Gramicidin stability

Fig. 8 Proposed model for gramicidin S in a membrane according to the orientational constraints obtained from and N-NMR. The upright backbone alignment (r 80°) and slant of the /3-sheets (p -45°) are compatible with the formation of an oligomeric /3-barrel that is stabilized by hydrogen bonds (dotted lines). A The oligomer is depicted sideways from within the lipid bilayer interior (showing only backbone atoms for clarity, but with hydrophobic side chains added to one of the monomers). Atomic coordinates of GS were taken from a monomeric structure [4], and the two DMPC lipid molecules are drawn to scale (from a molecular dynamics simulation coordinate file). The bilayer cross-section is coloured yellow in its hydrophobic core, red in the amphiphilic regions, and light blue near the aqueous surface. B Illustrates a top view of the putative pore, although the number of monomers remains speculative...

A Gadow, J Vater, W Schlumbohm, Z Palacz, J Salnikow, H Kleinkauf. Gramicidin S synthetase. Stability of reactive thioester intermediates and formation of 3-amino-2-piperidone. Eur J Biochem 132 229-234, 1983. 

A detailed understanding of the transport of the linear gramicidins requires not only the structure of the channel but also a knowledge of channel properties. The dependence of channel properties on the amino acid residues, position in the sequence and side-chain orientation, have been used to assist in elucidating the molecular mechanism of ion transport through the channel. The side-chains are important contributors to the formation and stability of the channel in the membrane-like environments. They are regulators of the... 

Although tyrothricin is too toxic for parenteral therapy, it was formerly sold in the United States as oral lozenges. Modem tyrothricin formulations are composed of 70—80% tyrocidines and 30—20% linear gramicidins. Tyrocidines are not as active as linear gramicidins and are too toxic for any therapeutic use by themselves. The bactericidal linear gramicidins are used in the United States solely as an ophthalmic solution in combination with polymyxin B sulfate and neomycin sulfate. The linear gramicidin is used in this aqueous product as a substitute for bacitracin, which lacks stability under such conditions. 

In this connection the unusual stability of cyclic structures should be mentioned. In the case of carbohydrates this was clearly demonstrated by Swanson and Cori (1948) and by Myrback (1949), who showed that the cyclic Schardinger dextrins are considerably more stable than corresponding open chain polysaccharides. Similarly Consden et al. (1947b) found the cyclopeptide gramicidin S to be unusually... 

The biosynthesis of a variety of biologically active peptides proceeds nucleic acid-free on protein templates (IK Peptide synthetases generally activate an acceptor amino acid by formation of amino-acyl adenylates or phosphates, which will be stabilized in an enzyne-aminoacylation step, similar as in tRNA-aminoacylation. Reaction with a donor peptide, which may be covalently bound, leads to a specific chain elongation. While small peptides like glutathione are formed by "one-step"-synthetases, more complex structures like gramicidin S are produced by multienzvme systems, which may contain multifunctional polypeptides. Characteristic features of such systems are 1.)activation as aminoacyl adenylates, 2.) aminoacylation of enzyme thiol-groups, 3.) covalently bound peptide intermediates and 4.) a specific intrinsic transport mechanism similar to the biosynthesis of fatty acids. 

The primary structure of P. is elucidated by the standard methods of sequence analysis (see Proteins). The conformation of P. is an important determinant of their biological activity. It is stabilized by peptide and disulfide bonds In P. containing unusual bonds and/or constituents other factors also stabilize the conformation. Although X-ray crystallography (see) was used in the elucidation of the three-dimensional structures of insulin and gramicidin S, the conformational analysis of P. is now by preference carried out in solution, using the spectroscopic methods ORD, CD, IR, NMR and ESR. 

There are a number of small peptide-forming channels. One of the most studied is gramicidin. Gramicidin is a mixture of similar pentadecapeptides containing alternating D- and L-amino acids. These peptides can form a helix with an internal diameter of around 4 A. The helix length is approximately half of the membrane width and, upon being dimerization stabilized by tail to tail interactions, they form... 

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