A non-ribosomal system of peptide biosynthesis
Kleinkauf, H.
Institute of Biochemistry and Molecular Biology, Technical University Berlin,
Franklinstr. 29, D-10587 Berlin, Germany
The biosynthesis of peptides from amino acids is accomplished by three systems of varying complexity, correlating with the size of the products. Polypeptides or proteins are assembled by the ribosomal system, a step-by-step addition of amino acids to activated precursors, or in a non-ribosomal system operating without the direct participation of nucleic acids. Although its products are well known, like the most successful antibiotic penicillin, the toxins from Amanita species, amanitin and phalloidin, the immunomodulator cyclosporin, the biosurfactant surfactin, new antibiotics like teicoplanin and daptomycin, new antifungals like pneumocandin, the unifying principles of the biosynthetic steps have just recently been recognised. Peptide synthetases catalyse the complete processing of amino acids into their final products, including carboxyl group activation. Within the respective biosynthetic gene clusters precursor forming enzymes or modifying enzymes are generally included. To illustrate a current application of the new biocatalysts, the total synthesis of analogs of cyclosporin will be used. Cyclosporin synthetase with a size of 1.7 MDa catalyses activation of the constituents, seven N-methylations, and the ring closure. The sequence of reactions is reflected by the modular gene structure. Each domain has a defined specificity profile, thus permitting the synthesis of peptide analogues of the same structural type. Employing a variety of amino acid analogues, more than 200 cyclosporins have been synthesized for structure-function studies.
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