CN102978266B - A kind of sugar alcohol mixing feed supplement new method applied to abomacetin fermentation - Google Patents
A kind of sugar alcohol mixing feed supplement new method applied to abomacetin fermentation Download PDFInfo
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Abstract
The present invention relates to a kind of sugar alcohol mixing feed supplement new methods applied to abomacetin fermentation.The feed process of the present invention controls the utilization ratio of normal propyl alcohol by the sugared rate of the benefit for controlling the different fermentations stage, rate is added to normal propyl alcohol to regulate and control, can control thalline well and be in the best physiological status for being suitable for erythromycin synthesis according to glucose fed rate simultaneously.
Description
Technical field
The invention belongs to bioengineering fields；More particularly it relates to a kind of sugar alcohol applied to abomacetin fermentation
Mix feed supplement new method.
Background technology
Erythromycin is to pass through the ten quaternary macrolide antibiotics that cometabolism synthesizes by red saccharopolyspora, is mainly answered
For treating gram positive bacterial infection.Its mechanism of action is by being combined suppression with bacterium ribosome 50S subunit ribosomes
Pathogenic bacteria is killed in transpeptidation processed and messenger RNA (mRNA) displacement.Erythromycin is the anti-infectious agent that global sales ranks forefront
Object, global marketing volume reach multi-billion dollar.With mould as the novel semi-synthetic erythromycin drug such as Luo Hong of raw material using erythromycin
Surging year after year for the sales volumes such as element, azithromycin and clarithromycin, has driven being continuously increased for erythromycin demand, erythromycin raw material
The production and selling of medicine becomes more and more active.
Current most of manufacturers are using soybean cake powder and starch as main Media Components.The base being formulated herein
A small amount of quick-acting nitrogen sources are added on plinth can promote the early growth of red saccharopolyspora thalline and effectively improve erythromycin
Fermentation level.During the fermentation with the consumption of starch, thalline can be forced hydrolysis and utilize soybean cake powder.The deamination of soybean cake powder
Base acts on the raising for causing pH.In order to control the pH value of fermentation process, the method control fermentation process for adding soda acid may be used
pH.It is gradual perfect with technique, in abomacetin fermentation industry, generally using ferment enter thalli growth stationary phase after open
As a result the zymotechnique to begin using stream plus glucose control ph shows that this method is not only better than adding soda acid control ph merely
Method, and it is more horizontal than can more improve final abomacetin fermentation according to the glucose fed technique of residual sugar in zymotic fluid.
Other than adding glucose during the fermentation, soya-bean oil and normal propyl alcohol synthesize the important next of precursor as erythromycin
The important content of source and process feed supplement.However, not yet forming the replenishment method of unified soya-bean oil and normal propyl alcohol all the time.
Some producers carry out the supplying technics of soya-bean oil and normal propyl alcohol according to knowhow for many years completely.These methods lack certain
Theoretical foundation relies on the analytical judgment of skilled engineer more in force.
Therefore, there is an urgent need in the art to further investigate the fermentation mechanism of erythromycin, optimize the zymotechnique of erythromycin, effectively
Improve the yield of erythromycin.
Invention content
The purpose of the present invention is to provide a kind of sugar alcohol mixing feed supplement new methods applied to abomacetin fermentation.
In the first aspect of the present invention, a kind of method that abomacetin fermentation is carried out using pH value feedback control method, institute are provided
The method of stating includes：PH preset values 6.95-7.1 (such as 6.95,7.0,7.05,7.1) is set, three stage fermentations are carried out：
First stage：The red more born of the same parents bacterium of sugar of culture open to thalli growth stationary phase when zymotic fluid pH value is higher than preset value
Beginning second stage；
Second stage：When zymotic fluid pH value is higher than preset value, organic acid is generated come control ph by adding glucose
In preset value；Normal propyl alcohol is added simultaneously, the amount of the glucose of addition and the entire carbon atom of normal propyl alcohol is made to meet needed for thalline production；
Rate, which is added, when normal propyl alcohol is less than 0.07-0.08gL-1h-1(such as 0.076gL-1h-1) when, start the phase III；
Phase III：Normal propyl alcohol is maintained to add rate 0.07-0.08gL-1h-1(such as 0.076gL-1h-1)；Adding glucose makes
Zymotic fluid pH value is in preset value.
