CN102220396A - Simple fermentation method for acarbose - Google Patents
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Abstract
The invention discloses a simple fermentation method for acarbose. The method adopts actinoplanessp or a strain of the same species of the actinoplanessp as a fermentation strain. The method comprises fermentation steps of: (1) shaking flask fermentation, (2) carrying out fermenting in a 100-L fermenter, (3) carrying out fermenting in a 30-m<3> fermenter. According to the simple fermentation method for the acarbose provided by the present invention, a carbon source control strategy for fed-batch fermentation of the acarbose is researched through adopting the actinoplanessp or other strains of the same species of the actinoplanessp, and research results show that a controlled concentration of total sugar in a feeding phase, especially the controlled concentrations of maltose and glucose have remarkable effects on the synthesis of the acarbose. Based on this point, two key parameters of the total sugar and reducing sugar (the maltose and the glucose) are screened as amplification factors, such that an industrial fermentation scale-up of the acarbose from the 100-L fermenter to the 30-m<3> fermenter is realized.
Description
Technical field
The present invention relates to a kind of fermentation process of acarbose, utilize specifically actinoplanes (
Actinoplanessp) study it at 30-m
3The industrialization amplification method of acarbose is produced in the jar top fermentation.
Background technology
Acarbose be by actinoplanes (
Actinoplanessp) the false tetrose material that produces of fermentation, can with alpha-glucosidase generation competitive inhibition (Wehmeier UF, Piepersberg W. Biotechnology and molecular biology of the α-glucosidase inhibitor acarbose[J]. Appl Microbiol Biotechnol, 2004,63:613 – 625).Because acarbose is difficult to be digested in human body, do not find at present that in addition it is toxic to human body, therefore acarbose is widely used in the treatment of type II diabetes, to reach purpose (the Hanefeld M that reduces diabetic subject's postprandial hyperglycemia, Schaper F, Koehler C. Effect of Acarbose on Vascular Disease in Patients with Abnormal Glucose[J]. Tolerance Cardiovasc Drugs Ther, 2008,22:225 – 231).
Acarbose by aminocyclitol, 4-amino-4,6-dideoxy glucose and a part maltose three parts are formed (Gu Juefen, Chen Jing. acarbose biosynthesizing and Study on Fermentation progress [J]. external medical microbiotic fascicle, 2006,27 (3): 122-125; Lee S, Saueribrei B, Niggemann J, Egelkraut E. Biosynthesic studies on the α-glucosidase inhibitor acarbose in Actinoplanes sp:source of the maltose unit[J]. J Antibiot, 1997,50:954 – 961), this shows that the biosynthesizing of acarbose and the katabolism of carbon source material have confidential relation.(Lee JS such as Lee, Hai T, Pape H, Kim TJ, Suh JW. Three trehalose synthetic pathways in the acarbose-producing Actinoplanes sp SN223/29 and evidence for the TreY role in biosynthesis of component C[J]. Appl Microbiol Biotechnol, 2008,80:767 – 778) sets forth in detail biosynthetic gene cluster of relevant acarbose and enzyme group.Form the acarbose of a part, maltose (the Heinz GF that needs dimolecular glucose and a part in theory, Pau1 JK, John MB. Studies on the biosynthesis of antibiotics[J]. Journal of Natural Products, 1986,49 (6): 957-970; Arakawa K, Bowers SG, Michels B, et a1. Biosynthetic studies on the alpha-glucosidase inhibitor acarbose:the chemical synthesis of isotopically labeled 2-epi-5-epi-valiolone analogs[J]. Carbohydr Res, 2003,338 (20): 2075-2082; Stratmann A, Mahmud T, Lee S, et a1. The AcbC protein from Actinoplanes specise is a C7-cyclitol synthase related to 3-dehydroquinate synthases and is involved in the biosynthesis of the α-glucosidase inhibitor acarbose[J]. The Journal of Biological Chemistry, 1999,274 (16): 10889-10896).
