CN105200093A - Fermentation additive capable of changing generation rate of epothilone compound and improving yield of epothilone A - Google Patents

Fermentation additive capable of changing generation rate of epothilone compound and improving yield of epothilone A Download PDF

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CN105200093A
CN105200093A CN201510759275.8A CN201510759275A CN105200093A CN 105200093 A CN105200093 A CN 105200093A CN 201510759275 A CN201510759275 A CN 201510759275A CN 105200093 A CN105200093 A CN 105200093A
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epothilone
additive
ebormycine
fermentation
ebomycin
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CN105200093B (en
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李越中
胡玮
郑连帅
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Shandong University
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Abstract

The invention discloses a fermentation additive capable of changing the generation rate of an epothilone compound and improving the yield of epothilone A. The additive is 2,3,5,6-tetrahydroxy-2-hydrosorbic acid-4-lactone; and the final adding concentration in an epothilone liquid fermentation culture medium is 100+/-15 mu mol/L. An experiment proves that the additive disclosed by the invention is capable of keeping the reducibility of metal ions and metabolic intermediates and adjusting the secondary metabolism flow direction of sorangium cellulosum, so that the gross of the epothilone A is averagely improved by 62%-105% in comparison with that when the additive is not added; the ratio of the epothilone A to the epothilone B in a fermentation liquid is significantly changed; and (1.83+/-0.16):1 (the epothilone A to the epothilone B) before addition is changed into (5.67+/-0.71):1 (the epothilone A to the epothilone B). According to the fermentation additive, regulation and control on the secondary metabolism flow direction and the product type of the epothilone compound in the fermentation process are achieved; the fermentation cost of the epothilone A is reduced; and a way is also provided for production of the epothilone A.

Description

A kind of epothilones that can change produces ratio and the additives for ferment improving ebomycin A yield
Technical field
The present invention relates to a kind of additive and application thereof of fermentative production ebormycine, particularly relate to a kind of epothilones that can change and produce ratio and the additive and the application thereof that improve ebomycin A yield, belong to antitumor drug fermentation preparing technical field.
Background technology
Short microtubule polymerization compounds taxol (Paclitaxel, ) and analogue Docetaxel be current the most successful antineoplastic chemotherapy medicine clinically, being used to the treatment of the solid carcinomas such as ovarian cancer, thymic carcinoma, colorectal carcinoma, lung cancer and liver cancer, is the choice drug of the solid-tumor chemotherapy that U.S. FDA is assert.Have in the natural compounds of same or similar biological function with taxol, ebormycine (Epothilones) is only had to derive from the tunning of antimicrobial fiber heap capsule bacterium, and it is water-soluble large compared with taxol, cytotoxicity is less, being considered to the renewal product of taxol, is better cancer therapy drug.
At present, existing multiple epothilones enters the different steps of application and development.In October, 2007, first ebormycine class medicine ixabepilone by FDA's approval listing, and also has six kinds of epothilones to enter clinical trial: the BMS-310750 of hundred beautiful Shi Shiguibao companies; The EPO906 of Novartis Co., Ltd and analogue ABJ879 thereof; Also have KOS-862 and KOS-1584 of Roche Holding Ag; And the ZK-Epo of Schering Corp.A large amount of clinical study results demonstrates this compounds great pharmaceutical use.
Because the complete synthesis step of chemistry is various, yield is lower, does not possess cost advantage compared with biological fermentation process, and therefore biological synthesis process becomes the main flow direction of ebormycine technology for producing research.But the secondary metabolism utilizing fermentation additive to control ebormycine flows to, and the research changing proportion of products is less.Maintain the reductibility of metal ion or ebormycine synthetic mesophase product by adding predetermined substance, thus change the biological ratio of epothilones, the patent documentation that specificity improves a kind of epothilone compounds output has not yet to see report so far.
