CN102978266A - Novel sugar alcohol mixed feed supplement method applied to erythrocin fermentation - Google Patents
Novel sugar alcohol mixed feed supplement method applied to erythrocin fermentation Download PDFInfo
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- CN102978266A CN102978266A CN201210571737XA CN201210571737A CN102978266A CN 102978266 A CN102978266 A CN 102978266A CN 201210571737X A CN201210571737X A CN 201210571737XA CN 201210571737 A CN201210571737 A CN 201210571737A CN 102978266 A CN102978266 A CN 102978266A
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Abstract
The invention relates to a novel sugar alcohol mixed feed supplement method applied to erythrocin fermentation. The feed supplement method provided by the invention comprises the following steps: controlling the utilization ratio of normal propyl alcohol by controlling the carbohydrate supplementation rates in different fermenting stages; and regulating the normal propyl alcohol supplementing rate according to glucose supplementing rate. Bacteria cells are well controlled in an optimal physiological status suitable for synthesis of erythrocin.
Description
Technical field
The invention belongs to bioengineering field; More specifically, the present invention relates to a kind of sugar alcohol mixing feed supplement novel method that is applied to abomacetin fermentation.
Background technology
Erythromycin is by ten synthetic quaternary macrolide antibiotics of red saccharopolyspora process secondary metabolism, is mainly used in the treatment gram positive bacterial infection.Its mechanism of action is for suppressing transpeptidation and malignant bacteria is killed in messenger RNA(mRNA) (mRNA) displacement by being combined with bacterium ribosome 50S subunit rrna.Erythromycin is the anti-infectives that global sales ranks forefront, and the global marketing volume reaches the over ten billion dollar.Along with the novel semi-synthetic erythromycin medicine take erythromycin as raw material such as the year after year surge of the sales volumes such as Roxithromycin, Azythromycin and clarithromycin, driven the continuous increase of erythromycin demand, the production and selling of erythromycin bulk drug is increasingly active.
Most manufacturer adopts soybean cake powder and starch as the culture medium mainly composition.Add the fermentation level that a small amount of quick-acting nitrogenous sources can promote the early growth of red saccharopolyspora thalline and effectively improve erythromycin on the basis of this prescription.Along with the consumption of starch, thalline can be forced to hydrolysis and utilize soybean cake powder during the fermentation.The deamination of soybean cake powder causes the rising of pH.For the pH value of controlled fermentation process, can adopt the method controlled fermentation process pH that adds soda acid.Perfect gradually along with technique, in abomacetin fermentation industry, generally adopt and enter thalli growth in fermentation and begin to adopt stream to add the zymotechnique of glucose control pH value after stationary phase, the result shows that the method not only is better than adding merely the method for soda acid control pH value, and more can improve final abomacetin fermentation level than the glucose fed technique according to residual sugar in the fermented liquid.
Except adding during the fermentation the glucose, soya-bean oil and n-propyl alcohol also are the important contents of process feed supplement as the important sources of the synthetic precursor of erythromycin.Yet, not yet form unified soya-bean oil and the replenishment method of n-propyl alcohol all the time.Some producers carry out the supplying technics of soya-bean oil and n-propyl alcohol fully according to knowhow for many years.These methods lack certain theoretical foundation, and the experienced technician of dependence analysis is judged more in force.
Therefore, the zymotechnique of erythromycin is optimized, the output of Effective Raise erythromycin in the urgent need to the fermentation mechanism of further investigation erythromycin in this area.
Summary of the invention
The object of the present invention is to provide a kind of sugar alcohol mixing feed supplement novel method that is applied to abomacetin fermentation.
In a first aspect of the present invention, provide a kind of pH of employing value feedback control method to carry out the method for abomacetin fermentation, described method comprises: set pH preset value 6.95-7.1 (such as 6.95,7.0,7.05,7.1), carry out three stage fermentations:
Fs: cultivate red sugared many born of the same parents bacterium to thalli growth stationary phase, when fermented liquid pH value is higher than preset value, begin subordinate phase;
Subordinate phase: when fermented liquid pH value is higher than preset value, control the pH value at preset value by adding glucose generation organic acid; Add simultaneously n-propyl alcohol, make the amount of total carbon atom of the glucose of adding and n-propyl alcohol satisfy thalline and produce required; Add speed when n-propyl alcohol and be lower than 0.07-0.08gL
-1h
-1(such as 0.076gL
-1h
-1) time, the beginning phase III;
Phase III: keep n-propyl alcohol and add speed 0.07-0.08gL
-1h
-1(such as 0.076gL
-1h
-1); Adding glucose makes fermented liquid pH value at preset value.
