CN114592020B - Method for producing N-acetylglucosamine by fermentation - Google Patents
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Abstract
The invention discloses a method for producing N-acetylglucosamine by fermentation. The method comprises the steps of feeding glucose in the process of culturing escherichia coli, wherein the initial concentration of the glucose in the feeding process is 0.4-0.8%, the feeding speed is 9.8-10.5 g/L/h, and the percentages are mass-volume ratios; the culture medium used in the culture process comprises: KH (KH) 2 PO 4 6.67g/L, citric acid 3.25g/L, caCl 2 ·H 2 O0.05 g/L, etc.; the fermentation time of the method is more than 40 hours. The invention maintains higher thallus concentration, ensures that the N-acetylglucosamine can be produced to the maximum extent, greatly improves the yield of the N-acetylglucosamine, shortens the fermentation period and has larger influence on thallus growth and the production of byproduct acetic acid.
Description
Technical Field
The invention relates to the field of biological fermentation, in particular to a method for producing N-acetylglucosamine by fermentation, and especially relates to a method for improving N-acetylglucosamine in escherichia coli fermentation.
Background
Glucosamine is widely used in the production of nutritional health products, pharmaceuticals and foods. The united states is the country worldwide where glucosamine is most used, and surveys indicate that 90% of the glucosamine feedstock currently on the united states market comes from china. With the increasing population aging and the increasing health care consciousness of people, the market demand of products is still increasing. At the end of the 90 s of the last century, china has become the largest global glucosamine feedstock producer and exporter. At present, the main method for producing the glucosamine is still a chitin extraction method, but along with the enhancement of environmental awareness, the method is eliminated, more and more manufacturers aim at a microbial fermentation method, and the construction of genetic engineering bacteria fermentation is a relatively advantageous one in the microbial fermentation method, the method is used for producing the N-acetylglucosamine through engineering bacteria fermentation, and then the N-acetylglucosamine is hydrolyzed by hydrochloric acid to obtain the glucosamine (SuareDC, kilikian BV. Active acid accumulation in aerobic growth of recombinant Escherichia coll. Process Biochemistry,2000, 35:1051-1055.) but the genetic engineering bacteria fermentation has more problems, such as longer fermentation period, low fermentation liquid quality brings difficulty to the subsequent separation and extraction, phage pollution and the like in the escherichia coli fermentation process (Qin Zhijie, yue Qiulin, liu Xinli. Engineering bacteria construction, fermentation and application development [ J ]. Brewing, 2018 (6): 6-9.) which lead to the continuous improvement of the N-acetylglucosamine production level in China fermentation, and the aim at reducing the environmental pollution of the product quality, and the improvement of the quality of the fermentation product is not capable of reducing the cost of the environmental pollution.
The prior N-acetylglucosamine fermentation process comprises the following steps: inoculating seeds in a shake flask into a seed culture medium [ the components are as follows: k (K) 2 HPO 4 16g，KH 2 PO 4 14g，MgSO 4 ·7H 2 O 25g，CaCl 2 ·H 2 O 0.015g，(NH 4 ) 2 SO 4 7.5g]Sterilized at 121℃for 20 minutes, 20g/L glucose, 1g/L trace element solution, and kanamycin at a final concentration of 200. Mu.g/mL were added after sterilization. The inoculation amount is 70mL/15L, the culture temperature is 36 ℃,ammonia water is automatically regulated to pH 6.9, dissolved oxygen is 20-30%, and the mixture is cultured in a 25L automatic control fermentation tank for 14-20h to logarithmic phase, and the mixture is inoculated into a fermentation culture medium according to an inoculum size of 5 percent, wherein each liter of the mixture comprises the following components: KH (KH) 2 PO 4 6.7g, 3g of citric acid, 5g of KCl and CaCl 2 0.05g, trace element mother liquor 10mL]After fermentation, the dissolved oxygen is controlled to be more than 20% by adjusting ventilation and tank pressure, the temperature is 37 ℃, and the pH is controlled to be 6.8-7.2 by automatic feeding of ammonia water. Glucose feeding strategy: initial glucose 0.4g/100mL, glucose concentration 70% used in fed-batch, maximum sugar supplement 13g/L per hour, cultivation 72h, N-acetamido glucose yield 110g/L.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a fermentation process for fermenting N-acetylglucosamine by escherichia coli. The yield of N-acetylglucosamine is improved, the specific growth rate of thalli is controlled, the generation of acetic acid byproducts is reduced, the production capacity is improved, and the production cost is reduced by changing the initial glucose control amount and the highest glucose supplementing amount of glucose.
