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Biosynthesis and Molecular Genetics of Fungal Secondary Metabolites pp 65–88Cite as

Cyclosporines: Biosynthesis and Beyond

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Part of the book series: Fungal Biology ((FUNGBIO))

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.

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Abbreviations

AdoMet:

S-adenosyl-l-methionine

A-domain:

Adenylation domain

Bmt:

(4R)-4-[(E)-2-butyl]-4-methyl-l-threonine

CoA:

Coenzyme A

C-domain:

Condensation domain

CsA:

Cyclosporine A

CySyn:

Cyclosporine synthetase

d-Hiv:

d-hydroxy isovaleric acid

E-domain:

Epimerization domain

N-MTase:

N-methyltransferase

NRPS:

Non-ribosomal peptide synthetase

Ppant:

4′-phosphopantetheine

PKS:

Polyketide synthase

PCP:

Peptidyl carrier protein

T-domain:

Thiolation domain

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Acknowledgements

T. Velkov is a National Health and Medical Research Council of Australia CDA1 Industry Fellow (1003836).

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Authors and Affiliations

  1. Department of Pharmaceutics, Monash University, Parkville, VIC, Australia

    Tony Velkov

  2. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Melbourne, VIC, Australia

    Alfons Lawen

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  1. Tony Velkov
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Correspondence to Alfons Lawen .

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  1. Department of Molecular Biology, University of León, León, Spain

    Juan-Francisco Martín

  2. Parque Científico de León, Instituto de Biotecnología de León (INBIOTEC), León, Spain

    Carlos García-Estrada

  3. Institute of Chemical Engineering, Vienna University of Technology, Vienna, Austria

    Susanne Zeilinger

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Velkov, T., Lawen, A. (2014). Cyclosporines: Biosynthesis and Beyond. In: Martín, JF., García-Estrada, C., Zeilinger, S. (eds) Biosynthesis and Molecular Genetics of Fungal Secondary Metabolites. Fungal Biology. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1191-2_4

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