Cyclosporins, biosynthesis structure

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],... 

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. 

Contents L. Jaenicke and F.-J. Marner The Irones and Their Precursors. — M. Lounasmaa and P. Somersalo The Condylocarpine Group of Indole Alkaloids. — U. Sequin The Antibiotics of the Pluramycin Group (4//-Anthra [l,2- ]pyran Antibiotics). — R. M. Wenger Cyclosporine and Analogues — Isolation and Synthesis — Mechanism of Action and Structural Requirements for Pharmacological Activity. — H. Inouye and S. Uesato Biosynthesis of Iridoids and Secoiridoids. 

Ttaber R, Kobel H, Loosli H-R, Senn H, Rosenwirth B, Lawen A. [Melle Jcyclosporin, a novel tratural cyclosporin with ami-HlV activity Structural elucidation, biosynthesis and biological properties. Antiviral Chem Chemother 1994 5 331-339. 

---