The invention is realized by the following technical scheme:
the invention provides a method for producing N-acetylglucosamine by fermentation, which comprises the steps of feeding glucose in the process of culturing escherichia coli, wherein the initial concentration of the glucose in the feeding process is 0.4-0.8%, the feeding speed is 9.8-10.5 g/L/h, and the percentage is the mass-volume ratio;
the culture medium used in the culture process comprises:
KH 2 PO 4 6.67g/L, citric acid 3.25g/L, caCl 2 ·H 2 O 0.05g/L、MgSO 4 ·7H 2 O 2.5g/L、FeSO 4 ·7H 2 O 5mg/L、ZnSO 4 ·7H 2 O 3.8mg/L、MnSO 4 ·H 2 O 0.33mg/L、CuSO 4 ·5H 2 O0.1 mg/L and CoCl.6H 2 O 0.1mg/L；
The fermentation time of the method is more than 40 hours.
Preferably, the concentration of glucose fed is 70%, said percentage being mass volume.
Preferably, the initial concentration is 0.6% to 0.8%, more preferably, the initial concentration is 0.65%.
Preferably, the feeding speed is 10g/L/h.
In a specific embodiment of the invention, the initial concentration of glucose fed-batch is 0.65%, and the feeding speed is 10g/L/h.
In the fermentation production process, the dissolved oxygen amount may be conventional in the art, preferably 20% or more.
In the fermentation production process, the temperature and pH may be conventional in the art, preferably the temperature is 37℃and the pH is 6.8 to 7.2.
As a preferred embodiment, in the fermentation production process, the dissolved oxygen amount is more than 20%, the temperature is 37 ℃, and the pH is 6.8-7.2.
The invention achieves the technical effects that: on the basis of an optimized culture medium, the primary sugar concentration with a certain concentration is adopted to keep the thalli in a good growth state, and the low sugar flow processing technology is adopted to reduce the inhibition effect of glucose in the later fermentation period, so that the higher thalli concentration is maintained, the capability of maximally producing N-acetylglucosamine is achieved, the yield of the N-acetylglucosamine is greatly improved, the fermentation period is shortened, and the thalli growth and the production of byproduct acetic acid are greatly influenced. The invention improves the fermentation process of N-acetylglucosamine from a new angle, and has innovative, practical and industrial application prospects.
Drawings
FIG. 1 is a schematic diagram showing the effect of different maximum sugar supplements on the bacterial concentration.
FIG. 2 is a graph showing the effect of different maximum sugar supplements on acetic acid content.
FIG. 3 is a graph showing the effect of different maximum amounts of supplemental sugar on N-acetylglucosamine production.
FIG. 4 is a schematic representation of the effect of different initial glucose concentrations on the concentration of bacteria.
FIG. 5 is a schematic representation of the effect of different initial glucose concentrations on acetic acid content.
FIG. 6 is a graph showing the effect of different initial glucose concentrations on N-acetylglucosamine production.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention.
The method for culturing E.coli genetically engineered bacteria species may be a conventional method in the art, and in the examples described below, the strain used in this study is recombinant E.coli-glmS-gna1 (Chen Xin, liu Long, li Jianghua, liu Jie, national institute of technology, chen Jian. Effect of Red homologous recombination knockout nagE and manX on the fermentative production of glucosamine by E.coli. Journal of bioengineering. 2012,28 (3): 305-319). Inoculating the strain into slant culture medium, and culturing at 35deg.C for 24 hr; then inoculating the seed into a primary seed culture medium, culturing the primary seed for 6 hours at 36 ℃ and the rotation speed of a shaking table of 6.8-7.2 and 240rpm, inoculating the secondary seed, and culturing for 7 hours.
