An effective and simplified scale-up strategy for acarbose fermentation based on the carbon source control

Li, Kun-tai; Wie, Sai-jin; Huang, Lin; Cheng, Xin

doi:10.1007/s11274-011-0835-y

Cited by 11 publications

(7 citation statements)

References 14 publications

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“…Moreover, the by-product component C was seen to decrease by 90% to 43 mg/l when compared with the levels obtained in the absence of valienamine. Besides our own previous study [21], until the present time, the maximal acarbose titer in fermentation broth was obtained by Li et al [13] at 4,327 mg/l in a 30 L fermentor by a fedbatch process, when controlling total sugar and reducing sugar at 75-80 and 45-50 g/l, respectively. S-Adenosylmethionine (SAM), a ubiquitous substance in living organisms, is generally known to be a methyl donor in various biosynthetic processes.…”

supporting

confidence: 51%

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Significantly Enhanced Production of Acarbose in Fed-Batch Fermentation with the Addition of S-Adenosylmethionine

Sun

Li²,

Wang³

et al. 2012

J. Microbiol. Biotechnol.

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Acarbose, a pseudo-oligosaccharide, is widely used clinically in therapies for non-insulin-dependent diabetes. In the present study, S-adenosylmethionine (SAM) was added to selected media in order to investigate its effect on acarbose fermentation by Actinoplanes utahensis ZJB-08196. Acarbose titer was seen to increase markedly when concentrations of SAM were added over a period of time. The effects of glucose and maltose on the production of acarbose were investigated in both batch and fed-batch fermentation. Optimal acarbose production was observed at relatively low glucose levels and high maltose levels. Based on these results, a further fed-batch experiment was designed so as to enhance the production of acarbose. Fed-batch fermentation was carried out at an initial glucose level of 10 g/l and an initial maltose level of 60 g/l. Then, 12 h post inoculation, 100 µmol/l SAM was added. In addition, 8 g/l of glucose was added every 24 h, and 20 g/l of maltose was added at 96 h. By way of this novel feeding strategy, the maximum titer of acarbose achieved was 6,113 mg/l at 192 h. To our knowledge, the production level of acarbose achieved in this study is the highest ever reported.

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supporting

confidence: 51%

“…Complex carbon sources consisting of glucose and maltose are the preferable carbon sources for cell growth and acarbose biosynthesis [4,13,22]. Glucose has always been regarded as the most easily utilizable carbon source.…”

Section: Effects Of Glucose Concentrations On the Process Of Acarbosementioning

confidence: 99%

Significantly Enhanced Production of Acarbose in Fed-Batch Fermentation with the Addition of S-Adenosylmethionine

Sun

Li²,

Wang³

et al. 2012

J. Microbiol. Biotechnol.

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“…To increase the yield of acarbose, producing strains have been continuously selected by conventional mutagenesis and screening, along with appropriate optimization of fermentation processes, including media, osmolality, and fed-batch culture [4] , [5] , [6] , [7] . In addition, Actinoplanes sp.…”

Section: Introductionmentioning

confidence: 99%

Improving acarbose production and eliminating the by-product component C with an efficient genetic manipulation system of Actinoplanes sp. SE50/110

Zhao

Xie

Peng

et al. 2017

Synthetic and Systems Biotechnology

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The α-glucosidase inhibitor acarbose is commercially produced by Actinoplanes sp. and used as a potent drug in the treatment of type-2 diabetes. In order to improve the yield of acarbose, an efficient genetic manipulation system for Actinoplanes sp. was established. The conjugation system between E. coli carrying ØC31-derived integrative plasmids and the mycelia of Actinoplanes sp. SE50/110 was optimized by adjusting the parameters of incubation time of mixed culture (mycelia and E. coli), quantity of recipient cells, donor-to-recipient ratio and the concentration of MgCl2, which resulted in a high conjugation efficiency of 29.4%. Using this integrative system, a cloned acarbose biosynthetic gene cluster was introduced into SE50/110, resulting in a 35% increase of acarbose titer from 2.35 to 3.18 g/L. Alternatively, a pIJ101-derived replicating plasmid combined with the counter-selection system CodA(sm) was constructed for gene inactivation, which has a conjugation frequency as high as 0.52%. Meanwhile, almost all 5-flucytosine-resistant colonies were sensitive to apramycin, among which 75% harbored the successful deletion of targeted genes. Using this replicating vector, the maltooligosyltrehalose synthase gene treY responsible for the accumulation of component C was inactivated, and component C was eliminated as detected by LC-MS. Based on an efficient genetic manipulation system, improved acarbose production and the elimination of component C in our work paved a way for future rational engineering of the acarbose-producing strains.

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“…Remarkable improvements on acarbose titer, acarbose productivity, and proportion of acarbose/impurity C were successfully achieved when 20 mg/L of validamine was added in the fermentation medium prior to inoculation both in batch and fed-batch cultures. The acarbose titer and acarbose productivity obtained in fed-batch culture in this work are the highest that have been reported for all the submerged fermentations of A. utahensis [10, 12–15, 19, 20, 27]. This simple and effective strategy would be of great value to acarbose production on commercial scale.…”

Section: Discussionmentioning

confidence: 52%

“…However, major difficulties still exist in improving the yield of acarbose, leading to a high cost for its manufacture. Recently, Li et al [12, 13] reported the medium optimization and scale-up strategy for acarbose fermentation by Actinoplanes sp. A56 and developed an optimized industrial fermentation processes for acarbose production, as a result about 5000 mg/L of acarbose was obtained.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Production of Acarbose and Concurrently Reduced Formation of Impurity C by Addition of Validamine in Fermentation ofActinoplanes utahensisZJB-08196

Xue

Qin²,

Wang

et al. 2013

BioMed Research International

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Commercial production of acarbose is exclusively via done microbial fermentation with strains from the genera of Actinoplanes. The addition of C7N-aminocyclitols for enhanced production of acarbose and concurrently reduced formation of impurity C by cultivation of A. utahensis ZJB-08196 in 500-mL shake flasks was investigated, and validamine was found to be the most effective strategy. Under the optimal conditions of validamine addition, acarbose titer was increased from 3560 ± 128 mg/L to 4950 ± 156 mg/L, and impurity C concentration was concurrently decreased from 289 ± 24 mg/L to 107 ± 29 mg/L in batch fermentation after 168 h of cultivation. A further fed-batch experiment coupled with the addition of validamine (20 mg/L) in the fermentation medium prior to inoculation was designed to enhance the production of acarbose. When twice feedings of a mixture of 6 g/L glucose, 14 g/L maltose, and 9 g/L soybean flour were performed at 72 h and 96 h, acarbose titer reached 6606 ± 103 mg/L and impurity C concentration was only 212 ± 12 mg/L at 168 h of cultivation. Acarbose titer and proportion of acarbose/impurity C increased by 85.6% and 152.9% when compared with control experiments. This work demonstrates for the first time that validamine addition is a simple and effective strategy for increasing acarbose production and reducing impurity C formation.

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An effective and simplified scale-up strategy for acarbose fermentation based on the carbon source control

Cited by 11 publications

References 14 publications

Significantly Enhanced Production of Acarbose in Fed-Batch Fermentation with the Addition of S-Adenosylmethionine

Significantly Enhanced Production of Acarbose in Fed-Batch Fermentation with the Addition of S-Adenosylmethionine

Improving acarbose production and eliminating the by-product component C with an efficient genetic manipulation system of Actinoplanes sp. SE50/110

Enhanced Production of Acarbose and Concurrently Reduced Formation of Impurity C by Addition of Validamine in Fermentation ofActinoplanes utahensisZJB-08196

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