Nonribosomal peptide synthetases as technological platforms for the synthesis of highly modified peptied bioeffectors - cyclosporin synthetase as a complex example

Many microbial peptide secondary metabolites possess important medicinal properties, of which the immunosuppressant cyclosporin A is an example. The enormous structural and functional diversity of these low-molecular weight peptides is attributable to their mode of biosynthesis. Peptide secondary metabolites are assembled non-ribosomally by multi-functional enzymes, termed non-ribosomal peptide synthetases. These systems consist of a multi-modular arrangement of the functional domains responsible for the catalysis of the partial reactions of peptide assembly. The extensive homology shared among NRPS systems allows for the generalisation of the knowledge garnered from studies of systems of diverse origins. In this review we shall focus the contemporary knowledge of non-ribosomal peptide biosynthesis on the structure and function of the cyclosporin biosynthetic system, with some emphasis on the re-direction of the biosynthetic potential of this system by combinatorial approaches.