Cyclosporines: Biosynthesis and Beyond

Abstract

The immunosuppressive properties of cyclosporine A have been widely exploited clinically, predominantly in bone marrow and organ transplantations and in the treatment of certain autoimmune diseases. Cyclosporine A is the main product of the secondary metabolism of the fungal species Tolypocladium inflatum (syn. Beauveria nivea). This cyclic undecapeptide contains three unusual, non-proteinogenic, amino acids and seven of its eleven amide nitrogens in the backbone are N-methylated. As these features cannot be introduced by classical translation, the biosynthesis of cyclosporine A is elaborated by a non-ribosomal peptide synthetase (NRPS). Cyclosporine synthetase (CySyn) is one of the most complex NRPS systems known, consisting of a single 1.7 MDa polypeptide capable of catalyzing a total of 40 partial reaction steps in the synthesis of cyclosporine A. The CySyn polypeptide can be divided into eleven semiautonomous modular units, which are composed of homologous domains responsible for the activation, modification, and polymerization (and in seven of the eleven modules, N-methylation) of the constituent amino acids of cyclosporine A. This chapter surveys the current knowledge-base on this complex multifunctional enzyme system and provides a perspective on its future development as a biosynthetic platform for the production of a new generation of safer cyclosporines.