CN102174426A - Production process for high-density fermentation of sprangium cellulosum and separation coupling of epothilone product - Google Patents
Production process for high-density fermentation of sprangium cellulosum and separation coupling of epothilone product Download PDFInfo
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- CN102174426A CN102174426A CN2010106031147A CN201010603114A CN102174426A CN 102174426 A CN102174426 A CN 102174426A CN 2010106031147 A CN2010106031147 A CN 2010106031147A CN 201010603114 A CN201010603114 A CN 201010603114A CN 102174426 A CN102174426 A CN 102174426A
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Abstract
The invention discloses a production process for high-density fermentation of sprangium cellulosum and separation coupling of an epothilone product. In the invention, the high-density fermentation of the sprangium cellulosum is realized by feeding carbon and nitrogen source substances and precursors; and at the same time, a polymeric adsorbent which can be repeatedly used can be used for separating the epothilone product and the high-density fermentation and product separation coupling are realized, thus feedback inhibition of the epothilone on the sprangium cellulosum is removed and output of the epothilone is increased. The invention has the technical characteristics of cost conservation, simple process, convenience in operation and high production efficiency.
Description
Technical field
The present invention relates to the production technique of a kind of sorangium cellulosum high density fermentation and ebormycine product separation coupling, belong to the fermentation engineering field.
Background technology
1993, the G. of German national biotechnology center (GBF)
Reported them from the fermented liquid of sorangium cellulosum So.ce 90 bacterial strains of slime bacteria Deng the people, separated Epothilone A and B (Fig. 1) with inhibition fungi activity and cytotoxic activity.Nineteen ninety-five, the graduate D.M.Bollag of Merck etc. find that when screening the microtubule inhibitor on a large scale the fermented product extract of a strain sorangium cellulosum SMP 44 has the depolymerization of the tubulin of inhibition, destroys mitotic activity, identify that by analysis this active constituent is Epothilone A and B, it has the mechanism of action of identical inhibition growth of tumour cell with taxol, and has than taxol and more to many advantage.2007 have the derivative Yi Shapilong of a kind of ebormycine class B to go on the market through drugs approved by FDA, there are six kinds of ebormycine compounds to enter clinical study at present, the ebormycine compounds is a dark horse in current cancer therapy drug field, and the mass production techniques research of this compounds is extremely urgent.
But, the generation bacterium sorangium cellulosum of ebormycine for duration, poor growth, the nutrition intake rate is very low, the consumption rate of oxygen is less, fermentation period is long, cell concn is lower during fermentation, every ml cells number is not more than 10 in the wild type strain fermented liquid
9Individual.Less to the research of sorangium cellulosum fermentative production ebormycine both at home and abroad.The detection output that report in 1996 such as Gerth So ce90 strain fermentation produces ebormycine is 22mg/L, and the ratio of ebomycin A and B is approximately 2: 1.Gerth etc. are also by isotope-labeled substrate method, set forth the composition of the carbon skeleton of ebormycine, and studied relation between several main natural ebormycine, be the interpolation of precursor substance in the ebormycine fermenting process, and illustrate further that the pathways metabolism of ebormycine lays the foundation in the original strain.Domestic only have fragmentary several patents to report that the sorangium cellulosum fermentation produced the technology (ZL02110068.3, ZL02110067.5, ZL200510100338.5) of ebormycine, but do not have the report at sorangium cellulosum high density fermentation and ebormycine product separation coupling production technique.
Summary of the invention
The present invention is directed to the deficiency in the current sorangium cellulosum fermentative production ebormycine technology, disclose the production technique of a kind of sorangium cellulosum high density fermentation and ebormycine product separation coupling.
Technical scheme of the present invention is as follows:
The high density fermentation that adds carbon nitrogen source material and precursor substance realization sorangium cellulosum by stream, use can recycled for multiple times polymeric adsorbent, realize that the ebormycine product separates, and with high density fermentation and product separation coupling, remove the feedback inhibition of end product ebormycine, improve the output of ebormycine sorangium cellulosum.