In a preference of the present invention, in the subordinate phase of described method, the amount of the glucose of adding and total carbon atom of n-propyl alcohol was added the carbon atom absolute magnitude with per 12 hours and is calculated, at 0.25-0.35mol/L.
In another preference of the present invention, the amount of the glucose that adds and total carbon atom of n-propyl alcohol was added the carbon atom absolute magnitude with per 12 hours and is calculated, 0.26mol/L when initial by subordinate phase is increased to 0.31mol/L, and (preferably, dropping to 0.24mol/L) afterwards descends.
In another preference of the present invention, described pH preset value is 7.0-7.05.
In another preference of the present invention, in the subordinate phase of described method, the amount of the glucose that each time point adds and total carbon atom of n-propyl alcohol equals the amount of total carbon atom of glucose and n-propyl alcohol in following fermentation process a corresponding (or identical) the time point fermented liquid:
When being higher than 6.9, fermented liquid pH value adds glucose, average glucose fed speed 0.170gL
-1h
-1Add simultaneously n-propyl alcohol, average n-propyl alcohol is added speed 0.058gL
-1h
-1To fermentation ends.
In another preference of the present invention, in the described method, n-propyl alcohol is added speed=(fermentation process a glucose fed speed * 6+ fermentation process a n-propyl alcohol is added speed * 3)-glucose fed speed * 6] ÷ 3.
In another preference of the present invention, the temperature of fermentation is at 34 ± 1 ℃.
In another preference of the present invention, the dissolved oxygen 30 ± 5% of fermentation.
In another preference of the present invention, the initial medium of fermentation comprises: starch 35 ± 5g/L, dextrin 5 ± 1g/L, soybean cake powder 33 ± 5g/L, corn steep liquor 18 ± 2g/L, NaCl2 ± 0.4g/L, CaCO
37 ± 1.5g/L, soya-bean oil 5 ± 1mL/L.
In another preference of the present invention, the initial medium of fermentation also comprises: defoamer.
Other side of the present invention is because the disclosure of this paper is apparent to those skilled in the art.
Description of drawings
The inoculation of Fig. 1, red sugared many born of the same parents bacterium-fermentation flow process.
Fig. 2, height are mended the lower impact on abomacetin fermentation of sugar.
Line represents that pattern a mends sugared curve (default pH=6.9),
Line represents the benefit sugar curve under the pattern b (default pH=7.3), ● line represents erythromycin resultant curve under the pattern a, and zero line represents the erythromycin resultant curve under the default pH=7.3.
Fig. 3, mending under the sugar dissolved oxygen curve relatively at height.
The feed supplement pattern of Fig. 4, four kinds of total carbon atom equal principles designing on the basis of Fig. 2-3 has shown the variation of mending sugar and mending pure speed, namely in the ratio of different steps control glucose and n-propyl alcohol.
Fig. 5, according to the process fermentation parameter that obtains under pattern 1-pattern 4 techniques.
Fig. 6, difference are added oxygen uptake rate OUR and the respiratory quotient RQ under the pattern.
Fig. 7, glucose and the n-propyl alcohol whereabouts in metabolism is investigated.
Embodiment
Mend sugar benefit alcohol in the prior art in the Erythromycin Fermentation Process take experience as problem main, that be theoretically unsound in order to solve, the present invention is starting point from the cognation between the mutual utilization between glucose and the n-propyl alcohol, has disclosed a kind of sugar alcohol mixing feed supplement novel method.Compare with traditional supplement art, feed supplement method of the present invention is controlled the utilising efficiency of n-propyl alcohol by the benefit sugar speed in control different fermentations stage, simultaneously according to glucose fed speed n-propyl alcohol is added speed and regulate and control, can control well thalline and be in and be suitable for the synthetic best physiological status of erythromycin.
Method of the present invention is based on following principle: by regulating and control within the specific limits the pH set(ting)value in the fermenting process, can effectively change the speed of adding of glucose, when the glucose fed rate reduction, the speed of utilizing of n-propyl alcohol can increase.N-propyl alcohol is the important sources of the synthetic precursor of erythromycin, and its utilization ratio increase is then so that the yield of erythrocin increase.Based on this, studied and change the regulation and control of pH set(ting)value and mend sugared speed and add the novel mixing feed supplement pattern of speed according to glucose fed rate-controlling n-propyl alcohol, realized the raising of abomacetin fermentation level.
