Cell-free biosynthesis of new cyclosporins

Alfons Lawen, Rainer Zocher, Horst Kleinkauf, René Trader, Dieter Geyl

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An enzyme preparation, isolated from extracts of the fungus Beauveria nivea (previously designated Tolypocladium inflatum), is able to synthesize cyclosporins (Cy's) in vitro. At suboptimal temperature it was possible to yield about 50 μg of CyA per ml. The enzyme also produces several of the naturally occuring congeners of CyA, such as the Cy's B, C, D, G, M, O, Q, U and V and some of the analogues known to be produced by the fungus via precursor directed biosynthesis, like dihydro-CyA, [N-methyl-L-β-cyclohexylalanine1]CyA, [L-allylglycine2]CyA and [D-serine8]CyA. Furthermore, Cy's not obtainable by the fungus could be prepared by the enzyme system in the presence of the appropriate precursor amino acids; the synthesis of [N-methyl(+)-2-amino-3-hydroxy-4, 4-dimethyloctanoic acid1]CyA, [1-norvaline2, 5, N-methyl-L-norvaline11]CyA, [L-norvaline5, N-methyl-L-norvaline11]CyA, [L-allo-isoleucine5, N-methyl-L-allo-isoleucine11]CyA; [L-allo-isoleucine5, 11]CyA, [D-2-aminobutyric acid8]CyA and [β-chloro-D-alanine8]CyA could be established. The immunosuppressive effects of the new derivatives are discussed.

Original languageEnglish
Pages (from-to)1283-1289
Number of pages7
JournalJournal of Antibiotics
Issue number8
Publication statusPublished - 1 Jan 1989
Externally publishedYes

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