Concrete processing step is:
1. sorangium cellulosum strain preparation: ebormycine is produced bacterial strain sorangium cellulosum So0157-2, is provided by professor Li Yuezhong of State Key Laboratory for Microbial Technology of Shandong University, is preserved in Chinese representative microbial preservation center, numbering CCTCC NO.M208078.Cultivate activation in 5-7 days through solid-state activation medium at 28-32 ℃ before bacterial classification uses, cultivated 3-5 days at 30-32 ℃ through liquid seed culture medium, when cell concentration reaches 10
10The time inoculation fermentation substratum, the canned liquid coefficient 70% that ferments, inoculum size is 5-10% (V/V), fermentation period 7-9 days.
As 1 described solid-state activation medium be: potato starch 0.1-3%, soy peptone 0.1-2%, glucose 0.1-2%, yeast extract paste 0.2-1%, MgSO
40.1-1%, CaCL
20.1-1%; TE 1.0-2.0ml/L; PH7.0-8.0.Add 0.5-1.5% agar, 121 ℃ of sterilization 20min use.
As 1 described liquid seed culture medium be: potato starch 0.1-3%, soy peptone 0.1-2%, glucose 0.1-2%, yeast extract paste 0.2-1%, MgSO
40.1-1%, CaCL
20.1-1%; TE 1.0-2.0ml/L; PH7.0-8.0.121 ℃ of sterilization 20min use.
As 1 described fermention medium be: yam starch 0.1-4%, glucose 0.1-3%, peptone 0.1-2%, soybean cake powder 0.1-2% and skim-milk 0.1-2%, Na
2HPO
40.01-1%, K
2HPO
40.01-1%, MgSO
40.1-1%, CaCl
20.1-1%, FeCl
3-EDTA0.001-0.01%, pH adjusts 7.0-9.0.121 ℃ of sterilization 20min use.
2. fed batch fermentation: the 30-70h after the fermentation beginning adds the glucose that concentration is 2g/L, and per hour stream adds the 0.01-0.1% of original fermentating liquid volume.70-120h from fermenting process adds precursor nutritive substance mixed solution.This mixed solution is put into fermentor tank feed supplement bottle, and the peristaltic pump auto-feeding is adopted in the sterilization back, and per hour stream adds the 0.01-0.05% of original fermentating liquid volume.
As 2 described precursor substance mixture formulas be: Threonine 5mg/L, Serine (Ser) 5mg/L, methionine(Met) and each 2mg/L of halfcystine, sodium acetate 20mg/L, pyruvic acid 30mg/L, VB
121mg/L, corn steep liquor 2g/L.With the deionized water preparation, 121 ℃ of sterilization 20min used before glucose and precursor substance mixed solution used.
3. the separation of absorption ebormycine resin: by with fermentation link coupled adsorption resin column continuous adsorption fermented liquid in ebormycine, concrete technical process as shown in Figure 2: fermented liquid → peristaltic pump → resin column → fermented liquid is back to fermentor tank.
As the 3 described polymeric adsorbent consumptions 0.5-3% that is original fermentating liquid volume; Resin column and pipeline will be sterilized before using, resin column enabling time after for the fermentation beginning the 48th hour, the fermented liquid speed of circulation is per minute 10-100mL, circulation absorption 72h changes resin column, and 2-4 resin column uses in turn, behind resin absorption 72h, collect ebormycine by resin volume 6-10 methanol-eluted fractions doubly, and, realize resin regeneration with 6-10 deionized water doubly washing resin successively, continue after the sterilization to recycle.
Production technique of the present invention has the following advantages:
1, realized the high density fermentation of sorangium cellulosum by supplying technics, maximum cell density reaches 10 for every milliliter in the fermented liquid
12Individual.
2, add by stream that glucose high density fermentation, stream add the synthetic required precursor substance of ebormycine, fermentation link coupled ebormycine separates the measure of three aspects, removed the feedback inhibition of ebormycine end product, realized the high yield of ebormycine, ebomycin A yield reaches 127mg/L in every liter of fermented liquid, and epothilone B output reaches 53mg/L.