Wherein, the slant culture medium contains 10g/L tryptone, 5g/L yeast powder, 10g/L NaCl and 14g/L agar powder, kanamycin is added to make the final concentration of the slant culture medium be 2mg/L, the pH value is 6.8-7.2, and the slant culture medium is sterilized for 15min at 121 ℃ before being used.
Wherein, the primary seed culture medium contains 10g/L tryptone, 5g/L yeast powder and 10g/L NaCl, kanamycin is added, the final concentration is 2mg/L, the pH is 6.8-7.2, and sterilization is carried out for 20min at 121 ℃ before use.
Wherein the secondary seed culture medium contains K 2 HPO 4 16g/L，KH 2 PO 4 14g/L，MgSO 4 ·7H 2 O25g/L，CaCl·2H 2 O 0.015g/L，(NH 4 ) 2 SO 4 7.5g/L was sterilized at 121℃for 20min before use, and after sterilization, 0.1% of a 2% glucose and trace element solution was added, and the final concentration was 200. Mu.g/mL kanamycin.
The microelement solution contains FeSO 4 ·7H 2 O 0.5g/L，ZnSO 4 ·7H 2 O 0.38g/L，MnSO 4 ·H 2 O0.033g/L，CuSO 4 ·5H 2 O 0.01g/L，CoCl·6H 2 O 0.01g/L。
Example 1
Placing the strain subjected to slant culture and seed culture medium culture into a mechanical stirring fermentation tank containing a basic fermentation medium, stirring with stirring paddles containing paddles during fermentation, and supplementing materials until fermentation is completed. Wherein the fermentation tank is BMR-B series mechanical stirring fermentation tank (Shanghai biological engineering equipment Co., ltd.) with volume of 25L. Basic fermentation medium: KH (KH) 2 PO 4 6.67g/L, citric acid 3.25g/L, caCl 2 ·H 2 O 0.05g/L、MgSO 4 ·7H 2 O 2.5g/L、FeSO 4 ·7H 2 O 5mg/L、ZnSO 4 ·7H 2 O 3.8mg/L、MnSO 4 ·H 2 O 0.33mg/L、CuSO 4 ·5H 2 O0.1 mg/L and CoCl.6H 2 O0.1 mg/L. Sterilization was performed at 121 ℃ for 20min before use. And on the premise of consistent fermentation conditions, the initial concentration of glucose is designed to be 0.4% (the mass-volume ratio of glucose to fermentation broth) and 70.0% of glucose solution is fed in, wherein the highest feeding amount of glucose per hour is 7g/L (the mass-volume ratio of fed glucose to fermentation broth).
Example 2
The specific details of this example were the same as in example 1, except that the initial glucose concentration was 0.4% and a 70.0% glucose solution was started to be fed at a maximum glucose feed per hour of 10g/L, based on the same fermentation conditions.
Example 3
The specific details of this example were the same as in example 1, except that the initial glucose concentration was 0.4% and a 70.0% glucose solution was started to be fed at a maximum glucose feed rate of 13g/L per hour under the condition that the fermentation conditions were identical.
Example 4
The specific details of this example were the same as in example 1, except that the initial glucose concentration was 0.4% and a 70.0% glucose solution was started to be fed at a maximum glucose feed rate of 16g/L per hour under the condition that the fermentation conditions were identical.
Example 5
The specific details of this example were the same as in example 1, except that the initial glucose concentration was 0.65% and a 70.0% glucose solution was started to be fed at a maximum glucose feed per hour of 10g/L, based on the same fermentation conditions.