Glucose and the n-propyl alcohol whereabouts in metabolism as shown in Figure 7, glucose can the synthesis of erythromycin precursor, n-propyl alcohol also can the synthesis of erythromycin precursor.Glucose metabolism will be passed through the pathways metabolisms such as EMP, TCA, in these approach, so that most of glucose discharges with the form of carbonic acid gas, does not have good synthesis of erythromycin.And the n-propyl alcohol metabolism is synthetic more directly related with erythromycin, and n-propyl alcohol can be high by the utilization ratio that bacterial strain utilizes.Therefore, the inventor only satisfies the principle of control pH in line with the adding reinforced, glucose that enough total carbon nucleidic mass is provided and improves n-propyl alcohol, has developed the method for efficient product erythromycin of the present invention.
As used herein, described " thalli growth stationary phase " refers to that microorganism is through after a while growth, because nutritive substance is few in the substratum, can only keep the needs of the basic metabolism of thalline and synthetic secondary metabolite, therefore the ratio speed of growth of thalline is zero substantially, and cell concentration is in constant basically.
As optimal way of the present invention, the inventor adds speed according to the carbon atom summation principle of invariance raising n-propyl alcohol of glucose and n-propyl alcohol.Under carbon atom summation principle of invariance, glucose is on average added rate reduction, and n-propyl alcohol is on average added speed and improved, and yield of erythrocin significantly increases.Mend sugar according to pH and mend pure strategy with constant speed and compare merely with traditional, the utilization that the method fully takes into account glucose and n-propyl alcohol concerns, has guaranteed thalline synthesis of erythromycin product continuously and healthily.
Method of the present invention is taked three stage fermentation methods, at first cultivate red sugared many spores genetic engineering bacterium, glucose concn is reduced to when approaching zero in fermented liquid, and the pH value of fermented liquid can begin to raise, when fermented liquid pH value was higher than preset value, the beginning subordinate phase was added glucose with control pH value.
Afterwards, carry out subordinate phase, start n-propyl alcohol when adding glucose and add program, go out the speed of adding of n-propyl alcohol according to Equation for Calculating.Equation is that n-propyl alcohol is added speed=(the former technique n-propyl alcohol of former technique glucose fed speed * 6+ is added speed * 3)-glucose fed speed * 6] ÷ 3, adding speed unit is mmol L
-1h
-1.
Afterwards, carry out the phase III, add under the speed at lower n-propyl alcohol, add glucose control pH value at preset value.
Compare with traditional sugar alcohol supplying technics, novel sugar alcohol mixing feed supplement method of the present invention have the bacterial metabolism active period mend sugared speed low, mend pure speed high and the bacterial metabolism decline phase mend sugared speed high, mend the low characteristics of pure speed.These characteristics make thalline be in a physiological status that is suitable for synthesis of erythromycin, be that the bacterial metabolism active period reduces the utilization of mending sugared stimulation rate n-propyl alcohol, thereby improve the concentration of the erythromycin precursor that derives from n-propyl alcohol, and improve the decline that the sugared speed of benefit is slowed down thalline at the bacterial metabolism decline phase, reduce simultaneously and mend pure speed, thereby reduced the injury effect of n-propyl alcohol to thalline.
In embodiment of the present invention, adopt novel feeding strategy to carry out abomacetin fermentation, the result shows that novel feed supplement method can realize the glucose fed speed in different fermentations stage and the connected effect that n-propyl alcohol is added speed.Reduce the speed of utilizing that glucose fed speed can significantly improve n-propyl alcohol.Adopt novel sugar alcohol mixing feed supplement method, can realize thalline synthesis of erythromycin continuously and healthily, increased substantially final erythromycin level.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is write according to normal condition such as J. Pehanorm Brooker etc. usually, molecular cloning experiment guide, the third edition, Science Press, the condition described in 2002, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and umber calculate by weight.
1, cultural method and parameter detection method
Bacterial classification: red sugared many born of the same parents genetic engineering bacterium ZL1004 (Saccharopolyapora erythraea ZL1004) (genotype is permK*-K-K-G+permE*-K+permA*-G).
First class seed pot substratum: starch 30g/L, DEXTRIN g/L, bean powder 20g/L, CaCO
35g/L, NaCl3g/L, (NH4)
2SO
42g/L.