In the preference of the present invention, in the second stage of the method, the glucose of addition and normal propyl alcohol it is total
The amount of carbon atom added carbon atom absolute magnitude to calculate, in 0.25-0.35mol/L with every 12 hours.
In another preference of the present invention, the amount of the glucose of addition and the entire carbon atom of normal propyl alcohol was mended with every 12 hours
Carbon atom absolute magnitude is added to calculate, 0.26mol/L when being originated by second stage increases to 0.31mol/L, declines later (preferably
Ground drops to 0.24mol/L).
In another preference of the present invention, the pH preset values are 7.0-7.05.
In another preference of the present invention, in the second stage of the method, glucose that each time point is added and
The amount of the entire carbon atom of normal propyl alcohol is equal to glucose and normal propyl alcohol in corresponding (or identical) the time point zymotic fluids of following fermentation process a
Entire carbon atom amount：
Glucose is added when zymotic fluid pH value is higher than 6.9, average glucose adds rate 0.170gL-1h-1；Simultaneously
Normal propyl alcohol is added, average normal propyl alcohol adds rate 0.058gL-1h-1To fermentation ends.
In another preference of the present invention, in the method, normal propyl alcohol adds rate=(fermentation process a glucose benefit
Rate of acceleration × 6+ fermentation process a normal propyl alcohols add rate × 3)-glucose fed rate × 6] ÷ 3.
In another preference of the present invention, the temperature of fermentation is at 34 ± 1 DEG C.
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 includes：35 ± 5g/L of starch, 5 ± 1g/L of dextrin,
33 ± 5g/L of soybean cake powder, corn steep liquor 18 ± 2g/L, NaCl2 ± 0.4g/L, CaCO37 ± 1.5g/L, 5 ± 1mL/L of soya-bean oil.
In another preference of the present invention, the initial medium of fermentation further includes：Antifoaming agent.
The other aspects of the present invention are apparent to those skilled in the art due to this disclosure
's.
Description of the drawings
Inoculation-fermentation process of the sugared more born of the same parents bacterium of Fig. 1, red.
Fig. 2, height mend the influence under sugar to abomacetin fermentation.Line intermediate scheme a mends sugared curve (default pH=6.9),
Benefit sugar curve under line intermediate scheme b (default pH=7.3), ● erythromycin resultant curve under line intermediate scheme a, zero line indicate pre-
If the erythromycin resultant curve under pH=7.3.
Fig. 3, in the case where height mends sugar, dissolved oxygen curve compares.
The fed-batch mode of Fig. 4, four designed on the basis of Fig. 2-3 kind entire carbon atom equal principle, it is shown that mend sugar and
The variation of alcohol rate is mended, i.e., controls the ratio of glucose and normal propyl alcohol in different phase.
Fig. 5, according to the process fermentation parameter obtained under 4 technique of pattern 1- patterns.
Fig. 6, the different oxygen uptake rate OUR and respiratory quotient RQ added under pattern.
The whereabouts of Fig. 7, glucose and normal propyl alcohol in metabolism is investigated.
Specific implementation mode
Alcohol is mended based on experience, asking of being theoretically unsound in order to solve to mend sugar in Erythromycin Fermentation Process in the prior art
Topic, the relevance between mutual utilization of the present invention between glucose and normal propyl alcohol is starting point, discloses a kind of sugar alcohol mixing
Feed supplement new method.Compared with traditional supplement art, feed process of the invention pass through control the different fermentations stage benefit sugar rate
It controls the utilization ratio of normal propyl alcohol, while rate is added to normal propyl alcohol according to glucose fed rate and is regulated and controled, it can be very
Thalline is controlled well is in the best physiological status for being suitable for erythromycin synthesis.
The method of the present invention is based on following principle：By regulating and controlling the pH setting values in fermentation process, energy in a certain range
Enough effectively change glucose adds rate, and when glucose fed rate reduces, the utilization rate of normal propyl alcohol can increase.Just
Propyl alcohol is the important sources of erythromycin synthesis precursor, and utilization rate increase then makes yield of erythrocin increase.Based on this, have studied
Change the novel mixing benefit that the regulation and control of pH setting values mend sugared rate and add rate according to glucose fed rate control normal propyl alcohol
Material pattern realizes the raising of abomacetin fermentation level.