Example 6
The specific details of this example were the same as in example 1, except that the initial glucose concentration was 0.85% and a 70.0% glucose solution was started to be fed at a maximum glucose feed per hour of 10g/L, based on the same fermentation conditions.
Example 7
The specific details of this example were the same as in example 1, except that the initial concentration of glucose was designed to be 1.0% and a 70.0% glucose solution was initially fed at a maximum glucose feed per hour of 10g/L under the same fermentation conditions.
Effect examples
The cell concentrations, glcNAc units, and acetic acid contents of examples 1 to 7 were measured to determine the optimal grape addition amount. The cell growth rate is determined by the cell concentration OD value; the GlcNAc units and acetic acid were determined by HPLC.
The specific test method is as follows:
fermentation unit measurement: high performance liquid chromatography, chromatographic conditions: instrument: agilent1200; chromatographic column: c18 reverse phase chromatography column (250 mm. Times.4.6 mm,5 μm); flow rate: 0.6mL/min; detection wavelength: 195nm; sample injection amount: 20. Mu.L; column temperature: 30 ℃; configuration of mobile phase: 0.5g of sodium heptanesulfonate is weighed, 0.5mL of phosphoric acid and 56g/L of KOH 4mL are added, distilled water is diluted to 1000mL, 50mL of acetonitrile is added, and after filtration, microwave ultrasound is carried out for 10min for standby.
Determination of acetic acid: HPLC method, chromatographic conditions: column ZORBAX SB-C18 column (4.6mm. Times.250 mm,5 μm); mobile phase: 0.5% KH 2 PO 4 Aqueous solution (with 85% H) 3 PO 4 To ph 2.7) -hexanenitrile (93: 13 A) is provided; the flow rate is 0.8ml/min; column temperature 45 ℃; the detection wavelength is 210nm; the sample loading was 2.5. Mu.l. Wherein, high performance liquid chromatographIs a 1200 type high performance liquid chromatograph (Agilent company, usa).
OD measurement: the optical density (i.e., the value of OD 600) of the cell suspension was measured using a spectrophotometer and expressed as the cell concentration of E.coli. The fermentation broth was diluted appropriately with distilled water to ensure an OD600 between 0.2 and 0.8, and read at 660nm with distilled water as a blank.
The test results of examples 1 to 4 are shown in FIGS. 1 to 3 and tables 1 to 3, and the test results of examples 5 to 7 are shown in FIGS. 4 to 6 and tables 4 to 6.
Examples 1-4 describe the effect of different glucose maximum amounts on fermentation. As can be seen from the results of FIGS. 1 to 3 and tables 1 to 3, the sugar supplement amount is less than 10g/L/h, the early growth rate of the cells is slower, the acetic acid content is lower, but the increase of the GlcNAc yield is also slower; when the sugar supplementing amount is too high, the metabolic pathway of thalli is changed, so that acetic acid is accumulated in a large amount, and the growth of thalli and the yield of GlcNAc are affected; when the highest sugar supplementing amount is 10g/L/h, the bacterial growth state is good, the bacterial concentration is high, the content of byproduct acetic acid is low, the yield of GlcNAc is improved to 131g/L, the fermentation period is prolonged to 48h, and the yield in the later period of fermentation is stably increased.
TABLE 1
TABLE 2
TABLE 3 Table 3
Examples 5 to 7 describe the effect of different initial glucose concentrations on fermentation. As can be seen from fig. 4 and table 4, different primary sugar concentrations have a large effect on the growth of the bacterial cells: the higher the primary sugar concentration, the smaller the cell amount; as can be seen from FIGS. 6 and Table 6, when the primary sugar concentration was 0.4% and 0.8%, the final concentration of GlcNAc in the fermentation broth was about 130 g/L; as can be seen from FIG. 5, the initial concentration of the grape has a significant effect on acetic acid accumulation, and the acetic acid content in the fermentation broth reaches 3g/L under the condition of 1.0% of the initial concentration of the sugar, and only 1.6g/L under the condition of 0.65% of the initial concentration of the sugar; when the initial sugar concentration was 0.65%, the concentration of GlcNAc reached 140g/L at the end of 48h fermentation, and the yield was 7% higher than that at other concentrations, so that the initial concentration of glucose was 0.65%.