Secondary seed tank substratum: starch 30g/L, dextrin 30g/L, bean powder 30g/L, corn steep liquor 10g/L, CaCO35g/L, defoamer 10mL/L.
Fermention medium: starch 35g/L, dextrin 5g/L, soybean cake powder 33g/L, corn steep liquor 18g/L, NaCl2g/L, CaCO
37g/L, soya-bean oil 5mL/L, defoamer (silicone based defoamer, chemical industry company limited when high available from Yixing City) 56mL/L.
Cultural method
Adopt the three grade fermemtation mode, (1cm * 1cm) be inoculated in the 500mL seed shaking flask that the 50mL substratum is housed, lower 34 ℃ of 220r/min rotating speed cultivate 40h, change afterwards the 15L seeding tank over to take fresh slant strains, the secondary seed culturing process is kept dissolved oxygen more than 40%, cultivates 40h for 34 ℃.The secondary seed nutrient solution is moved into the 50L fermentor tank, cultivate 191h for 34 ℃, process is kept dissolved oxygen more than 30%.Main flow process such as Fig. 1.
The research (pattern a-pattern b) of different pH value set(ting)values
Fermented initial 1-34 hour, and reduced with dissolved oxygen and improve gradually rotating speed and ventilation is kept dissolved oxygen more than 30%, the composition Growth and reproduction that thalline provides by utilizing substratum.Rose to fermentation ends in the 35th hour, and taked the mode of table 1 to set pH and feed supplement.
Table 1
Novel sugar alcohol mixing feed supplement method (pattern 1-pattern 4)
Fermented initial 1-34 hour, and reduced with dissolved oxygen and improve gradually rotating speed and ventilation is kept dissolved oxygen more than 30%, the composition Growth and reproduction that thalline provides by utilizing substratum.Rose in the 35th hour, glucose adopts automatic pH feedback mode control, and when pH surpassed set(ting)value, automatic feedback control was added glucose.N-propyl alcohol adjusting in per 1 hour is once added speed and is added once, adds speed and is calculated by equation 1.The equation that equates according to the total carbon atom of sugar alcohol:
N-propyl alcohol is added speed=(n-propyl alcohol is added speed * 3 under glucose fed speed under the pattern a technique * 6+ pattern a technique)-this pattern and is kept the default required glucose fed speed of pH * 6] ÷ 3, adding speed unit is mmol L
-1h
-1(equation 1).
Table 2
After 131h, continue the control glucose fed, make fermented liquid pH value with 35-131h in identical set(ting)value; Add speed when n-propyl alcohol and be lower than 0.076gL
-1h
-1The time, it is added speed and maintains 0.076gL
-1h
-1
Total carbon atom is calibrated standard really
Rose in the 35th hour, and calculated total carbon atom number over time curve such as the table 3 of adding glucose and n-propyl alcohol according to original process (pattern 1).
Add speed when n-propyl alcohol and be lower than 0.076gL
-1h
-1The time, it is added speed and maintains 0.076gL
-1h
-1, in implementation, the n-propyl alcohol that calculates after 131 hours of fermenting is added speed and is lower than 0.076gL
-1h
-1So n-propyl alcohol is according to 0.076gL after 131 hours
-1h
-1Speed is added.In other words, namely implement the time period of total carbon atom number equal principle for fermenting initial rear 35-131 hour.
In order to determine total carbon atom span of control, can the total carbon atomic molar number in per stage be set according to following table.Control the total carbon nucleidic mass and also namely determined the total amount that sugar alcohol is added, carried out on this basis the adjusting of sugar, pure ratio.
Table 3
Annotate: the not a large amount of accumulation of residual sugar and residual alcohol.
Actually add that glucose solution concentration is 30% (g/g) in the process, n-propyl alcohol concentration is 50% (v/v).
Parameter detection method
Chemical titer: adopt conventional sulphuric acid hydrolysis to measure.
Erythromycin Components in the fermented liquid: adopt the HPLC analytical method, Waters Xbridge C18 chromatographic column (4.6mm * 250mm, 5 μ m, Waters Corporation).Moving phase 0.025mol/L potassium dihydrogen phosphate: acetonitrile=60:40, flow velocity 1ml/min, 35 ℃ of column temperatures detect wavelength 215nm, sample size 20 μ l.
2, experimental result
(1) pattern a and pattern b
Pattern a and pattern b (table 1) be by adjusting the pH set(ting)value, when the pH set(ting)value transfers to 7.30 by 6.90, average glucose fed rate reduction 42.6%, and final abomacetin fermentation level has only reduced by 1%.The benefit sugar speed of pattern a and pattern b and the figure of the pure speed of benefit are shown in Figure 2.