Summary of the invention
For the deficiencies in the prior art, the problem to be solved in the present invention is to provide a kind of epothilones that can change and produces ratio and the additives for ferment improving ebomycin A yield.
The epothilones that can change of the present invention produces ratio and the additive improving ebomycin A yield, it is characterized in that: described additive is 2,3,5,6-tetrahydroxy-2-hexenoic acid-4-lactone (i.e. vitamins C, have another name called L-AA), its interpolation final concentration in ebormycine liquid fermentation medium is 100 ± 15 μm of ol/L.
Further, described additive is preferably 2,3,5,6-tetrahydroxy-2-hexenoic acid-4-lactone (i.e. vitamins C, has another name called L-AA), and its interpolation final concentration in ebormycine liquid fermentation medium is 100 μm of ol/L.
The epothilones that can change of the present invention produces ratio and the application of additive in fermentative production ebormycine improving ebomycin A yield.
Wherein, the method of described fermentative production ebormycine is: be in the ebormycine liquid fermentation medium of the additive of 100 ± 15 μm of ol/L (preferably 100 μm of ol/L) by the sorangium cellulosum (Sorangiumcellulosum) after activation being added with final concentration, in pH7.5,30 ± 2 DEG C, the condition bottom fermentation of 200 ± 10rpm cultivates 9 ± 1 days, obtains the fermented liquid containing ebormycine.
Wherein, described ebormycine liquid fermentation medium is referred to as VCM substratum, and its component and content are: potato starch 8g/L, soybean cake powder 2.1g/L, glucose 0.9g/L, sucrose 0.5g/L, yeast powder 0.6g/L, corn steep liquor 1ml/L, MgSO 47H 2o2.5g/L, trace element solution 0.5ml/L, CaCl 21g/L, macroporous adsorbent resin XAD-1620mL/L; Wherein, described trace element solution formula is: MnCl 24H 2o100mg/L, CoCl 220mg/L, CuSO 410mg/L, Na 2moO 42H 2o10mg/L, ZnCl 220mg/L, LiCl5mg/L, SnCl 22H 2o5mg/L, H 3bO 310mg/L, KBr20mg/L, KI20mg/L.
Further, described sorangium cellulosum is preferably sorangium cellulosum (Sorangiumcellulosum) So0157-2.
Concrete, the application method of additive of the present invention in fermentative production ebormycine is:
(1) selection of fermentation strain: sorangium cellulosum (Sorangiumcellulosum) So0157-2 in slime bacteria bacterial strain.
(2) activation of bacterial strain: be seeded in by above-mentioned bacterial strains on solid plate substratum, cultivate 7 days for 30 DEG C, inoculate to liquid nutrient medium, 30 DEG C, 200rpm cultivates 5 days.
Then the bacterium liquid of acquisition is poured in the rolling bottle containing granulated glass sphere and break up 2 minutes, for subsequent use.
Wherein,
The composition of described solid plate substratum is: KNO 30.5g/L, Na 2hPO 40.25g/L, MgSO 47H 2o1g/L, FeCl 30.01g/L, trace element solution 1ml/L, agar 15g/L, pH7.2 (be down flat plate solidifies after, paste the square filter paper of 1.5 × 1.5cm).
The composition of described liquid nutrient medium is: potato starch 8g/L, soy peptone 2g/L, glucose 2g/L, yeast powder 2g/L, MgSO 41g/L, CaCl 21g/L, EDTA-Fe3+1ml/L, trace element solution 1.0ml/L, pH7.2.
Described trace element solution formula is: MnCl 24H 2o100mg/L, CoCl 220mg/L, CuSO 410mg/L, Na 2moO 42H 2o10mg/L, ZnCl 220mg/L, LiCl5mg/L, SnCl 22H 2o5mg/L, H 3bO 310mg/L, KBr20mg/L, KI20mg/L.