The whereabouts of glucose and normal propyl alcohol in metabolism is as shown in fig. 7, glucose can be with synthesis of erythromycin precursor, normal propyl alcohol
It can also synthesis of erythromycin precursor.Glucose metabolism will pass through the metabolic pathways such as EMP, TCA, in these approach so that big portion
Glucose is divided to be discharged in the form of carbon dioxide, there is no good synthesis of erythromycin.And normal propyl alcohol metabolism is closed with erythromycin
At more directly related, normal propyl alcohol can be high by utilization rate that bacterial strain utilizes.Therefore, the present inventor is in line with the enough entire carbon atoms of offer
The charging of amount and raising normal propyl alcohol, the addition of glucose only meet the principle of control pH, and the efficiently production for developing the present invention is red mould
The method of element.
As used herein, " the thalli growth stationary phase " refers to microorganism through growth after a period of time, due to training
Nutriment is few in foster base, can only maintain the needs of thalline basic metabolism and synthesis secondary metabolite, therefore bacterium
The ratio speed of growth of body is substantially zeroed, and cell concentration lies substantially in constant.
As the preferred embodiment of the present invention, the present inventor carries according to the carbon atom summation principle of invariance of glucose and normal propyl alcohol
High normal propyl alcohol adds rate.Under carbon atom summation principle of invariance, glucose averagely adds rate reduction, and normal propyl alcohol is averagely added
Rate improves, and yield of erythrocin is significantly increased.Compared with traditional simple and constant speed benefit alcohol strategy sugared according to pH benefits, this method is filled
Divide the utilization relationship in view of glucose and normal propyl alcohol, ensure that the synthesis of erythromycin product of thalline continuously and healthily.
The method of the present invention takes three stage fermentation methods, the first red more spore genetic engineering bacteriums of sugar of culture, in zymotic fluid
When concentration of glucose is reduced to close to zero, the pH value of zymotic fluid can start to increase, and when zymotic fluid pH value is higher than preset value, start
Second stage adds glucose with control ph.
Later, second stage is carried out, starts normal propyl alcohol while adding glucose and adds program, gone out just according to equation calculation
Propyl alcohol adds rate.Equation is that normal propyl alcohol adds rate=(former technique glucose fed rate × 6+ original technique normal propyl alcohols benefit
Rate of acceleration × 3)-glucose fed rate × 6] ÷ 3, it is mmol L to add rate unit-1h-1。
Later, the phase III is carried out, in the case where lower normal propyl alcohol adds rate, adds glucose control ph default
Value.
Compared with traditional sugar alcohol supplying technics, novel sugar alcohol mixing feed process of the invention has lives in bacterial metabolism
The jump phase mends the feature that sugar rate is low, benefit alcohol rate height is low with sugared rate height, benefit alcohol rate is mended in bacterial metabolism decline phase.The feature
Thalline is set to be in a physiological status for being suitable for synthesis of erythromycin, i.e., bacterial metabolism active period, which reduces, mends sugared stimulation rate positive third
The utilization of alcohol to improve the concentration of the erythromycin precursor from normal propyl alcohol, and improves in bacterial metabolism decline phase and mends sugar speed
Rate slows down the decline of thalline, while reducing and mending alcohol rate, to reducing injury effect of the normal propyl alcohol to thalline.
In the embodiment of the present invention, abomacetin fermentation is carried out using novel feeding strategy, the results showed that novel feed supplement
The glucose fed rate in different fermentations stage may be implemented in method and normal propyl alcohol adds the connected effect of rate.Reduce glucose
The utilization rate of normal propyl alcohol can be significantly improved by adding rate.Using novel sugar alcohol mixing feed process, thalline may be implemented and hold
Continue quick synthesis of erythromycin, it is horizontal that final erythromycin is greatly improved.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part such as J. Pehanorm Brookers etc. is write, Molecular Cloning:A Laboratory guide, the third edition, Science Press, the condition described in 2002, or
According to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Embodiment 1, glucose-normal propyl alcohol (sugar alcohol) mixing feed supplement new method improve abomacetin fermentation level
1, cultural method and parameter detection method
Strain：The red more born of the same parents' genetic engineering bacterium ZL1004 (Saccharopolyapora erythraea ZL1004) of sugar
(genotype permK*-K-K-G+permE*-K+permA*-G).
