CN107723324A - A kind of method of microbial fermentation production cytidine - Google Patents
A kind of method of microbial fermentation production cytidine Download PDFInfo
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- CN107723324A CN107723324A CN201711213776.1A CN201711213776A CN107723324A CN 107723324 A CN107723324 A CN 107723324A CN 201711213776 A CN201711213776 A CN 201711213776A CN 107723324 A CN107723324 A CN 107723324A
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- fermentation
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- cytidine
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/26—Preparation of nitrogen-containing carbohydrates
- C12P19/28—N-glycosides
- C12P19/38—Nucleosides
- C12P19/385—Pyrimidine nucleosides
Abstract
The invention discloses a kind of method of microbial fermentation production cytidine, belong to Optimization of fermentation process field.By microorganism in fermentation tank growth metabolism by culture medium raw material（Predominantly glucose）It is converted into the fermentation production technology of cytidine.By using the culture medium prescription method of optimization in fermentation process, optimal course control method for use formula, reach the optimal product accumulation state of microorganism.Fermentation manufacturing technique provided by the present invention is relative to traditional RNA chemical hydrolysis process is simple, high yield, high income, no waste water,waste gas and industrial residue pollution.
Description
Technical field
A kind of method of microbial fermentation production cytidine, belongs to Optimization of fermentation process field.
Background technology
Cytidine（Hereinafter referred to as cytidine）It is the result part of RNA in human body and animal and plant body, in organism
Important adjustment effect is played in interior physiological and biochemical procedure, there is multi-method face physiologically active；Meanwhile cytidine is many disease-resistant again
The malicious antitumor and irreplaceable raw material of anti-AIDS drug.With going deep into for this kind of drug development, the demand meeting of cytidine
It is increasing.Cytidine derivatives can improve after head injury or after cerebral surgery operation the disturbance of consciousness state of consciousness and electroencephalogram,
Soft phosphatide biosynthesis and anti-phospholipase A is promoted to act on.Share, can protect and repairing pancreas group with protein breakdown enzyme inhibitor
Knit.
The traditional mode of production of cytidine is mainly RNA chemical hydrolysis at present, prepares two kinds of pyrimidine nucleosides, this not only needs largely
High quality rna material, and all necessary co-ordination of supply and marketing of two kinds of purine nucleosides and two kinds of pyrimidine nucleosides, otherwise cost is very high, and by-product
Thing is more, and separation process is complicated, and yield is low.
The content of the invention
It is an object of the invention to provide a kind of technique that cytidine is produced using microbial fermentation, this method can be by proferment
Material（Predominantly glucose）Cytidine efficiently is converted into, there is higher conversion ratio relative to current fermentation technique, it is relatively low
Cost and environment friendly and pollution-free.
According to experimental result, it can be deduced that during microbial fermentation produces cytidine, different nutritional ingredient methods of completing the square,
Different Engineering Control techniques, have a great influence to ultimate output.For the maximum amount of raising raw material and the utilization rate of equipment, shorten hair
The time required to ferment, increase the yield of cytidine, the present invention proposes a kind of high yield tech method stable through overtesting, makes microorganism
In the nutrient formulation method of more conducively product accumulation, dissolved oxygen, fermented under temperature conditionss.Concrete operation method is as follows.