3, polymeric adsorbent uses through the dress post and can protect resin particle not smashed by the fermentation stirring, saves cost than directly resin being added the method for adsorbing in the fermented liquid, and in addition, the present invention has the technical characterstic that technology is simple, easy to operate, production efficiency is high.
Description of drawings
Fig. 1 is an ebormycine epothilone A/B structural formula of compound;
Fig. 2 is fermentation and product separation coupling synoptic diagram; Wherein: 1. fermented liquid is gathered filter screen; 2. peristaltic pump; 3. adsorption resin column.
Embodiment
The present invention will be further described below in conjunction with embodiment and accompanying drawing, but protection domain is not limited thereto.
Embodiment 1
1. sorangium cellulosum strain preparation: ebormycine is produced bacterial strain sorangium cellulosum So0157-2, Chinese representative microbial preservation center preservation, numbering NO.M208078.Cultivate activation in 5 days through solid-state activation medium at 28 ℃ before bacterial classification uses, liquid seed culture medium was cultivated 3 days at 30 ℃, and cell concentration reaches 10
10The time inoculation fermentation substratum, the canned liquid coefficient 70% that ferments, inoculum size is 5% (V/V), fermentation period 7 days.
As 1 described solid-state activation medium be: potato starch 0.5%, soy peptone 1%, glucose 1%, yeast extract paste 0.5%, MgSO
40.5%, CaCL
20.5%; TE 1.0ml/L; PH7.0.Add 0.8% agar, 121 ℃ of sterilization 20min use.
As 1 described liquid seed culture medium be: potato starch 0.5%, soy peptone 1%, glucose 1%, yeast extract paste 0.5%, MgSO
40.5%, CaCL
20.5%; TE 1.0ml/L; PH7.0.121 ℃ of sterilization 20min use.
As 1 described fermention medium be: yam starch 0.5%, glucose 1%, peptone 0.5%, soybean cake powder 0.5% and skim-milk 0.5%, Na
2HPO
40.01%, K
2HPO
40.01%, MgSO
40.5%, CaCl
20.5%, FeCl
3-EDTA 0.001%, and pH adjusts 7.0.121 ℃ of sterilization 20min use.
2. fed batch fermentation: add the glucose that concentration is 2g/L continuously in the 30-70h of fermentation, per hour stream adds 0.01% of original fermentating liquid volume.70-120h from fermenting process adds precursor nutritive substance mixed solution.This mixed solution is put into fermentor tank feed supplement bottle, and the peristaltic pump auto-feeding is adopted in the sterilization back, and per hour stream adds 0.01% of original fermentating liquid volume.
As 2 described precursor substance mixed solutions be: Threonine 5mg/L, Serine (Ser) 5mg/L, methionine(Met) and each 2mg/L of halfcystine, sodium acetate 20mg/L, pyruvic acid 30mg/L, VB
121mg/L, corn steep liquor 2g/L.With the deionized water preparation, 121 ℃ of sterilization 20min used before glucose and precursor substance mixed solution used.
3. the separation of absorption ebormycine resin: by with fermentation link coupled adsorption resin column absorption fermented liquid in ebormycine, concrete technical process as shown in Figure 2: fermented liquid → peristaltic pump → resin column → fermented liquid is back to fermentor tank.
As 3 described polymeric adsorbent consumptions is 0.5% of original fermentating liquid volume; Resin column and pipeline will be sterilized before using, resin column enabling time is fermentation beginning after 48 hours, the fermented liquid speed of circulation is per minute 10mL, circulation absorption 72h changes resin column, 2 resin columns use in turn, circulation absorption gap, and methanol-eluted fractions by 6 times of resin volumes and 6 times deionized water be washing resin successively, realize resin regeneration, continue after the sterilization to recycle.
Maximum cell density reaches 3*10 for every milliliter in the fermented liquid after testing
12Individual.Ebomycin A yield reaches 108mg/L in every liter of fermented liquid, and epothilone B output reaches 46mg/L.