First class seed pot culture medium：Starch 30g/L, dextrin 40 g/L, bean powder 20g/L, CaCO35g/L, NaCl3g/L,
(NH4)2SO42g/L。
Secondary seed tank culture medium：Starch 30g/L, dextrin 30g/L, bean powder 30g/L, corn steep liquor 10g/L, CaCO35g/L,
Antifoaming agent 10mL/L.
Fermentation medium：Starch 35g/L, dextrin 5g/L, soybean cake powder 33g/L, corn steep liquor 18g/L, NaCl2g/L,
CaCO37g/L, soya-bean oil 5mL/L, antifoaming agent (organic silicon antifoaming agent is purchased from Yixing City Gao Shi Chemical Co., Ltd.s) 56mL/L.
Cultural method
Using three grade fermemtation mode, takes fresh slant strains (1cm × 1cm) and be inoculated into equipped with 50mL culture mediums
In 500mL seed flasks, the lower 34 DEG C of cultures 40h of 220r/min rotating speeds is transferred to 15L seeding tanks, secondary seed incubation later
Maintain 40% or more dissolved oxygen, 34 DEG C of culture 40h.Secondary seed culture solution is moved into 50L fermentation tanks, 34 DEG C of culture 191h, process dimension
Hold 30% or more dissolved oxygen.Main flow such as Fig. 1.
Research (the pattern a- patterns b) of different pH value setting values
Rotating speed and ventilation maintenance dissolved oxygen is gradually increased 30% or more, thalline with dissolved oxygen reduction in fermentation starting 1-34 hour
The ingredient growth and breeding provided by using culture medium.To fermentation ends from 35th hour, take the mode of table 1 set pH and
Feed supplement.
Table 1
Novel sugar alcohol mixing feed process (pattern 1- patterns 4)
Rotating speed and ventilation maintenance dissolved oxygen is gradually increased 30% or more, thalline with dissolved oxygen reduction in fermentation starting 1-34 hour
The ingredient growth and breeding provided by using culture medium.From 35th hour, glucose uses automatic pH feedback mode controls, when
When pH is more than setting value, automatic feedback control adds glucose.Normal propyl alcohol adjusts and once adds rate and add one for every 1 hour
It is secondary, it adds rate and is calculated by equation 1.The equation equal according to sugar alcohol entire carbon atom：
Normal propyl alcohol adds rate=(normal propyl alcohol adds speed under glucose fed rate × 6+ pattern a techniques under pattern a techniques
Rate × 3)-this pattern maintain preset pH needed for glucose fed rate × 6] ÷ 3, add rate unit be mmol L-1h-1(side
Journey 1).
Table 2
After 131h, continues to control glucose fed, make zymotic fluid pH value in the identical setting value with 35-131h；
Rate, which is added, when normal propyl alcohol is less than 0.076gL-1h-1When, it adds rate and maintains 0.076gL-1h-1。
Entire carbon atom calibrates standard really
From 35th hour, calculated according to original process (pattern 1) add the total carbon atom number of glucose and normal propyl alcohol with
The change curve of time such as table 3.
Rate, which is added, when normal propyl alcohol is less than 0.076gL-1h-1When, it adds rate and maintains 0.076gL-1h-1, specific real
Shi Zhong, the normal propyl alcohol that fermentation is calculated after 131 hours add rate and are less than 0.076gL-1h-1, therefore normal propyl alcohol after 131 hours
According to 0.076gL-1h-1Rate is added.In other words, that is, the period for implementing entire carbon atom number equal principle is that fermentation originates
35-131 hours afterwards.
In order to determine entire carbon atom control range, the entire carbon atom molal quantity in per stage can be set according to following table.Control
It has made entire carbon atom amount namely the total amount that sugar alcohol is added is determined, carried out the adjusting of sugar, alcohol ratio on this basis.
Table 3
Note：Residual sugar and residual alcohol do not accumulate largely.
Glucose concentration is 30% (g/g), normal propyl alcohol a concentration of 50% (v/v) during actually adding.