Technical side's bill of the present invention：Microorganism fungus kind is seeded to Shaking culture by glucose pipe and activated, and then moves to
Seed tank culture expands, and seed tank culture terminates to move to fermentation tank, control fermentation tank parameters to fermentation ends.Specific steps
It is as follows：
Step 1：Shake flask medium method of completing the square：Yeast extract 5g/L, the g/L of peptone 10, the g/L of sodium chloride 10, configuration
200mL sterilizes in 1000mL conical flasks in high pressure steam sterilization cabinet, 121 DEG C, 0.1MPa sterilizing 20min, is cooled to room temperature
Afterwards, glucose pipe strain, shaking table culture 10h, shaking speed 250rpm, 36 DEG C of temperature are inoculated with；
Step 2：Seed tank culture base is：Yeast extract 6g/L, the g/L of peptone 12, the g/L of sodium chloride 10, defoamer 0.1
G/L, configuration 15L 121 DEG C of high temperature and high pressure steam sterilizing pressurize 0.1MPa, insulation maintenance 15min, are cooled in 50L fermentation tanks
36℃；Shaking culture terminates the seeding tank that rear nutrient solution is moved to after sterilizing cooling, inoculum concentration 200ml, accounts for seeding tank feed liquid body
Product 1.33%, regulation seeding tank rotating speed 250rpm, ventilation ratio 3vvm, 36 DEG C, pressure 0.06MPa of temperature, incubation time after inoculation
8h；
Step 3：Fermentation tank culture medium method of completing the square is：The g/L of yeast extract 12, the g/L of glucose 50, the g/L of ammonium sulfate 10, phosphorus
The g/L of acid dihydride potassium 4, the g/L of magnesium sulfate 2, the g/L of sodium chloride 2, the g/L of calcium chloride 0.2, the g/L of zinc chloride 0.02, manganese sulfate
0.0002 g/L, the g/L of ferrous sulfate 6, in 50L fermentation tanks, high temperature and high pressure steam sterilizes by the g/L of defoamer 0.6, configuration 20L
121 DEG C of pressurize 0.1MPa, insulation maintenance 15min, are cooled to 36 DEG C；
Step 4：Seed tank culture terminates in the fermentation tank after rear culture transferring to the cooling that sterilizes, and fermentation tank culture transferring amount is 5L, accounts for fermentation
The 25% of the initial material liquid volume of tank, fermentation tank rotating speed 250rpm, ventilation ratio 2vvm, 36 DEG C of temperature initial value, pressure are adjusted after culture transferring
0.06MPa, the initial DO values of correction dissolved oxygen level are 100%；
Step 5：Speed of agitator is associated with dissolved oxygen level DO values during fermented and cultured, speed of agitator and dissolved oxygen level DO values
Association is realized by fermentation tank automation control system, when dissolved oxygen level DO values drop to 35% by initial value 100%, speed of agitator
Automatically adjust and maintain DO values 35%, to fermentation ends, it is 36 DEG C that temperature is controlled during fermentation tank culture, until fermentation ends,
When cytidine amount is not further added by zymotic fluid, terminate fermentation.
According to experimental result, using the method can significantly improve the yield of cytidine.Cytidine fermentation work provided by the present invention
Skill is simple, efficient, has important industrial application value, while just have certain guidance to the fermenting and producing of other amino acid etc.
With inspiration meaning.
Specific embodiment party French
Microbiological Culture Collection used in the present invention uses glucose pipe ultralow temperature preservation.Fermentation process is sent out using second order fermentation tank
Ferment.Present invention experiment fermentation tank used is 50L fermentation tanks.
Nutritional ingredient used in 50L tanks of the present invention contained by culture medium and the nutrition contained by industrial production used medium
Composition is identical, so the achievement reached can be easily transformed into commercial scale level very much.
The present invention is in the technique of existing microbial fermentation production cytidine, by improving fermentative medium formula method, carbon
Source nitrogen source vitamin and microelement content ratio is optimal, and optimizing process control reaches the optimal level of production.Experiment shows, ferments
Cheng Butong is cultivated and method of completing the square, different temperatures difference DO controlling party French have a significant impact to ultimate output.In many experiments base
Present invention optimizes fermentative medium formula method on plinth, and propose optimal Engineering Control technique.
As a result 3. show cytidine zymotechnique stable yield proposed by the present invention, feed liquid cytidine average content during fermentation ends
Reach 35g/L.More traditional cytidine production technology, yield significantly improve, and most important extraction purification is simple, environmentally friendly, product
Quality is also more preferable.With reference to specific embodiment, the present invention is described further, but protection scope of the present invention and not only
It is limited to this：
Embodiment 1：Microbiological Culture Collection used in the present invention uses glucose pipe ultralow temperature preservation.Fermentation process uses two level
Ferment tank.Present invention experiment fermentation tank used is 50L fermentation tanks.