(3) fermentation culture mode: getting the obtained bacterium liquid 3mL of step (2), to be seeded to containing concentration be respectively 10 μMs, in the VCM substratum of 100 μMs and 1000 μMs additives, in pH7.5,30 ± 2 DEG C, the condition bottom fermentation cultivation of 200 ± 10rpm.
(4) the separation and Extraction purifying of ebormycine: ferment and use the resin of 80 eye mesh screen collecting by filtration detection limits for 9 days afterwards in 10ml centrifuge tube, adds 3ml methyl alcohol and to spend the night lixiviate.Get 1ml vat liquor 12000rpm, centrifugal 10 minutes, cross 0.22 μm of organic phase filter, HPLC detects.
(5) chromatographic test strip part:
Chromatographic column: Shim-packMRC-ODS, 4.6mmX250mm
Moving phase: methanol-water (volume ratio 55:45)
Flow velocity: 0.7ml/min
Ultraviolet detection wavelength: 249nm; Sample size: 10 μ L
(6) output of ebormycine is calculated according to the relation curve of absorption peak area and ebormycine concentration, three groups of results averaged miscalculation.
Comparative test result shows:
Compared with ordinary culture medium, use the liquid fermentation medium containing additive of the present invention, changed dramatically in the generation ratio of ebomycin A and epothilone B in fermented liquid.Further, compared with ordinary culture medium, use the liquid fermentation medium containing additive of the present invention, effectively improve the output of ebomycin A.
Concrete, ebormycine creates a difference as shown in table 1.
Table 1: when adding 2,3,5,6-tetrahydroxy-2-hexenoic acid-4-lactone of different concns, ebormycine production comparison sheet
In upper table, result display 2,3,5,6-tetrahydroxy-2-hexenoic acid-4-lactone produces ebomycin A for sorangium cellulosum promoter action, and changed dramatically in the generation ratio of ebomycin A and epothilone B in fermented liquid.The output of adding ebomycin A during 100 μMs (final concentration) 2,3,5,6-tetrahydroxy-2-hexenoic acid-4-lactone improves 62%-105% relative to contrast, and the effectiveness comparison improving ebomycin A fermentation yield is remarkable; Meanwhile, the generation ratio of ebomycin A and B changes into 5.67 ± 0.71:1 (ebomycin A: B) by the 1.83 ± 0.16:1 (ebomycin A: B) of blank.During excessive interpolation 1000 μMs (final concentration) 2,3,5,6-tetrahydroxy-2-hexenoic acid-4-lactone, thalli growth is suppressed, and cannot detect ebomycin A and B in fermented liquid.
The present invention discloses a kind of epothilones that can change and produces ratio and the additive (2 improving ebomycin A yield, 3,5,6-tetrahydroxy-2-hexenoic acid-4-lactone), this additive is utilized to improve the component of ebormycine fermention medium, the reductibility of metal ion and metabolic intermediate can be kept, the secondary metabolism of sorangium cellulosum is regulated to flow to, success realizes the generation ratio changing ebomycin A and epothilone B in fermented liquid, effectively improves the object of ebomycin A yield.
The invention has the beneficial effects as follows:
(1) epothilones that can change disclosed by the invention produces ratio and to improve the additive of ebomycin A yield cheap and easy to get, and good water solubility, preparation is added easy.
(2) experiment confirms: according to application method provided by the invention, described additive can improve the output increased 62%-105% of ebomycin A significantly, improves the fermentation efficiency of ebomycin A greatly, reduces cost.
(3) confirm according to application method provided by the invention, described additive significantly can change the ratio of ebomycin A and B in fermented liquid, change into 5.67 ± 0.71:1 (ebomycin A: B) by the 1.83 ± 0.16:1 (ebomycin A: B) before not adding, achieve the secondary metabolism flow direction of epothilones in fermenting process and the regulation and control of product types.
Accompanying drawing explanation
The chemical structure of Fig. 1 .2,3,5,6-tetrahydroxy-2-hexenoic acid-4-lactone.
