Tolypocladium strain

Cyclosporins, produced by the filamentous fungus Tolypocladium niveum and by numerous strains of Fusaria and Neocosmospora, are a class of cyclic undecapep-tides which are composed of hydrophobic aliphatic amino acids [73-75], They exhibit antiinflammatory, immunosuppressive, antifungal, and antiparasitic properties [74], The main metabolite, cyclosporin A, is in clinical use worldwide under the trade name SANDIMMUN to prevent allograft rejection [77,78], Besides cyclosporin A, there are 24 naturally occuring cyclosporins which have substitutions of amino acids in positions 1, 2, 4, 5, 7, and 11 and/or contain unmethylated peptide bonds in positions 1,4,6,9,10, or 11 [79-82], Cyclosporin A contains three nonproteinogenic amino acids D-alanine in position 8, L-a-aminobutyric acid in position 2, and, in position 1, the unusual amino acid 4(R)-4-[(E)-2-butenyl]-4-methyl-L-threonine (Bmt) (Fig. 8). All three amino acids have to be synthesized by a pathway independent of the primary metabolism. In addition, several peptide bonds of the cyclosporin molecule are A -mcthylated similar to the depsipeptides enniatin, beauvericin and PF1022A-related peptides. 

The biogenesis of the amino acids in position 2-11 in C. A proceeds through the usual biosynthetic routes with subsequent /V-methylation by 5-adenosylmethi-onine-dependent methyltransferases. The amino acid in position 1 is built up on the polyketide pathway and subsequently methylated at C-4. It has bron demonstrated that MeBmt is the starter of the non-ribo-somal peptide synthesis by means of a mutant strain of Tolypocladium inflatum Recent clinical data show, that C. application in transplantation medicine significantly increases the risk of cancer . 

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