Configure the culture of 200mL medicine bottles to be based in 1000mL conical flasks, Shake flask medium method of completing the square：Yeast extract 5g/L,
The g/L of peptone 10, the g/L of sodium chloride 10, high pressure steam sterilization cabinet is interior to sterilize, and 121 DEG C, 0.1MPa sterilizing 20min, is cooled to room
Wen Hou, it is inoculated with glucose pipe strain, shaking table culture 10h, shaking speed 250rpm, 36 DEG C of temperature；
Seed tank culture base 15L is configured in 50L fermentation tanks, seed tank culture base is：Yeast extract 6g/L, peptone 12
G/L, the g/L of sodium chloride 10, the g/L of defoamer 0.1,121 DEG C of high temperature and high pressure steam sterilizing pressurize 0.1MPa, insulation maintenance 15min,
36 DEG C are cooled to, Shaking culture terminates the seeding tank that rear nutrient solution is moved to after sterilizing cooling, inoculum concentration 200ml, accounts for seeding tank
Material liquid volume 1.33%, seeding tank rotating speed 200rpm is adjusted after inoculation, ventilation ratio 3vvm, 36 DEG C, pressure 0.06MPa of temperature, is cultivated
Time 8h；
Fermentation tank culture medium 20L is configured in 50L fermentation tanks, fermentation tank culture medium method of completing the square is：The g/L of yeast extract 12, Portugal
Grape sugar 50 g/L, the g/L of ammonium sulfate 10, the g/L of potassium dihydrogen phosphate 4, the g/L of magnesium sulfate 2, the g/L of sodium chloride 2, the g/ of calcium chloride 0.2
L, the g/L of zinc chloride 0.02, manganese sulfate .0002 g/L, the g/L of ferrous sulfate 6, the g/L of defoamer 0.6, high temperature and high pressure steam sterilizing
121 DEG C of pressurize 0.1MPa, insulation maintenance 15min, are cooled to 36 DEG C；
Seed tank culture terminates in the fermentation tank after rear culture transferring to the cooling that sterilizes, and fermentation tank culture transferring amount is 5L, and it is initial to account for fermentation tank
The 25% of material liquid volume, fermentation tank rotating speed 250rpm, ventilation ratio 2vvm, 36 DEG C of temperature initial value, pressure are adjusted after culture transferring
0.06MPa, the initial DO values of correction dissolved oxygen level are 100%, and speed of agitator is related to dissolved oxygen level DO values during fermented and cultured
Connection, speed of agitator is associated with dissolved oxygen level DO values and realized by fermentation tank automation control system, when dissolved oxygen level DO values are by first
Initial value 100% drops to 35%, and speed of agitator, which automatically adjusts, maintains DO values 35%, and it is 36 DEG C to control temperature, when cytidine amount in zymotic fluid
When not being further added by, terminate fermentation, final zymotic fluid cytidine concentration is 35.9g/L.
Embodiment 2：Configure the culture of 200mL medicine bottles to be based in 1000mL conical flasks, Shake flask medium method of completing the square：Extraction from yeast
Thing 5g/L, the g/L of peptone 10, the g/L of sodium chloride 10, high pressure steam sterilization cabinet is interior to sterilize, 121 DEG C, 0.1MPa sterilizing 20min,
After being cooled to room temperature, glucose pipe strain, shaking table culture 10h, shaking speed 250rpm, 36 DEG C of temperature are inoculated with；
Seed tank culture base 15L is configured in 50L fermentation tanks, seed tank culture base is：Yeast extract 6g/L, peptone 12
121 DEG C of g/L, the g/L of sodium chloride 10, the g/L of defoamer 0.1, high-temp steam sterilizing pressurize 0.1MPa, insulation maintenance 15min, cooling
To 36 DEG C, Shaking culture terminates the seeding tank that rear nutrient solution is moved to after sterilizing cooling, inoculum concentration 200ml, accounts for seeding tank feed liquid
Volume 1.33%, regulation seeding tank rotating speed 200rpm, ventilation ratio 3vvm, 36 DEG C, pressure 0.06MPa of temperature, incubation time after inoculation
8h；
Fermentation tank culture medium 20L is configured in 50L fermentation tanks, fermentation tank culture medium method of completing the square is：The g/L of yeast extract 12, Portugal
Grape sugar 50 g/L, the g/L of ammonium sulfate 10, the g/L of potassium dihydrogen phosphate 4, the g/L of magnesium sulfate 2, the g/L of sodium chloride 2, the g/ of calcium chloride 0.2
L, the g/L of zinc chloride 0.02, manganese sulfate .0002 g/L, the g/L of ferrous sulfate 6, the g/L of defoamer 0.6, high temperature and high pressure steam sterilizing
121 DEG C of pressurize 0.1MPa, insulation maintenance 15min, are cooled to 36 DEG C；
Seed tank culture terminates in the fermentation tank after rear culture transferring to the cooling that sterilizes, and fermentation tank culture transferring amount is 5L, and it is initial to account for fermentation tank
The 25% of material liquid volume, fermentation tank rotating speed 250rpm, ventilation ratio 2vvm, 36 DEG C of temperature initial value, pressure are adjusted after culture transferring
0.06MPa, the initial DO values of correction dissolved oxygen level are 100%, and speed of agitator is related to dissolved oxygen level DO values during fermented and cultured
Connection, speed of agitator is associated with dissolved oxygen level DO values and realized by fermentation tank automation control system, when dissolved oxygen level DO values are by first
Initial value 100% drops to 35%, and speed of agitator, which automatically adjusts, maintains DO values 35%, and it is 36 DEG C to control temperature, when cytidine amount in zymotic fluid
When not being further added by, terminate fermentation, final zymotic fluid cytidine concentration is 35.1g/L.
