitro selected ribozyme that can catalyze the same type of peptide bond formation as a ribosome, however such a biocatalyst seem does not to be suitable for simple practical use rather than using a chemical coupling reagent. In principle, this conclusion is also valid for the nonribosomal poly- or multienzymes which are involved in the biosynthesis of peptide antibiotics[7Z. Up to now, they have only found application in the synthesis field of cyclosporin, gramicidin S, special P-lactam antibiotics and analogs. 

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