Fig. 2. the HPLC of tunning detects schematic diagram (wherein solid line is VCM substratum tunning, and dotted line is for the addition of the VCM substratum tunning of 2,3,5,6-tetrahydroxy-2-hexenoic acid-4-lactone).
Embodiment
Below in conjunction with embodiment, the inventive method is elaborated, but described example is explanation of the invention instead of restriction.
Embodiment 1:
(1) selection of fermentation strain: sorangium cellulosum (Sorangiumcellulosum) So0157-2 in slime bacteria bacterial strain.
(2) activation of bacterial strain: be seeded in by above-mentioned bacterial strains on solid plate substratum, cultivate 7 days for 30 DEG C, inoculate to liquid nutrient medium, 30 DEG C, 200rpm cultivates 5 days.
Then the bacterium liquid of acquisition is poured in the rolling bottle containing granulated glass sphere and break up 2 minutes, for subsequent use.
Wherein,
The composition of described solid plate substratum is: KNO 30.5g/L, Na 2hPO 40.25g/L, MgSO 47H 2o1g/L, FeCl 30.01g/L, trace element solution 1ml/L, agar 15g/L, pH7.2 (be down flat plate solidifies after, paste the square filter paper of 1.5 × 1.5cm).
The composition of described liquid nutrient medium is: potato starch 8g/L, soy peptone 2g/L, glucose 2g/L, yeast powder 2g/L, MgSO 41g/L, CaCl 21g/L, EDTA-Fe3+1ml/L, trace element solution 1.0ml/L, pH7.2.
Described trace element solution formula is: MnCl 24H 2o100mg/L, CoCl 220mg/L, CuSO 410mg/L, Na 2moO 42H 2o10mg/L, ZnCl 220mg/L, LiCl5mg/L, SnCl 22H 2o5mg/L, H 3bO 310mg/L, KBr20mg/L, KI20mg/L.
(3) fermentation culture mode: getting the obtained bacterium liquid 3mL of step (2), to be seeded to containing concentration be respectively in the VCM substratum of 10 μMs of additives, in pH7.5,32 DEG C, oscillation and fermentation cultivation under the condition of 190rpm.
Wherein: described VCM nutrient media components and content are: potato starch 8g/L, soybean cake powder 2.1g/L, glucose 0.9g/L, sucrose 0.5g/L, yeast powder 0.6g/L, corn steep liquor 1ml/L, MgSO 47H 2o2.5g/L, trace element solution 0.5ml/L, CaCl 21g/L, macroporous adsorbent resin XAD-1620mL/L; Wherein, described trace element solution formula is: MnCl 24H 2o100mg/L, CoCl 220mg/L, CuSO 410mg/L, Na 2moO 42H 2o10mg/L, ZnCl 220mg/L, LiCl5mg/L, SnCl 22H 2o5mg/L, H 3bO 310mg/L, KBr20mg/L, KI20mg/L.
(4) the separation and Extraction purifying of ebormycine: ferment and use the resin of 80 eye mesh screen collecting by filtration detection limits for 10 days afterwards in 10ml centrifuge tube, adds 3ml methyl alcohol and to spend the night lixiviate.Get 1ml vat liquor 12000rpm, centrifugal 10 minutes, cross 0.22 μm of organic phase filter, HPLC detects.
(5) chromatographic test strip part:
Chromatographic column: Shim-packMRC-ODS, 4.6mmX250mm
Moving phase: methanol-water (volume ratio 55:45)
Flow velocity: 0.7ml/min
Ultraviolet detection wavelength: 249nm; Sample size: 10 μ L.
(6) output of ebormycine is calculated according to the relation curve of absorption peak area and ebormycine concentration.