Parameter detection method
Chemical titer：It is measured using conventional sulphuric acid hydrolysis.
Erythromycin Components in zymotic fluid：Using HPLC analytic approach, Waters Xbridge C18 chromatographic columns (4.6mm ×
250mm, 5 μm, Waters Corporation).Mobile phase 0.025mol/L potassium dihydrogen phosphates：Acetonitrile=60:40, flow velocity
1ml/min, 35 DEG C, Detection wavelength 215nm of column temperature, 20 μ l of sample size.
2, experimental result
(1) pattern a and pattern b
Pattern a and pattern b (table 1) is by adjusting pH setting values, when pH setting values are adjusted to 7.30 by 6.90, average grape
Sugar, which adds rate, reduces 42.6%, and final abomacetin fermentation level reduced by only 1%.The benefit sugar rate of pattern a and pattern b and
The figure for mending alcohol rate is shown in Fig. 2.
The above results illustrate, the raised methods of pH are controlled by adding glucose generation organic acid, to final erythromycin
Fermentation level influence is smaller, but change setting pH can cause the large change of glucose fed rate in a certain range.
Glucose and normal propyl alcohol utilize relationship in investigation pattern a and pattern b, as a result such as Fig. 2, illustrate by adjusting pH controls
Process mends sugared rate, but yield does not change significantly.
Fermentation process dissolved oxygen situation is investigated, as a result such as Fig. 3, pulse dissolved oxygen curve proves, in the sugared rate of low benefit (pattern b) thorns
The consumption of normal propyl alcohol is swashed.That is pattern a and pattern b in such a way that benefit alcohol per hour is primary, in this case, it is high to mend sugar simultaneously
Pattern a there is no a dissolved oxygen pulse, and mend the low pattern b of sugar and the pulse curve consistent with alcohol is mended occur, therefore show that low benefits is sugared
Rate coerces thalline and utilizes more normal propyl alcohol.
(2) pattern 1,2,3,4
On the basis of the experimental result of aforementioned " (1) ", the pH by adjusting zymotic fluid is set pattern 1,2,3,4 (table 2)
Value (6.85,6.90,7.05,7.15) continuously decreases the benefit sugar rate of fermentation process.
The glucose fed situation for investigating the fed-batch mode of the four kinds of entire carbon atom equal principles as above designed, such as Fig. 4 A；
The normal propyl alcohol for investigating the fed-batch mode of the four kinds of entire carbon atom equal principles as above designed adds situation, such as Fig. 4 B.
Investigation pattern 1,2,3,4 times process fermentation parameters obtained, wet thallus concentration (PMV) situation such as Fig. 5 A；Erythromycin
Output condition such as Fig. 5 B；Residual glucose situation such as Fig. 5 C；Remain normal propyl alcohol situation such as Fig. 5 D.As a result：Erythromycin is in pattern 3
Maximum production is obtained under part, cell concentration is declined slightly.Substrate glucose and normal propyl alcohol is added also not accumulate largely.Pattern 3
Compared with pattern 1, yield of erythrocin improves 20.8%, and compared with pattern a, yield of erythrocin improves 16.8%.
Further investigate pattern 1,2,3, the oxygen uptake rate OUR and respiratory quotient RQ of 4 times fermentation systems.As a result such as Fig. 6.Show
The physiological metabolism characteristic that pattern fully takes into account thalline newly is added, thalline is made to be in the state of preferably synthesis of erythromycin.I.e.：
Early period, bacterial metabolism intensity was high (OUR high), can be using more normal propyl alcohol, and it is also high to add propyl alcohol under new process at this time, is sending out
Ferment later stage, bacterial metabolism activity taper off (OUR is low), and the sugar added increases, and mending alcohol reduces.Mend at this time sugar increase be because
It mends early period caused by the quick increases of the very few caused pH at this time of sugar.And the later stage improves and mends sugar so that the OUR under new process is obviously high
In former technique, (OUR of pattern a) can make erythromycin continue efficiently to synthesize.