The above results explanation produces the method that organic acid is controlled the pH rising by adding glucose, and is less to final abomacetin fermentation level affects, sets the larger variation that pH can cause glucose fed speed but change within the specific limits.
Glucose and n-propyl alcohol utilization relation among investigation pattern a and the pattern b, result such as Fig. 2 illustrate by regulating the pH control process and mend sugared speed, but output significantly do not change.
Investigate fermenting process dissolved oxygen situation, result such as Fig. 3, pulse dissolved oxygen curve prove, have stimulated the consumption of n-propyl alcohol in the low sugared speed of benefit (pattern b).Be that pattern a and pattern b adopt per hour benefit alcohol mode once simultaneously, in this case, mending the high pattern a of sugar does not have the dissolved oxygen pulse, has occurred and mends the consistent pulse curve of alcohol and mend the low pattern b of sugar, therefore shows lowly to mend sugared speed and coerce thalline and utilize more n-propyl alcohol.
(2) pattern 1,2,3,4
Investigate the as above glucose fed situation of the feed supplement pattern of four kinds of total carbon atom equal principles of design, such as Fig. 4 A; Investigate the n-propyl alcohol of the feed supplement pattern of four kinds of total carbon atom equal principles that as above design and add situation, such as Fig. 4 B.
Oxygen uptake rate OUR and the respiratory quotient RQ of further investigation pattern 1,2,3,4 bottom fermentation systems.Result such as Fig. 6.Show and newly add the physiological metabolism characteristic that pattern fully takes into account thalline, make thalline be in the state of more excellent synthesis of erythromycin.That is: in bacterial metabolism intensity in early stage high (OUR is high), can utilize more n-propyl alcohol, it is also high that add propyl alcohol under the novel process this moment, and in the fermentation later stage, the bacterial metabolism activity tapers off (OUR is low), and the sugar of adding increases, and mends alcohol and reduces.Mending sugared increase this moment is because mend early stage due to sugar quick the increasing of pH of very few this moment that causes.And the later stage is improved benefit sugar, and (pattern OUR a), it is synthetic efficiently that erythromycin is continued so that the OUR under the novel process is apparently higher than former technique.
The above results shows that the output of mode 3 is the highest, and pattern 4 causes output to descend to some extent because the n-propyl alcohol addition is too high on the contrary.Mode 3 is compared with pattern 1, and glucose is on average added rate reduction 28.6%.Under the condition of glucose fed rate reduction, improve n-propyl alcohol add speed keep all fermenting processs each constantly add glucose and n-propyl alcohol the total number of carbon atoms equates; The result shows that n-propyl alcohol on average adds speed and improve 77.6%.Because mend under the sugar level low, thalline is forced to utilize n-propyl alcohol, so the speed of utilizing of n-propyl alcohol increases.N-propyl alcohol utilizes the increase of speed, has promoted the generation of the synthetic precursor of erythromycin.Fig. 7 is the metabolic flux distribution of the 59-83h that calculates by macroscopical metabolism flowmeter, and the result shows that the synthetic precursor propionyl-CoA of erythromycin and methylmalonyl-CoA obviously increase, and have finally accelerated the synthetic speed of erythromycin.
To sum up, mend sugared strategy according to pH merely with tradition and compare, novel sugar alcohol is mixed to be mended novel method and fully takes into account the more rational feeding strategy that proposes after the mutual relationship between the sugar alcohol utilization.The method is the speed of adding by control glucose and n-propyl alcohol successfully, by the approach flux of synthesis of erythromycin in the cell that changed environment parameter control, has greatly improved the fermentation level of erythromycin.
All quote in this application as a reference at all documents that the present invention mentions, just as each piece document is quoted separately as a reference.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. a method that adopts pH value feedback control method to carry out abomacetin fermentation is characterized in that, described setting pH preset value 6.95-7.1 carries out three stage fermentations:
Fs: cultivate red sugared many born of the same parents bacterium to thalli growth stationary phase, when fermented liquid pH value is higher than preset value, begin subordinate phase;
Subordinate phase: when fermented liquid pH value is higher than preset value, control the pH value at preset value by adding glucose generation organic acid; Add simultaneously n-propyl alcohol, make the amount of total carbon atom of the glucose of adding and n-propyl alcohol satisfy thalline and produce required; Add speed when n-propyl alcohol and be lower than 0.07-0.08gL
-1h
-1The time, the beginning phase III;
Phase III: keep n-propyl alcohol and add speed 0.07-0.08gL
-1h
-1Adding glucose makes fermented liquid pH value at preset value.