Embodiment 3：Configure the culture of 200mL medicine bottles to be based in 1000mL conical flasks, Shake flask medium method of completing the square：Extraction from yeast
Thing 5g/L, the g/L of peptone 10, the g/L of sodium chloride 10, high pressure steam sterilization cabinet is interior to sterilize, 121 DEG C, 0.1MPa sterilizing 20min,
After being cooled to room temperature, glucose pipe strain, shaking table culture 10h, shaking speed 250rpm, 36 DEG C of temperature are inoculated with；
Seed tank culture base 15L is configured in 50L fermentation tanks, seed tank culture base is：Yeast extract 6g/L, peptone 12
121 DEG C of g/L, the g/L of sodium chloride 10, the g/L of defoamer 0.1, high-temp steam sterilizing pressurize 0.1MPa, insulation maintenance 15min, cooling
To 36 DEG C, Shaking culture terminates the seeding tank that rear nutrient solution is moved to after sterilizing cooling, inoculum concentration 200ml, accounts for seeding tank feed liquid
Volume 1.33%, regulation seeding tank rotating speed 200rpm, ventilation ratio 3vvm, 36 DEG C, pressure 0.06MPa of temperature, incubation time after inoculation
8h；
Fermentation tank culture medium 20L is configured in 50L fermentation tanks, fermentation tank culture medium method of completing the square is：The g/L of yeast extract 12, Portugal
Grape sugar 50 g/L, the g/L of ammonium sulfate 10, the g/L of potassium dihydrogen phosphate 4, the g/L of magnesium sulfate 2, the g/L of sodium chloride 2, the g/ of calcium chloride 0.2
L, the g/L of zinc chloride 0.02, manganese sulfate .0002 g/L, the g/L of ferrous sulfate 6, the g/L of defoamer 0.6, high temperature and high pressure steam sterilizing
121 DEG C of pressurize 0.1MPa, insulation maintenance 15min, are cooled to 36 DEG C；
Seed tank culture terminates in the fermentation tank after rear culture transferring to the cooling that sterilizes, and fermentation tank culture transferring amount is 5L, and it is initial to account for fermentation tank
The 25% of material liquid volume, fermentation tank rotating speed 250rpm, ventilation ratio 2vvm, 36 DEG C of temperature initial value, pressure are adjusted after culture transferring
0.06MPa, the initial DO values of correction dissolved oxygen level are 100%, and speed of agitator is related to dissolved oxygen level DO values during fermented and cultured
Connection, speed of agitator is associated with dissolved oxygen level DO values and realized by fermentation tank automation control system, when dissolved oxygen level DO values are by first
Initial value 100% drops to 35%, and speed of agitator, which automatically adjusts, maintains DO values 35%, and it is 36 DEG C to control temperature, when cytidine amount in zymotic fluid
When not being further added by, terminate fermentation, final zymotic fluid cytidine concentration is 35.2g/L.
It is described above be only the present invention be preferable to carry out method formula, protection scope of the present invention is not limited merely to above-mentioned reality
Example is applied, all technical side's bills belonged under thinking of the present invention belong to protection scope of the present invention.It should be pointed out that for this technology
For the those of ordinary skill in field, some improvements and modifications without departing from the principles of the present invention, these are improved and profit
Decorations also should be regarded as protection scope of the present invention.
Claims (6)
- A kind of 1. method of microbial fermentation production cytidine, it is characterised in that including following operating procedure：Step 1：Configure 200mL Shaking cultures to be based in 1000mL conical flasks, Shake flask medium method of completing the square：Yeast extract 5g/ L, the g/L of peptone 10, the g/L of sodium chloride 10, high pressure steam sterilization cabinet is interior to sterilize, and 121 DEG C, 0.1MPa sterilizing 20min, is cooled to It is inoculated with after room temperature；Step 2：Seed tank culture base 15L is configured in 50L fermentation tanks, seed tank culture base is：Yeast extract 6g/L, egg 121 DEG C of white peptone 12 g/L, the g/L of sodium chloride 10, the g/L of defoamer 0.1, high-temp steam sterilizing pressurize 0.1MPa, insulation maintenances 15min, 36 DEG C are cooled to, Shaking culture terminates the seeding tank that rear nutrient solution is moved to after sterilizing cooling；Step 3：Configure 20L fermented and cultureds to be based in 50L fermentation tanks, high temperature and high pressure steam sterilizing pressurize 0.1MPa, insulation 121 DEG C maintain 15min, be cooled to 36 DEG C；Step 4：Seed tank culture terminates in the fermentation tank after rear culture transferring to the cooling that sterilizes；Step 5：Speed of agitator is associated with dissolved oxygen level DO values during fermented and cultured, speed of agitator and dissolved oxygen level DO values Association is realized by fermentation tank automation control system.