When in original ebormycine fermention medium, interpolation 2,3,5,6-tetrahydroxy-2-hexenoic acid-4-lactone is 10 μMs to final concentration, the unitary determination result of ebormycine production is as shown in table 2:
Table 2: ebormycine production comparison sheet
From the data in table, when VCM substratum adds 2,3,5, when 6-tetrahydroxy-2-hexenoic acid-4-lactone is 10 μMs to final concentration, improve 19.1% when the output of ebomycin A is not added, in fermented liquid, the ratio of ebomycin A and B there occurs remarkable change.
Embodiment 2:
(1) selection of fermentation strain: sorangium cellulosum (Sorangiumcellulosum) So0157-2 in slime bacteria bacterial strain.
(2) activation of bacterial strain: be seeded in by above-mentioned bacterial strains on solid plate substratum, cultivate 7 days for 30 DEG C, inoculate to liquid nutrient medium, 30 DEG C, 200rpm cultivates 5 days.
Then the bacterium liquid of acquisition is poured in the rolling bottle containing granulated glass sphere and break up 2 minutes, for subsequent use.
Wherein,
The composition of described solid plate substratum is: KNO 30.5g/L, Na 2hPO 40.25g/L, MgSO 47H 2o1g/L, FeCl 30.01g/L, trace element solution 1ml/L, agar 15g/L, pH7.2 (be down flat plate solidifies after, paste the square filter paper of 1.5 × 1.5cm).
The composition of described liquid nutrient medium is: potato starch 8g/L, soy peptone 2g/L, glucose 2g/L, yeast powder 2g/L, MgSO 41g/L, CaCl 21g/L, EDTA-Fe3+1ml/L, trace element solution 1.0ml/L, pH7.2.
Described trace element solution formula is: MnCl 24H 2o100mg/L, CoCl 220mg/L, CuSO 410mg/L, Na 2moO 42H 2o10mg/L, ZnCl 220mg/L, LiCl5mg/L, SnCl 22H 2o5mg/L, H 3bO 310mg/L, KBr20mg/L, KI20mg/L.
(3) fermentation culture mode: getting the obtained bacterium liquid 3mL of step (2), to be seeded to containing concentration be respectively in the VCM substratum of 100 μMs of additives, in pH7.5,30 DEG C, oscillation and fermentation cultivation under the condition of 210rpm.
Wherein: described VCM nutrient media components and content are: potato starch 8g/L, soybean cake powder 2.1g/L, glucose 0.9g/L, sucrose 0.5g/L, yeast powder 0.6g/L, corn steep liquor 1ml/L, MgSO 47H 2o2.5g/L, trace element solution 0.5ml/L, CaCl 21g/L, macroporous adsorbent resin XAD-1620mL/L; Wherein, described trace element solution formula is: MnCl 24H 2o100mg/L, CoCl 220mg/L, CuSO 410mg/L, Na 2moO 42H 2o10mg/L, ZnCl 220mg/L, LiCl5mg/L, SnCl 22H 2o5mg/L, H 3bO 310mg/L, KBr20mg/L, KI20mg/L.
(4) the separation and Extraction purifying of ebormycine: ferment and use the resin of 80 eye mesh screen collecting by filtration detection limits for 9 days afterwards in 10ml centrifuge tube, adds 3ml methyl alcohol and to spend the night lixiviate.Get 1ml vat liquor 12000rpm, centrifugal 10 minutes, cross 0.22 μm of organic phase filter, HPLC detects.
(5) chromatographic test strip part:
Chromatographic column: Shim-packMRC-ODS, 4.6mmX250mm
Moving phase: methanol-water (volume ratio 55:45)
Flow velocity: 0.7ml/min
Ultraviolet detection wavelength: 249nm; Sample size: 10 μ L.
(6) output of ebormycine is calculated according to the relation curve of absorption peak area and ebormycine concentration.