1. sorangium cellulosum strain preparation: ebormycine is produced bacterial strain sorangium cellulosum So0157-2, Chinese representative microbial preservation center preservation, numbering NO.M208078.Cultivate activation in 6 days through solid-state activation medium at 30 ℃ before bacterial classification uses, liquid seed culture medium was cultivated 4 days at 31 ℃, and cell concentration reaches 10
10The time inoculation fermentation substratum, the canned liquid coefficient 70% that ferments, inoculum size is 10% (V/V), fermentation period 8 days.
As 1 described solid-state activation medium be: potato starch 1%, soy peptone 1.5%, glucose 1.5%, yeast extract paste 0.8%, MgSO
40.7%, CaCL
20.7%; TE 1.5ml/L; PH7.5.Add 1% agar, 121 ℃ of sterilization 20min use.
As 1 described liquid seed culture medium be: potato starch 2%, soy peptone 1.5%, glucose 1.5%, yeast extract paste 0.8%, MgSO
40.7%, CaCL
20.7%; TE 1.5ml/L; PH7.5.121 ℃ of sterilization 20min use.
As 1 described fermention medium be: yam starch 2%, glucose 2%, peptone 1.5%, soybean cake powder 1.5% and skim-milk 1.5%, Na
2HPO
40.5%, K
2HPO
40.5%, MgSO
40.8%, CaCl
20.8%, FeCl
3-EDTA0.005%, pH adjusts 8.0.121 ℃ of sterilization 20min use.
2. fed batch fermentation: 30-70h adds the glucose that concentration is 2g/L from the fermentation beginning, and per hour stream adds 0.05% of original fermentating liquid volume.70-120h from fermenting process adds precursor nutritive substance mixed solution.This mixed solution is put into fermentor tank feed supplement bottle, and the peristaltic pump auto-feeding is adopted in the sterilization back, and per hour stream adds 0.03% of original fermentating liquid volume.
As 2 described precursor substance mixed solutions be: Threonine 5mg/L, Serine (Ser) 5mg/L, methionine(Met) and each 2mg/L of halfcystine, sodium acetate 20mg/L, pyruvic acid 30mg/L, VB
121mg/L, corn steep liquor 2g/L.With the deionized water preparation, 121 ℃ of sterilization 20min used before glucose and precursor substance mixed solution used.
3. the separation of absorption ebormycine resin: by with fermentation link coupled adsorption resin column absorption fermented liquid in ebormycine, concrete technical process as shown in Figure 2: fermented liquid → peristaltic pump → resin column → fermented liquid is back to fermentor tank.
As 3 described polymeric adsorbent consumptions is 1.5% of original fermentating liquid volume; Resin column and pipeline will be sterilized before using, resin column enabling time is fermentation beginning after 48 hours, the fermented liquid speed of circulation is per minute 50mL, circulation absorption 72h changes resin column, 3 resin columns use in turn, circulation absorption gap, and methanol-eluted fractions by 8 times of resin volumes and 8 times deionized water be washing resin successively, realize resin regeneration, continue after the sterilization to recycle.
Maximum cell density reaches 4*10 for every milliliter in the fermented liquid after testing
12Individual.Ebomycin A yield reaches 116mg/L in every liter of fermented liquid, and epothilone B output reaches 51mg/L.
Embodiment 3
1. sorangium cellulosum strain preparation: ebormycine is produced bacterial strain sorangium cellulosum So0157-2, Chinese representative microbial preservation center preservation, numbering NO.M208078.Cultivate activation in 7 days through solid-state activation medium at 32 ℃ before bacterial classification uses, liquid seed culture medium was cultivated 5 days at 32 ℃, and cell concentration reaches 10
10The time inoculation fermentation substratum, the canned liquid coefficient 70% that ferments, inoculum size is 5% (V/V), fermentation period 9 days.
As 1 described solid-state activation medium be: potato starch 3%, soy peptone 2%, glucose 2%, yeast extract paste 1%, MgSO
41%, CaCL
21%; TE 2.0ml/L; PH8.0.Add 1.5% agar, 121 ℃ of sterilization 20min use.