- 2. the method for microbial fermentation production cytidine as claimed in claim 1, it is characterised in that configuration 200mL shakes Bottle culture is based in 1000mL conical flasks, after disinfection inoculation, shaking table culture 10h, shaking speed 250rpm, and 36 DEG C of temperature.
- 3. the method for microbial fermentation production cytidine as claimed in claim 1, it is characterised in that Shaking culture terminates The seeding tank that nutrient solution is moved to after sterilizing cooling afterwards, shake flask culture 200ml account for seeding tank material liquid volume 1.33%, adjusted after inoculation Save seeding tank rotating speed 200rpm, ventilation ratio 3vvm, 36 DEG C, pressure 0.06MPa, incubation time 8h of temperature.
- 4. the method for microbial fermentation production cytidine as claimed in claim 1, it is characterised in that fermentation tank culture medium Method of completing the square is：The g/L of yeast extract 12, the g/L of glucose 50, the g/L of ammonium sulfate 10, the g/L of potassium dihydrogen phosphate 4, magnesium sulfate 2 G/L, the g/L of sodium chloride 2, the g/L of calcium chloride 0.2, the g/L of zinc chloride 0.02, manganese sulfate .0002 g/L, the g/L of ferrous sulfate 6, disappear The g/L of infusion 0.6.
- 5. the method for microbial fermentation production cytidine as claimed in claim 1, it is characterised in that seeding tank moves to hair Fermentation tank culture transferring amount is 5L, accounts for the 25% of the initial material liquid volume of fermentation tank, fermentation tank rotating speed 250rpm, ventilation ratio are adjusted after culture transferring 2vvm, 36 DEG C, pressure 0.06MPa of temperature initial value, the initial DO values of correction dissolved oxygen level are 100%.
- 6. the method for microbial fermentation production cytidine as claimed in claim 1, it is characterised in that dissolved oxygen level DO values 35% is dropped to by initial value 100%, and speed of agitator, which automatically adjusts, maintains DO values 35%, controls the temperature to be during fermentation tank culture 36 DEG C, until fermentation ends.
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| JPS4840758B1 (en) * | 1969-03-24 | 1973-12-03 | ||
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| JPH04152891A (en) * | 1990-10-17 | 1992-05-26 | Asahi Chem Ind Co Ltd | Production of cytidine by fermentation and gene used in the same production |
| CN105505844A (en) * | 2014-09-24 | 2016-04-20 | 中国科学院天津工业生物技术研究所 | High-throughput screening method of microorganism strain producing cytidine at high yield |
| CN105671007A (en) * | 2015-12-31 | 2016-06-15 | 天津科技大学 | Pyrimidine nucleoside high-yielding strain and carbamyl phosphate synthetase adjusting site thereof |
| CN106754602A (en) * | 2017-01-04 | 2017-05-31 | 苏州华赛生物工程技术有限公司 | A kind of method of the recombinant microorganism for producing cytidine and production cytidine |
-
2017
- 2017-11-28 CN CN201711213776.1A patent/CN107723324A/en active Pending
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|---|---|---|---|---|
| JPS4840758B1 (en) * | 1969-03-24 | 1973-12-03 | ||
| JPS5718871B2 (en) * | 1976-04-27 | 1982-04-19 | ||
| JPH04152891A (en) * | 1990-10-17 | 1992-05-26 | Asahi Chem Ind Co Ltd | Production of cytidine by fermentation and gene used in the same production |
| CN105505844A (en) * | 2014-09-24 | 2016-04-20 | 中国科学院天津工业生物技术研究所 | High-throughput screening method of microorganism strain producing cytidine at high yield |
| CN105671007A (en) * | 2015-12-31 | 2016-06-15 | 天津科技大学 | Pyrimidine nucleoside high-yielding strain and carbamyl phosphate synthetase adjusting site thereof |
| CN106754602A (en) * | 2017-01-04 | 2017-05-31 | 苏州华赛生物工程技术有限公司 | A kind of method of the recombinant microorganism for producing cytidine and production cytidine |
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