Enhancement of tacrolimus productivity in Streptomyces tsukubaensis by the use of novel precursors for biosynthesis

Turło, Jadwiga; Gajzlerska, Wanda; Klimaszewska, Marzenna; Król, Marek; Dawidowski, Maciej; Gutkowska, B

doi:10.1016/j.enzmictec.2012.08.008

Cited by 44 publications

(30 citation statements)

References 31 publications

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“…Figure 1 shows that the highest concentration of tacrolimus obtained was 41.87 mg.L -1 , which is greater than the concentration reported on literature, reached in a fermentation conducted using glucose as the carbon source. 15 This result was expected and agreed with the results of other papers which used other vegetable oils as carbon sources. [12][13][14] It is believed that one of the factors which regulates the bacterial production of secondary metabolites, such as FK506, is the response to nutrients.…”

Section: Discussionsupporting

confidence: 92%

“…18,19 Results Tacrolimus and Biomass Production By aiming to enhance the tacrolimus production, the fermentative process was conducted based on previous literature. 15 The tacrolimus production increased along the fermentation, reaching a maximum concentration of 41.87 g.L -1 at 96 hours. After this period of time, the drug concentration reduced until 5.02 mg.L -1 (168 hours).…”

Section: Fermentable Sugars and Proteins Quantificationmentioning

confidence: 95%

“…The tacrolimus quantification method was based on consolidated literature. [14][15][16] After filtration, culture broth samples were purified by evaporating at reduced pressure until the formation of an oily compound. It was added 3.5 mL of mobile phase (acetonitrile-water 70:30) to the oily compound, which was centrifuged at 4 o C for 10 minutes.…”

Section: Hplc Analysismentioning

confidence: 99%

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Streptomyces tsukubaensis Fermentation Using Brazil Nut Oil to Enhance Tacrolimus Production

Silva

Ferrari

Moreira

et al. 2019

J Apple Biotechnol Rep

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Introduction Tacrolimus, also known as FK-506, is a drug first isolated in 1984, that has been widely used to prevent the rejection of transplanted organs, and to also treat dermatoses and eye diseases. 1-3 It is a 23 membered polyketide macrolide produced during fermentation through different Streptomyces species. The most commonly used is the Streptomyces tsukubaensis. 4 This medication is interesting to dermatology because it is rapidly absorbed by the epidermis and has less side effects than commonly used drugs. 5 Besides, as an immunosuppressant agent it is 10-100 times more potent than cyclosporine. 6 Nevertheless, the treatment cost using tacrolimus is high because of its low productivity. 7 Up to now, different strategies have been used to solve this problem, including the use of mutant bacteria, 8-11 and exogenous feeding of precursors in the biosynthesis. 12-14 Literature reports that S. tsukubaensis is capable of metabolizing different carbon sources, such as glucose, maltose, dextrin, soybean oil, cottonseed oil and groundnut oil. 14-16 Exogenous feeding of oil has played an important role in this bioprocess, since it is a complex source of nutrients which has increased the tacrolimus production. 12,14,17 The Brazil nut oil is rich in fatty acids and are broken in order to produce coenzymes (acetyl or propionyl) which are known as precursors for the polyketide production. 17 This study has investigated the influence of the Brazil nut (Bertholletia excelsa) oil on the tacrolimus production. The fermentative process was carried for 168 h using S. tsukubaensis. Materials and Methods Organism The Strain of S. tsukubaensis was acquired from the Leibniz Institute DSMZ. Culture Conditions Streptomyces tsukubaensis culture was maintained on petri dishes containing glucose 4 g.L-1 , yeast extract 1 g.L-1 , malt extract 10 g.L-1 , CaCO 3 2 g.L-1 and agar 12 g.L-1 , pH 7.2, and incubated at 28 o C. The seed culture medium and the production medium were based on Turlo et al 14 which are presented in Table 1 and Table 2, respectively. The seed culture medium was prepared, sterilized at 120 o C

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Section: Discussionsupporting

confidence: 92%

Section: Fermentable Sugars and Proteins Quantificationmentioning

confidence: 95%

Section: Hplc Analysismentioning

confidence: 99%

See 1 more Smart Citation

Streptomyces tsukubaensis Fermentation Using Brazil Nut Oil to Enhance Tacrolimus Production