TABLE 4 Table 4
TABLE 5
TABLE 6
Claims (5)
1. A method for producing N-acetylglucosamine by fermentation comprises feeding glucose in the process of culturing escherichia coli, and is characterized in that the escherichia coli is E.coli-glmS-gna1, the initial concentration of the glucose in the feeding process is 0.65%, and the feeding speed is 9.8 g/L/h-10.5 g/L/h, wherein the mass-volume ratio is given;
the culture medium used in the culture process is as follows:
KH 2 PO 4 6.67g/L, citric acid 3.25g/L, caCl 2 ·H 2 O 0.05 g/L、MgSO 4 ·7H 2 O 2.5 g/L、FeSO 4 ·7H 2 O 5mg/L、ZnSO 4 ·7H 2 O 3.8mg/L、MnSO 4 ·H 2 O 0.33mg/L、CuSO 4 ·5H 2 O0.1 mg/L and CoCl.6H 2 O 0.1mg/L；
The fermentation time of the method is more than 40 hours.
2. The method of claim 1, wherein the concentration of glucose fed is 70%, wherein% is mass volume percent.
3. The method of claim 1, wherein the rate of addition is 10g/L/h.
4. A method according to any one of claims 1 to 3, wherein the dissolved oxygen is 20% or more in the fermentation production process.
5. The method according to claim 4, wherein the temperature is 37 ℃ and the pH is 6.8-7.2 during the fermentation production.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104293724A (en) * | 2014-09-22 | 2015-01-21 | 上海工业生物技术研发中心 | Genetically engineered bacteria for efficiently producing N-acetylglucosamine |
| CN104988196A (en) * | 2015-07-30 | 2015-10-21 | 安徽丰原发酵技术工程研究有限公司 | Fermentation production method for N-acetylglucosamine |
| CN105463041A (en) * | 2015-12-17 | 2016-04-06 | 安徽丰原发酵技术工程研究有限公司 | Preparation method of glucosamine |
| WO2017174039A1 (en) * | 2016-04-05 | 2017-10-12 | 孙镧 | Method for producing n-acetyl-d-glucosamine and/or d-glucosamine salt by means of microbial fermentation |
| CN108103126A (en) * | 2016-11-25 | 2018-06-01 | 北大方正集团有限公司 | A kind of composition for improving Glucosamine fermentation unit yield and its application |
| CN110885870A (en) * | 2019-12-09 | 2020-03-17 | 山东润德生物科技有限公司 | Fermentation production method of N-acetylglucosamine |
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| CN107267576B (en) * | 2016-04-05 | 2020-08-21 | 孙镧 | Method for producing N-acetyl-D-glucosamine and/or D-glucosamine salt by microbial fermentation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104293724A (en) * | 2014-09-22 | 2015-01-21 | 上海工业生物技术研发中心 | Genetically engineered bacteria for efficiently producing N-acetylglucosamine |
| CN104988196A (en) * | 2015-07-30 | 2015-10-21 | 安徽丰原发酵技术工程研究有限公司 | Fermentation production method for N-acetylglucosamine |
| CN105463041A (en) * | 2015-12-17 | 2016-04-06 | 安徽丰原发酵技术工程研究有限公司 | Preparation method of glucosamine |
| WO2017174039A1 (en) * | 2016-04-05 | 2017-10-12 | 孙镧 | Method for producing n-acetyl-d-glucosamine and/or d-glucosamine salt by means of microbial fermentation |
| CN108103126A (en) * | 2016-11-25 | 2018-06-01 | 北大方正集团有限公司 | A kind of composition for improving Glucosamine fermentation unit yield and its application |
| CN110885870A (en) * | 2019-12-09 | 2020-03-17 | 山东润德生物科技有限公司 | Fermentation production method of N-acetylglucosamine |
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