As 1 described liquid seed culture medium be: potato starch 3%, soy peptone 2%, glucose 2%, yeast extract paste 1%, MgSO
41%, CaCL
21%; TE 2.0ml/L; PH8.0.121 ℃ of sterilization 20min use.
As 1 described fermention medium be: yam starch 4%, glucose 3%, peptone 2%, soybean cake powder 2% and skim-milk 2%, Na
2HPO
40.8%, K
2HPO
40.8%, MgSO
41%, CaCl
21%, FeCl
3-EDTA 0.01%, and pH adjusts 9.0.121 ℃ of sterilization 20min use.
2. fed batch fermentation: 30-70h adds the glucose that concentration is 2g/L from the fermentation beginning, and per hour stream adds 0.1% of original fermentating liquid volume.70-120h from fermenting process adds precursor nutritive substance mixed solution.This mixed solution is put into fermentor tank feed supplement bottle, and the peristaltic pump auto-feeding is adopted in the sterilization back, and per hour stream adds 0.05% of original fermentating liquid volume.
As 2 described precursor substance mixed solutions be: Threonine 5mg/L, Serine (Ser) 5mg/L, methionine(Met) and each 2mg/L of halfcystine, sodium acetate 20mg/L, pyruvic acid 30mg/L, VB
121mg/L, corn steep liquor 2g/L.With the deionized water preparation, 121 ℃ of sterilization 20min used before glucose and precursor substance mixed solution used.
3. the separation of absorption ebormycine resin: by with fermentation link coupled adsorption resin column absorption fermented liquid in ebormycine, concrete technical process as shown in Figure 2: fermented liquid → peristaltic pump → resin column → fermented liquid is back to fermentor tank.
As 3 described polymeric adsorbent consumptions is 3% of original fermentating liquid volume; Resin column and pipeline will be sterilized before using, resin column enabling time is fermentation beginning after 48 hours, the fermented liquid speed of circulation is per minute 100mL, circulation absorption 72h changes resin column, 3 resin columns use in turn, circulation absorption gap, and methanol-eluted fractions by 10 times of resin volumes and 10 times deionized water be washing resin successively, realize resin regeneration, continue after the sterilization to recycle.
Maximum cell density reaches 7*10 for every milliliter in the fermented liquid after testing
12Individual.Ebomycin A yield reaches 127mg/L in every liter of fermented liquid, and epothilone B output reaches 53mg/L.
Claims (4)
1. the production technique of sorangium cellulosum high density fermentation and ebormycine product separation coupling is characterized in that: add technology by stream, comprise carbon nitrogen source material and precursor substance, realize the high density fermentation of sorangium cellulosum; Use simultaneously can recycled for multiple times polymeric adsorbent, realize that the ebormycine product separates, and with high density fermentation and product separation coupling.
2. stream as claimed in claim 1 adds technology, it is characterized in that adding the glucose that concentration is 2g/L from the 30-70h that ferments after beginning, and per hour stream adds the 0.01-0.1% of original fermentating liquid volume.70-120h from fermenting process adds precursor nutritive substance mixed solution.This mixed solution is put into fermentor tank feed supplement bottle, and the peristaltic pump auto-feeding is adopted in the sterilization back, and per hour stream adds the 0.01-0.05% of original fermentating liquid volume.
As 2 described precursor substance mixture formulas be: Threonine 5mg/L, Serine (Ser) 5mg/L, methionine(Met) and each 2mg/L of halfcystine, sodium acetate 20mg/L, pyruvic acid 30mg/L, VB
121mg/L, corn steep liquor 2g/L.With the deionized water preparation, 121 ℃ of sterilization 20min used before glucose and precursor substance mixed solution used.
3. fermentation as claimed in claim 1 and product separation coupling technology is characterized in that: by with fermentation link coupled adsorption resin column continuous adsorption fermented liquid in ebormycine, concrete technical process is:
Fermented liquid → peristaltic pump → resin column → fermented liquid is back to fermentor tank.