Silva

Ferrari

Moreira

et al. 2019

J Apple Biotechnol Rep

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“…Substantial effort has led to yield improvements in wild-type producers through regulator manipulation [32], [33], precursor supplementation into culture media [31], [34], [46] or by introducing extra copies of FK506 biosynthetic enzymes [35]. To the best of our knowledge, our PAC-based conjugation strategy has afforded the first example of heterologous FK506 production in a more tractable expression host.…”

Section: Discussionmentioning

confidence: 99%

Phage P1-Derived Artificial Chromosomes Facilitate Heterologous Expression of the FK506 Gene Cluster

et al. 2013

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We describe a procedure for the conjugative transfer of phage P1-derived Artificial Chromosome (PAC) library clones containing large natural product gene clusters (≥70 kilobases) to Streptomyces coelicolor strains that have been engineered for improved heterologous production of natural products. This approach is demonstrated using the gene cluster for FK506 (tacrolimus), a clinically important immunosuppressant of high commercial value. The entire 83.5 kb FK506 gene cluster from Streptomyces tsukubaensis NRRL 18488 present in one 130 kb PAC clone was introduced into four different S. coelicolor derivatives and all produced FK506 and smaller amounts of the related compound FK520. FK506 yields were increased by approximately five-fold (from 1.2 mg L-1 to 5.5 mg L-1) in S. coelicolor M1146 containing the FK506 PAC upon over-expression of the FK506 LuxR regulatory gene fkbN. The PAC-based gene cluster conjugation methodology described here provides a tractable means to evaluate and manipulate FK506 biosynthesis and is readily applicable to other large gene clusters encoding natural products of interest to medicine, agriculture and biotechnology.

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“…High tacrolimus yielding (500 mg/l) Streptomyces strain development has been reported by sequential adaptation and tacrolimus resistance method 13 . Supplementation of biosynthetic presursors 14,15 , fermentation conditions optimization 16 , metabolic network guided engineering 17 , random mutagenesis and metabolic engineering 18,19 are approaches used by researchers to enhance the production of tacrolimus in Streptomyce tsukubaensis and reported significant enhancement in tacrolimus yield. Keeping aforesaid facts in view, author performed dual mutagenesis (random mutagenesis) in Streptomyces tacrolimicus ATCC 55098 to develop a high yielding strain for tacrolimus production and this is an innovative and productive scheme which could be immensely helpful for over production of tacrolimus at commercial level.…”

Section: Introductionmentioning

confidence: 99%

Improving Production of Tacrolimus In Streptomyces Tacrolimicus (ATCC 55098) Through Development of Novel Mutant by Dual Mutagenesis

Singh¹,

Kumar²,

Haque³

et al. 2017

Braz. arch. biol. technol.

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Tacrolimus is a polyketide macrolide produced by Streptomyces species which is widely used as anti-fibrotic agent and potent immunosuppressant. In this article dual mutagenesis approach using mutagens (NTG+EMS+UV) was used to develop a mutant strain of Streptomyces tacrolimicus (ATCC 55098) for higher tacrolimus production and this strain showed higher tacrolimus production at 82.5 mg/l. Interestingly; addition of L-Lysine (0.2 g/l) into the production medium further enhanced the tacrolimus production to ~102 mg/l at 7-L fed-batch bioreactor. To the best of our knowledge this is the first report mentioning efficient strain development for higher production of tacrolimus using dual mutagenesis. The obtained data presents an impressive model for higher production of tacrolimus and enhanced our understanding regarding improvement in production capacity of tacrolimus in Streptomyces tacrolimicus.

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Enhancement of tacrolimus productivity in Streptomyces tsukubaensis by the use of novel precursors for biosynthesis

Cited by 44 publications

References 31 publications

Streptomyces tsukubaensis Fermentation Using Brazil Nut Oil to Enhance Tacrolimus Production

Streptomyces tsukubaensis Fermentation Using Brazil Nut Oil to Enhance Tacrolimus Production

Phage P1-Derived Artificial Chromosomes Facilitate Heterologous Expression of the FK506 Gene Cluster

Improving Production of Tacrolimus In Streptomyces Tacrolimicus (ATCC 55098) Through Development of Novel Mutant by Dual Mutagenesis

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