Generation of high rapamycin producing strain via rational metabolic pathway‐based mutagenesis and further titer improvement with fed‐batch bioprocess optimization

Zhu, Xiangcheng; Zhang, Wei; Chen, Xiyang; Wu, Hu; Duan, Yanwen; Xu, Zhinan

doi:10.1002/bit.22819

Cited by 48Microbial Natural Products and BiosynthesisMicrobial Metabolic Engineering and BioproductionMicrobial Metabolism and Applications

Generation of high rapamycin producing strain via rational metabolic pathway‐based mutagenesis and further titer improvement with fed‐batch bioprocess optimization

Zhu, Xiangcheng, Zhang, Wei, Chen, Xiyang, Wu, Hu, Duan, Yanwen, Xu, Zhinan·2010·Biotechnology and Bioengineering

DOI 10.1002/bit.22819

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Abstract

Rapamycin is a triene macrolide antibiotic produced by Streptomyces hygroscopicus. Besides its wide application as an effective immunosuppressive agent, other important bioactivities have made rapamycin a potential drug lead for novel pharmaceutical development. However, the low titer of rapamycin in the original producer strain limits further industrialization efforts and restricts its use for other applications. Predicated on knowledge of the metabolic pathways related to rapamycin biosynthesis in S. hygroscopicus, we have rationally designed approaches to generate a rapamycin high producer strain of S. hygroscopicus HD‐04‐S. These have included alleviation of glucose repression, improved tolerance towards lysine and shikimic acid, and auxotrophy of tryptophan and phenylalanine through the application of stepwise UV mutagenesis. The resultant strain produced rapamycin at 450 mg/L in the shake flask scale. These fermentations were further scaled up in 120 and 20,000 L fermentors, respectively, at the pilot plant. Selected fermentation factors including agitation speed, pH, and on‐line supplementation were systematically evaluated. A fed‐batch strategy was established to maximize rapamycin production. With these efforts, an optimized fermentation process in the larger scale fermentor was developed. The final titer of rapamycin was 812 mg/L in the 120 L fermentor and 783 mg/L in the 20,000 L fermentor. This work highlights a high rapamycin producing strain derived by mutagenesis and subsequent screening, fermentation optimization of which has now made it feasible to produce rapamycin on an industrial scale by fermentation. The strategies developed here should also be applicable to titer improvement of other important microbial natural products on an industrial scale. Biotechnol. Bioeng. 2010;107: 506–515. © 2010 Wiley Periodicals, Inc.

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Low titer of rapamycin produced by S. hygroscopicus limits further development and industrialization of this natural product.
“The low titer of this drug produced by the organism has now become a rate-limiting factor in further development and industrialization of this natural product (Zhu et al. 2010).”
From Kinetics of rapamycin production by Streptomyces hygroscopicus MTCC 4003 (2014) · cites this paper as Zhu et al. 2010
The dissolved oxygen level was maintained at 10% of saturation level all the time.
“Finally, the DO level was maintained at 10 % of saturation level all the time (Zhu et al. 2010).”
From Kinetics of rapamycin production by Streptomyces hygroscopicus MTCC 4003 (2014) · cites this paper as Zhu et al. 2010
The obtained data clearly show that exponential phase of growth is very important for rapamycin production.
“However, the obtained data clearly show that exponential phase of growth is very important for rapamycin production (Zhu et al. 2010; Sanchez and Brana 1996).”
From Kinetics of rapamycin production by Streptomyces hygroscopicus MTCC 4003 (2014) · cites this paper as Zhu et al. 2010

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Authors: Zhu, X., Zhang, W., Chen, X., Wu, H., Duan, Y., & Xu, Z.
Affiliations: Zhejiang University (CN)
Corresponding author: Xu, Zhinan
ORCID: Zhu, Xiangcheng
Zhang, Wei
Chen, Xiyang
Duan, Yanwen
Xu, Zhinan
Venue: Biotechnology and Bioengineering
Publisher: Wiley
Published: 2010-08-20
Volume: 107
Issue: 3
Pages: 506-515
ISSN: 0006-3592 (ISSN-L)
1097-0290
DOI: 10.1002/bit.22819
OpenAlex: W2070229485
Cited by: 48
References: 32
Citations by year: 2024: 1 · 2022: 3 · 2021: 4 · 2020: 5 · 2019: 3 · 2018: 4 · 2017: 5 · 2016: 2 · 2015: 4 · 2014: 4 · 2013: 9 · 2012: 1
FWCI: 2.83
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Biotechnology and Bioengineering (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Metabolism and Applications
Keywords: rapamycin, Streptomyces hygroscopicus, UV mutagenesis, glucose repression, tryptophan auxotrophy, fed-batch fermentation, fermentation optimization, industrial-scale production
MeSH terms: Fermentation, Glucose, Lysine, Phenylalanine, Shikimic Acid, Streptomyces, Tryptophan, Ultraviolet Rays, Mutagenesis, Sirolimus, Metabolic Networks and Pathways

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Generation of high rapamycin producing strain via rational metabolic pathway‐based mutagenesis and further titer improvement with fed‐batch bioprocess optimization

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