Tolypocladium

A secondary metabolite produced by Tolypocladium inflation. This fungus was initially isolated in a soil sample collected in Norway. Cyclosporin A is a cyclic undecapeptide. Inside cells, cyclosporine A binds its immunophillin receptor known as cyclophillin. Like the FK506-FKBP12 complex, cyclosporin A-cyclophillin binds and inhibits the protein phosphatase calcineurin. 

Cyclic peptide from 11 amino acids. Preparation by fermentation of Tolypocladium inflatum Gams with addition of DL-a-aminobutyric acid to the fermentation medium. Isolation by homogenization of mycelium, extraction with 90 % methanol and column chromatographic purification. 

Weber, G., Schorgendorfer, K., Schneider-Scherzer, E. and Leitner, E. (1994) The peptide synthetase catalyzing cyclosporine production in Tolypocladium niveum is encoded by a giant 45.8-kilobase open reading frame. Current Genetics, 26 (2), 120-125. 

RM Wenger. Synthesis of cyclosporine. Total synthesis of cyclosporin A and cyclosporin H, two fungal metabolites isolated from the species Tolypocladium infla-tum Gams. Helv Chim Acta 67, 502, 1984. 

The cyclosporins are a group of cyclic peptides produced by fungi such as Cylindrocarpon lucidum and Tolypocladium inflatum. These agents show a rather narrow range of antifungal activity, but high levels of immunosuppressive and anti-inflammatory activities. The main component from the culture extracts is cyclosporin A, but some 25 naturally occurring cyclosporins have been characterized. 

Cyclosporine A Cyclosporine A, [R-[R, R -(E)]]-cyclo-(L-alanyl-D-alanyl-iV-methyl-L-leucyl-iV-methyl-L-leucyl-A-methyl-L-valyl-3-hydroxy-iV,4-dimethyl-L-2-amino-6-octenoyl-L-a-aminobutyryl-A-methylglycyl-iV-methyl-L-leucyl-L-valyl-iV-methyl-L-leucine) (31.2.2), is extracted from a cultural liquid of products of the vital activity of the mushroom Tolypocladium inflatum [14-17], and which is also proposed to obtain synthetically [18-20]. 

Cyclosporines are produced by mycelial mushrooms Tolypocladium inflatum. Tricoderma polysporum, and Cylindrocarpon lucidum, which are found in the ground. 

Immunosuppressant produced as a metabolite by the fungus species Beauvaria nivea Gams Tolypocladium inflatum Gams ... 

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. 

TH Aarino, SN Agathos. Production of extracellular enzymes and cyclosporin by Tolypocladium inflatum and morphologically related fungi. Biotechnol Lett 11 759-764, 1989. 

R Traber, H Hoffmann, HR Loosli, MPonelle, A von Wartburg. Neue Cyclosporine aus Tolypocladium inflatum. Die Cyclosporine K-Z. Helv Chim Acta 70 13-36, 1987. 

R Zocher, T Nihira, E Paul, N Madry, H Peeters, K Kleinkauf, U Keller. Biosynthesis of cyclosporin A partial purification and properties of a multifunctional enzyme from Tolypocladium inflatum. Biochemistry 25 550-553, 1986. 

G Weber, E Leitner. Disruption of the cyclosporin synthetase gene of Tolypocladium niveum. Curr Genet 26 461-467, 1994. 

Cyclosporin was isolated from the fungus Tolypocladium infiatum. Its immunosuppressive activity was discovered in 1976 [4]. Although since then many analogs have been prepared and investigated, cyclosporin A (CsA, Sandimmune, 17) remains the most effective cyclic peptide and is the major immunosuppressant dmg to prevent graft rejection after transplant surgery. 

Cyclosporin A, which has been used as an immunosuppressant with fungicidal and anti-inflammatory properties in bone marrow and organ transplants and in autoimmune diseases since 1983, was isolated from a fungal culture (Tolypocladium)144). 

I. V. Sotnikova, G. N. Telesnina, I. N. Krakhmaleva, J. O. Sazykin and S. M. Navashin (1990). High-molecular polyphosphate and pyrophosphate in cyclosporin-producing Tolypocladium sp. and their role in the process of growth and antibiotic synthesis (in Russian). Antibiot. Khimioter., 35, 9-11. 

Efrapeptins such as efrapeptin D (24 in Figure 5) were isolated from the entomopathogenic fungus Tolypocladium niveum. They have a unique linear peptide structure with a bicyclic amine moiety at their C-terminus and show insect toxicity by inhibiting mitochondrial ATPase.7... 

Voclosporin (ISA-247, R1524) 88 (Isotechnika) is being evaluated in a Phase III trial for the treatment of psoriasis,250 as well as a Phase III trial by Lux Biosciences as for the treatment of uveitis (coded as LX211, Luveniq ).251,252 In addition, voclosporin 88 has completed a Phase lib trial for the prevention of kidney graft rejection. Voclosporin 88253,254 is a slightly more potent but less toxic semi-synthetic derivative of the fungal-derived immunosuppressant cyclosporin A 89, which has the same mechanism of calcineurin inhibition. Cyclosporin A 89 was first isolated from Tolypocladium inflatum by workers at Sandoz and its structure was published in 1976.255,256... 

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