2. the method for claim 1 is characterized in that, in the subordinate phase, the amount of the glucose of adding and total carbon atom of n-propyl alcohol was added the carbon atom absolute magnitude with per 12 hours and calculated, at 0.25-0.35mol/L.
3. method as claimed in claim 2 is characterized in that, the amount of the glucose of adding and total carbon atom of n-propyl alcohol was added the carbon atom absolute magnitude with per 12 hours and calculated, and the 0.26mol/L when initial by subordinate phase is increased to 0.31mol/L, descends afterwards.
4. the method for claim 1 is characterized in that, described pH preset value is 7.0-7.05.
5. the method for claim 1 is characterized in that, in the subordinate phase, the amount of the glucose that each time point adds and total carbon atom of n-propyl alcohol equals the amount of total carbon atom of glucose and n-propyl alcohol in the corresponding time point fermented liquid of following fermentation process a:
When being higher than 6.9, fermented liquid pH value adds glucose, average glucose fed speed 0.170gL
-1h
-1Add simultaneously n-propyl alcohol, average n-propyl alcohol is added speed 0.058gL
-1h
-1To fermentation ends.
6. method as claimed in claim 5 is characterized in that, n-propyl alcohol is added speed=(fermentation process a glucose fed speed * 6+ fermentation process a n-propyl alcohol is added speed * 3)-described method glucose fed speed * 6] ÷ 3.
7. the method for claim 1 is characterized in that, the temperature of fermentation is at 34 ± 1 ℃.
8. the method for claim 1 is characterized in that, the dissolved oxygen 30 ± 5% of fermentation.
9. the method for claim 1 is characterized in that, the initial medium of fermentation comprises: starch 35 ± 5g/L, dextrin 5 ± 1g/L, soybean cake powder 33 ± 5g/L, corn steep liquor 18 ± 2g/L, NaCl2 ± 0.4g/L, CaCO
37 ± 1.5g/L, soya-bean oil 5 ± 1mL/L.
10. method as claimed in claim 9 is characterized in that, the initial medium of fermentation also comprises: defoamer.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114276942A (en) * | 2021-12-30 | 2022-04-05 | 安琪酵母股份有限公司 | Glutathione yeast, preparation method and application of glutathione yeast product |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RO79459A2 (en) * | 1980-03-13 | 1982-09-09 | Intreprinderea De Antibiotice,Ro | METHOD FOR BIOSYNTHESIS OF ERYTROMYCIN |
| CN1706960A (en) * | 2004-06-09 | 2005-12-14 | 中国科学院过程工程研究所 | Feedback material-replenishing process of producing nisin |
| CN1982467A (en) * | 2005-12-16 | 2007-06-20 | 中国科学院过程工程研究所 | Production of glutamic acid based on pII feedback supplement |
| CN102234654A (en) * | 2010-04-30 | 2011-11-09 | 邢安辉 | Method for recombining Saccharopolyspora erythraea strain containing exogenetic vitreoscilla hemoglobin gene (vgb) |
-
2012
- 2012-12-25 CN CN201210571737.XA patent/CN102978266B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RO79459A2 (en) * | 1980-03-13 | 1982-09-09 | Intreprinderea De Antibiotice,Ro | METHOD FOR BIOSYNTHESIS OF ERYTROMYCIN |
| CN1706960A (en) * | 2004-06-09 | 2005-12-14 | 中国科学院过程工程研究所 | Feedback material-replenishing process of producing nisin |
| CN1982467A (en) * | 2005-12-16 | 2007-06-20 | 中国科学院过程工程研究所 | Production of glutamic acid based on pII feedback supplement |
| CN102234654A (en) * | 2010-04-30 | 2011-11-09 | 邢安辉 | Method for recombining Saccharopolyspora erythraea strain containing exogenetic vitreoscilla hemoglobin gene (vgb) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114276942A (en) * | 2021-12-30 | 2022-04-05 | 安琪酵母股份有限公司 | Glutathione yeast, preparation method and application of glutathione yeast product |
| CN114276942B (en) * | 2021-12-30 | 2024-05-28 | 安琪酵母股份有限公司 | Glutathione yeast, preparation method and application of product |
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