Study of the Effect of Lower Eukaryotes on Tacrolimus (FK-506) Biosynthesis by the Streptomyces tsukubensis Strain VKM A
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UCERS, BIOLOGY, SELECTION, AND GENE ENGINEERING
Study of the Effect of Lower Eukaryotes on Tacrolimus (FK-506) Biosynthesis by the Streptomyces tsukubensis Strain VKM Ac-2618D V. Yu. Poshekhontsevaa, b, V. V. Fokinab, c, *, G. V. Sukhodolskayab, A. A. Shutovb, and M. V. Donovab, c aPushchino
State Natural Science Institute, Pushchino, Moscow oblast, 142290 Russia Scientific Center for Biological Research of the Russian Academy of Sciences, G.K. Skryabin Institute of Biochemistry and Physiology of Microorganisms, Pushchino, Moscow oblast, 142290 Russia cPharmins, Ltd., Pushchino, Moscow oblast, 142290 Russia *e-mail: [email protected]
bPushchino
Received July 17, 2019; revised August 2, 2019; accepted August 23, 2019
Abstract—The effect of inactivated yeast cells, individual components of the yeast cells, and the inactivated biomass of filamentous fungi (micromycetes) of various taxonomic positions on the biosynthesis of immunosuppressant tacrolimus (FK-506) by Streptomyces tsukubensis VKM Ac-2618D cells has been studied. The fractions of soluble and insoluble components of yeast cells positively influenced tacrolimus biosynthesis; the FK-506 concentrations reached 447.1± 22.4 mg/L and 514.3 ± 25.7 mg/L, respectively. The insoluble cell components, including the cell walls and cytoplasmic membranes, had a greater effect than other fractions. The presence of whole baker’s yeast cells and the filamentous fungus Aspergillus ochraceus biomass in the complex nutrient medium stimulated tacrolimus production by S. tsukubensis VKM Ac-2618D (667.5 ± 33.4 mg/L and 633.5 ± 31.7 mg/L, respectively). The biomass of deuteromycete Curvularia lunata had no effect on FK-506 biosynthesis (288.4 ± 14.4 mg/L). Conversely, the biomass of the Gongronella butleri fungus fully inhibited growth and tacrolimus production in S. tsukubensis. The increase in FK-506 biosynthesis in the presence of the cells of the tested micromycetes is more likely due to the polysaccharide composition of their cell walls than to the ergosterol content. The results expand the knowledge of S. tsukubensis physiology and may be useful for the development of the biotechnological process of tacrolimus production. Keywords: tacrolimus, biosynthesis, Streptomyces tsukubensis, yeasts, fungi, ergosterol DOI: 10.1134/S0003683820080062
INTRODUCTION Tacrolimus is a 23-membered lactone that is currently recognized as the most effective immunosuppressive agent of the drugs of this class (cyclosporine, ascomycin, mycophenolic acid, and others). Tacrolimus is produced by Streptomyces genus bacteria, such as S. tsukubensis, S. tacrolimicus, and S. clavuligerus (in total, about 20 producers have been described) [1]. FK-506 is widely used in medicine for organ and tissue transplantation [2, 3], for the treatment of atopic dermatites [4], and a number of immune (rheumatoid arthritis) [5], viral [6, 7], and inflammatory bowel (ulcerative colitis, Crohn’s disease) diseases. The compound is also helpful in the therapy of malignant tumors [9] and was shown to have antifungal [10]
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