A potent immunosuppressive activity was found in the culture broth of the fungus Isaria sinclairii (ATCC 24400). The metabolite, ISP-I ((2JS,3^,4^)-(j&)-2-amino-3,4-dihydroxy-2-hydroxymethyl-14-oxoeicos-6-enoic acid, myriocin = thermozymocidin) suppressed the proliferation of lymphocytes in mouse allogeneic mixed lymphocyte reaction, but had no effect on the growth of humantumor cell lines. It also suppressed the appearance of plaque-forming cells in response to sheep red blood cells and the generation of allo-reactive cytotoxic T lymphocytes in mice after intraperitoneal or oral administration.The metabolite was 10-to 100-fold more potent than cyclosporin A as an immunosuppressiveagent of the immuneresponse in vitro and in vivo, and appears to be a candidate for clinical application as a powerful immunosuppressant.

No abstract

The mRNA capping reaction catalyzed by rat liver mRNA guanylyltransferase proceeds through an enzyme‐GMP intermediate in which GMP is linked to the enzyme by a phosphoamide linkage. The studies described here show that GMP is bound to the epsilon‐amino group of lysine of rat liver guanylyltransferase. The enzyme‐[32P]GMP intermediate was digested with pronase to a [32P]GMP‐peptide which was then converted to [32P]phosphoryl‐peptide through periodate oxidation followed by beta‐elimination. After alkaline hydrolysis of the [32P]phosphoryl‐peptide, the major radioactive product co‐electrophoresed with the authentic N epsilon‐phospholysine on DEAE‐cellulose paper. Neither [32P]Nimid‐phosphohistidine nor Nguanido‐phosphoarginine was detected in the hydrolysates. Furthermore, formation of N epsilon‐guanylyl‐lysine linkage on the enzyme was more directly shown by isolation of [32P]GMP(5′ leads to N epsilon)lysine when the steps of periodate oxidation and beta‐elimination were omitted. The results indicate that the nucleophile in the guanylyltransferase to which the guanylyl residue is linked is the epsilon‐amino group of a lysine residue. [32P]Phosphoryl‐lysine was also isolated from the vaccinia virus capping enzyme‐[32P]GMP intermediate. Guanylyltransferase from HeLa cells, wheat germ, Artemia salina and yeast also formed the enzyme‐GMP complex and, from the stability of the complex, the linkage between the enzyme and GMP was suggested to be a phosphoamide.

Fungal Metabolites. Part 11. A Potent Immunosuppressive Activity Found in Isaria sinclairii Metabolite. -Myriocin (I), which is isolated from the title fungus, is 10 times more potent than cyclosporin A in terms of its inhibition of lymphocyte proliferation in mouse allogeneic mixed lymhocyte reaction. -(FUJITA, T.; INOUE, K.; YAMAMOTO, S.; IKUMOTO, T.; SASAKI, S.; TOYAMA, R.; CHIBA, K.; HOSHINO, Y.; OKUMOTO, T.; J. Antibiot. 47 (1994) 2, 208-215; Fac. Pharm. Sci., Kyoto Univ., Sakyo, Kyoto 606-01, Japan; EN)

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