As the 3 described polymeric adsorbent consumptions 0.5-3% that is original fermentating liquid volume; Resin column and pipeline will be sterilized before using, resin column enabling time after for the fermentation beginning the 48th hour, the fermented liquid speed of circulation is per minute 10-100mL, circulation absorption 72h changes resin column, and 2-4 resin column uses in turn, behind resin absorption 72h, collect ebormycine by resin volume 6-10 methanol-eluted fractions doubly, and, realize resin regeneration with 6-10 deionized water doubly washing resin successively, continue after the sterilization to recycle.
4. the application of the production technique of a kind of sorangium cellulosum high density fermentation as claimed in claim 1 and ebormycine product separation coupling aspect sorangium cellulosum fermentative production ebormycine compounds.
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Cited By (7)
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|---|---|---|---|---|
| CN102373252A (en) * | 2011-11-04 | 2012-03-14 | 陕西科技大学 | Fermentation production process of Epothilone B |
| CN102373251A (en) * | 2011-11-04 | 2012-03-14 | 陕西科技大学 | Fermentation production method of Epothilone D provided with molecular imprinting polymer |
| CN102399848A (en) * | 2011-11-15 | 2012-04-04 | 山东轻工业学院 | Method for increasing fermentation yield of epothilone by using competitive microorganism and application thereof |
| CN103088084A (en) * | 2013-01-30 | 2013-05-08 | 广州市微生物研究所 | Method for preparing epothilone by inducing sorangium cellulosum expression |
| CN104073530A (en) * | 2014-06-27 | 2014-10-01 | 陕西科技大学 | Method for producing epothilone B by continuous adsorption coupling fermentation |
| CN109055455A (en) * | 2018-07-23 | 2018-12-21 | 南京工业大学 | Method for producing epothilone |
| WO2020014868A1 (en) * | 2018-07-17 | 2020-01-23 | 厦门昶科生物工程有限公司 | Method for high-density fermentation of clostridium bifermentans, clostridium bifermentans bacterial agent and preparation method therefor |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102373252A (en) * | 2011-11-04 | 2012-03-14 | 陕西科技大学 | Fermentation production process of Epothilone B |
| CN102373251A (en) * | 2011-11-04 | 2012-03-14 | 陕西科技大学 | Fermentation production method of Epothilone D provided with molecular imprinting polymer |
| CN102373252B (en) * | 2011-11-04 | 2013-11-27 | 陕西科技大学 | Fermentation production process of Epothilone B |
| CN102373251B (en) * | 2011-11-04 | 2014-07-02 | 陕西科技大学 | Fermentation production method of Epothilone D provided with molecular imprinting polymer |
| CN102399848A (en) * | 2011-11-15 | 2012-04-04 | 山东轻工业学院 | Method for increasing fermentation yield of epothilone by using competitive microorganism and application thereof |
| CN102399848B (en) * | 2011-11-15 | 2014-09-24 | 山东轻工业学院 | Method for increasing fermentation yield of epothilone by using competitive microorganism and application thereof |
| CN103088084A (en) * | 2013-01-30 | 2013-05-08 | 广州市微生物研究所 | Method for preparing epothilone by inducing sorangium cellulosum expression |
| CN103088084B (en) * | 2013-01-30 | 2014-10-29 | 广州市微生物研究所 | Method for preparing epothilone by inducing sorangium cellulosum expression |
| CN104073530A (en) * | 2014-06-27 | 2014-10-01 | 陕西科技大学 | Method for producing epothilone B by continuous adsorption coupling fermentation |
| WO2020014868A1 (en) * | 2018-07-17 | 2020-01-23 | 厦门昶科生物工程有限公司 | Method for high-density fermentation of clostridium bifermentans, clostridium bifermentans bacterial agent and preparation method therefor |
| CN109055455A (en) * | 2018-07-23 | 2018-12-21 | 南京工业大学 | Method for producing epothilone |
| CN109055455B (en) * | 2018-07-23 | 2021-06-18 | 南京工业大学 | Method for producing epothilone |
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