When in original ebormycine fermention medium, interpolation 2,3,5,6-tetrahydroxy-2-hexenoic acid-4-lactone is 100 μMs to final concentration, the unitary determination result of ebormycine production is as shown in table 3:
Table 3: ebormycine production comparison sheet
From the data in table, when VCM substratum adds 2,3,5, when 6-tetrahydroxy-2-hexenoic acid-4-lactone is 100 μMs to final concentration, improve 101.6% when the output of ebomycin A is not added, in fermented liquid, the ratio of ebomycin A and B there occurs remarkable change.

Claims (5)

1. one kind can change epothilones generation ratio and improve the additive of ebomycin A yield, it is characterized in that: described additive is 2,3,5,6-tetrahydroxy-2-hexenoic acid-4-lactone, its interpolation final concentration in ebormycine liquid fermentation medium is 100 ± 15 μm of ol/L.
2. the epothilones that can change according to claim 1 produces ratio and the additive improving ebomycin A yield, it is characterized in that: described additive is 2,3,5,6-tetrahydroxy-2-hexenoic acid-4-lactone, its interpolation final concentration in ebormycine liquid fermentation medium is 100 μm of ol/L.
3. the epothilones that can change described in claim 1 or 2 produces ratio and the application of additive in fermentative production ebormycine improving ebomycin A yield.
4. application according to claim 3, it is characterized in that: the method for described fermentative production ebormycine is: be in the ebormycine liquid fermentation medium of the additive of 100 ± 15 μm of ol/L by the sorangium cellulosum (Sorangiumcellulosum) after activation being added with final concentration, in pH7.5,30 ± 2 DEG C, the condition bottom fermentation of 200 ± 10rpm cultivates 9 ± 1 days, obtains the fermented liquid containing ebormycine; Wherein: described ebormycine liquid fermentation medium is referred to as VCM substratum, and its component and content are: potato starch 8g/L, soybean cake powder 2.1g/L, glucose 0.9g/L, sucrose 0.5g/L, yeast powder 0.6g/L, corn steep liquor 1ml/L, MgSO 47H 2o2.5g/L, trace element solution 0.5ml/L, CaCl 21g/L, macroporous adsorbent resin XAD-1620mL/L; Wherein, described trace element solution formula is: MnCl 24H 2o100mg/L, CoCl 220mg/L, CuSO 410mg/L, Na 2moO 42H 2o10mg/L, ZnCl 220mg/L, LiCl5mg/L, SnCl 22H 2o5mg/L, H 3bO 310mg/L, KBr20mg/L, KI20mg/L.
5. application according to claim 4, is characterized in that: described sorangium cellulosum is sorangium cellulosum (Sorangiumcellulosum) So0157-2.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106086104A (en) * 2016-06-08 2016-11-09 山东大学 A kind of additive for improving slimeball rhzomorph fermentation yield and application thereof
CN107012240A (en) * 2017-05-08 2017-08-04 山东大学 A kind of method of Rapid identification epothilone gene cluster positive strain

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Publication number Priority date Publication date Assignee Title
CN1367255A (en) * 2002-02-07 2002-09-04 山东大学 Fermentation process for raising ebomycin A yield
CN1769468A (en) * 2005-10-19 2006-05-10 华南理工大学 Method for highly-effective producing epothilone using myxobacteria sorangium cellulosum
CN102747649A (en) * 2012-07-02 2012-10-24 川渝中烟工业有限责任公司 Functional cigarette paper additive and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1367255A (en) * 2002-02-07 2002-09-04 山东大学 Fermentation process for raising ebomycin A yield
CN1769468A (en) * 2005-10-19 2006-05-10 华南理工大学 Method for highly-effective producing epothilone using myxobacteria sorangium cellulosum
CN102747649A (en) * 2012-07-02 2012-10-24 川渝中烟工业有限责任公司 Functional cigarette paper additive and application thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106086104A (en) * 2016-06-08 2016-11-09 山东大学 A kind of additive for improving slimeball rhzomorph fermentation yield and application thereof
CN107012240A (en) * 2017-05-08 2017-08-04 山东大学 A kind of method of Rapid identification epothilone gene cluster positive strain

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