Biosynthesis of Tacrolimus by the Streptomyces tsukubensis VKM Ac-2618D Strain in the Presence of Polymeric Sorbents and
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ynthesis of Tacrolimus by the Streptomyces tsukubensis VKM Ac-2618D Strain in the Presence of Polymeric Sorbents and Development of a Method for Its Isolation and Purification D. S. Salionova, b, V. Yu. Poshekhontsevac, d, V. V. Fokinac, d, *, A. A. Shutovc, d, V. M. Nikolaevac, d, G. G. Vasiarovb, E. V. Titovab, V. S. Karasevb, S. M. Staroverova, b, and M. V. Donovac, d aChemistry
Department of the Lomonosov Moscow State University, Moscow, 119234 Russia b “BioChemMack S&T”, Moscow, 119234 Russia c PSCBR RAS, Skryabin Institute of Biochemistry and Physiology of Microorganisms, Russian Academy of Sciences, Pushchino, Moscow oblast, 142290 Russia d“Pharmins”, Pushchino, Moscow oblast, 142290 Russia *e-mail: [email protected] Received May 14, 2020; revised June 14, 2020; accepted July 2, 2020
Abstract—Tacrolimus is known as the most effective immunosuppressive drug which is synthesized by actinobacteria of the genus Streptomyces. Its biosynthesis is accompanied by the formation of the structural analogs. A new method for the production of tacrolimus by Streptomyces tsukubensis BKM Ac-2618D with the use of brominated styrene-divinylbenzene sorbent SP-207 was developed. This approach enabled to increase the yield, prevent undesirable destruction, and simplify the tacrolimus isolation procedure from the cultivation media. The preliminary separation step was optimized by means of the usage of regenerable sorbents such as methylmethacrylate (HP2MG) and chemically modified silica gel (Diasorb-100-Diol). By implementation of the silica gel-based cation exchange resins pretreated with silver ions for the final purification stage, it was possible to increase its productivity. The overall yield of tacrolimus by this method was found to around 60–70%. The results could be implemented for the full-cycle production development of the pharmaceutical grade tacrolimus. Keywords: biosynthesis, tacrolimus, Streptomyces tsukubensis, sorbent SP-207, chromatography, isolation, purification, ascomycin, tacrolimus 8-propyl-analog DOI: 10.1134/S0003683820060150
Tacrolimus (FK-506) is the international non-proprietary name of a widely used immunosuppressant having a 23-membered polyketide macrolide structure (822 Da). Tacrolimus is the mainstay of immunosuppression therapy after medulla, kidney and heart transplantation [1–3]; it is used for the treatment of immune diseases such as rheumatoid arthritis and inflammatory diseases [4, 5], in the therapy of atopic dermatitis [6, 7] and allergic ocular diseases [8]. FK-506 has an antiviral activity against orthopoxvirus, HIV and feline immunodeficiency virus [9, 10]. FK-506 is reported to exhibit both neuroprotective and neuroregenerative properties [11, 12]. Tacrolimus may be applied to the treatment of cancer [13]. The effectiveness of tacrolimus in preventing rejection after transplantation, as well as in diseases resistant to other therapies, is the basis of its medical application and significance. The tacrolimus biosynthesis begins with the formation of (4R,5R)-4,5-dihydroxycyclohex
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