The above results show the yield highest of pattern 3, and pattern 4 instead results in yield due to normal propyl alcohol adding too much
Declined.For pattern 3 compared with pattern 1, glucose, which averagely adds rate, reduces by 28.6%.It is reduced in glucose fed rate
Under the conditions of, improve normal propyl alcohol add rate maintain all fermentation process each moment add glucose and normal propyl alcohol carbon is former
Sub- sum is equal；The result shows that normal propyl alcohol, which averagely adds rate, improves 77.6%.Since under low benefit sugar level, thalline is forced profit
With normal propyl alcohol, so the utilization rate of normal propyl alcohol increases.Normal propyl alcohol utilizes the increase of rate, promotes erythromycin synthesis precursor
It generates.Fig. 7 is the metabolic flux distribution by the calculated 59-83h of macroscopical metabolic fluxes, the results showed that erythromycin synthesizes precursor third
Acyl-CoA and methylmalonyl-CoA are obviously increased, and finally accelerate the rate of erythromycin synthesis.
To sum up, compared with traditional pH of foundation merely mends sugared strategy, the mixed new method of mending of novel sugar alcohol fully takes into account sugar alcohol
Using correlation after the feeding strategy of more rationality that proposes.This method successfully passes through control glucose and normal propyl alcohol
Rate is added, by changing the environment parameter control approach flux of intracellular synthesis of erythromycin, substantially increases erythromycin
Fermentation level.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To be made various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (10)
1. a kind of method carrying out abomacetin fermentation using pH value feedback control method, which is characterized in that the setting pH preset values
6.95-7.1 carrying out three stage fermentations：
First stage：The red more born of the same parents bacterium of sugar of culture are to thalli growth stationary phase, when zymotic fluid pH value is higher than preset value, start the
Two-stage；
Second stage：When zymotic fluid pH value is higher than preset value, organic acid is generated come control ph pre- by adding glucose
If value；Normal propyl alcohol is added simultaneously, the amount of the glucose of addition and the entire carbon atom of normal propyl alcohol is made to meet needed for thalline production；When just
Propyl alcohol adds rate and is less than 0.07-0.08gL-1h-1When, start the phase III；
Phase III：Normal propyl alcohol is maintained to add rate 0.07-0.08gL-1h-1；Adding glucose makes zymotic fluid pH value in preset value.
2. the method as described in claim 1, which is characterized in that in second stage, the glucose of addition and the total carbon of normal propyl alcohol
The amount of atom added carbon atom absolute magnitude to calculate, in 0.25-0.35mol/L with every 12 hours.
3. method as claimed in claim 2, which is characterized in that the amount of the glucose of addition and the entire carbon atom of normal propyl alcohol is with every
Carbon atom absolute magnitude is added within 12 hours to calculate, and 0.26mol/L when being originated by second stage increases to 0.31mol/L, later
Decline.
4. the method as described in claim 1, which is characterized in that the pH preset values are 7.0-7.05.
5. the method as described in claim 1, which is characterized in that in second stage, glucose that each time point is added and just
The amount of the entire carbon atom of propyl alcohol is equal to the entire carbon atom of glucose and normal propyl alcohol in the corresponding time point zymotic fluids of following fermentation process a
Amount：
Glucose is added when zymotic fluid pH value is higher than 6.9, average glucose adds rate 0.170gL-1h-1；It adds just simultaneously
Propyl alcohol, average normal propyl alcohol add rate 0.058gL-1h-1To fermentation ends.
6. method as claimed in claim 5, which is characterized in that normal propyl alcohol adds rate=(fermentation process a glucose fed speed
Rate × 6+ fermentation process a normal propyl alcohols add rate × 3)-using pH value feedback control method carry out abomacetin fermentation method Portugal
Grape sugar adds rate × 6] ÷ 3.
7. the method as described in claim 1, which is characterized in that the temperature of fermentation is at 34 ± 1 DEG C.
8. the method as described in claim 1, which is characterized in that the dissolved oxygen 30 ± 5% of fermentation.
9. the method as described in claim 1, which is characterized in that the initial medium of fermentation includes：35 ± 5g/L of starch, dextrin
5 ± 1g/L, 33 ± 5g/L of soybean cake powder, corn steep liquor 18 ± 2g/L, NaCl 2 ± 0.4g/L, CaCO37 ± 1.5g/L, soya-bean oil 5
±1mL/L。
10. method as claimed in claim 9, which is characterized in that the initial medium of fermentation further includes：Antifoaming agent.
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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) |
-
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) |
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