The pathways metabolism of microorganism is to finish by the pathways metabolism of many associations is collaborative, and its Metabolic activity can carry out altitude mixture control (Chu Ju according to the variation of external environment, Li Yourong. the modern industry fermentation control is learned [M]. Beijing: Chemical Industry Press, 2002).Therefore, when utilizing microbial fermentation production purpose meta-bolites, the output of product is except the influence that is subjected to the bacterial classification self-characteristic, and the fermentation condition of various complexity also can produce significant effects to the generation of product, such as medium component, temperature, pH, dissolved oxygen etc.Choi and Shin (Choi BT, Shin CS. Reduced Formation of Byproduct Component C in Acarbose Fermentation by Actinoplanes sp CKD485-16[J]. Biotechnol Prog, 2003,19 (6): 1677 – 1682) by the osmotic pressure of control nutrient solution, the acarbose output in the 1500-L fermentor tank reaches 3490 mg/L.Beunink (Beunink J, Schedel M, Steiner U. Osmotically controlled fermentation process for the preparation of acarbose. German patent DE 19637591 (US patent 6130072), 1997) also studied osmotic pressure to the influence of acarbose synthetic, the result shows that the osmotic pressure of 400 mOsm/kg helps the synthetic of acarbose most.Yet, on the fermentation control strategy of acarbose industrially scalable, do not have the content of bibliographical information this respect at present.This laboratory is in carrying out actinomycetic sepn process, separate and obtain the actinoplanes A-5.6(Actinoplanes sp. A-5.6 that acarbose is produced in a strain) (Cheng Xin, slow wave, Wei Saijin, Deng. the separation of the rare actinomycete of one strain producing alpha-glycosidase inhibitor and evaluation [J]. food and fermentation industries, 2008,34 (9): 58-60).
200810038903.3 disclose a kind of preparation method of acarbose, it comprises following step:
(1) the actinoplanes inclined-plane is inoculated in slant medium and carries out slant culture;
(2) selecting the plentiful inclined-plane of growth is inoculated in seed culture medium and carries out seed culture;
(3) fermentor cultivation, stream adds glucose and maltose in fermention medium in culturing process; It is characterized in that: in the step (3) also stream add nitrogenous source, the content of amino nitrogen is less than or equal to 0.15mg/ml in the control substratum, but does not comprise 00.15mg/ml.
Summary of the invention
The object of the present invention is to provide a kind of fermentation process of acarbose, shaking employing carbon source control method on bottle and the 100-L fermentor tank, is amplifying parameters with total reducing sugar and reducing sugar then at first, has realized that successfully acarbose is at industrially scalable (30-m
3Fermentor tank) fermentation is amplified.
The objective of the invention is to be achieved through the following technical solutions:
The easy fermentation process of a kind of acarbose, the employing actinoplanes (
Actinoplanessp) or the bacterial classification of congeneric species be fermented bacterium, the substratum of employing comprises slant medium, seed culture medium and fermention medium, wherein:
Slant medium (g/L): glucose 20; Peptone 5; KCl 0.5; K
2HPO
41.0; MgSO
40.5; Agar 20; PH 7.0-7.2;
Seed culture medium (g/L): W-Gum 10; Glucose 20; Corn steep liquor 20; Soybean cake powder 10; KH
2PO
41.0; MgSO
41.0; CaCO
320; PH 7.0-7.2;
Fermention medium (g/L): W-Gum 30; Glucose 50; Corn steep liquor 10; Soybean cake powder 20; Sodium Glutamate 1.0; FeCl
30.5; K
2HPO
41.0; CaCO
32.0; PH 7.0-7.2;
Fermentation step comprises:
(1) shake flask fermentation
Every cultured fresh inclined-plane washes thalline with 10 ml sterilized waters, makes bacteria suspension.It is in 12% the 250ml triangular flask that the 1ml bacteria suspension is connected to the seed culture medium loading amount, under 28 ℃ of temperature condition, cultivates 48 h with the speed oscillation of 180r/min on shaking table, makes shake-flask seed liquid; By 10% inoculum size cultured shake-flask seed liquid being connected to the fermention medium loading amount is in 12% the 250 ml triangular flasks, cultivates 168 h with the speed oscillation of 180r/min under 28 ℃ of temperature condition;
(2) fermentation on the 100-L jar
Wash 4 thalline on the slant medium with 40 ml sterilized waters, make bacteria suspension, it is in 30% the 1000ml triangular flask that bacteria suspension is connected to the seed culture medium loading amount, cultivates 48 h with the speed oscillation of 180r/min under 28 ℃ of temperature condition on shaking table; With shake-flask seed liquid 3000 ml inoculation value loading amounts is in the fermention medium of 60 L/100-L jars, and culture condition is jar temperature 28 ℃, a tank pressure 0.04-0.05 MPa, by the adjusting of mixing speed and air flow, the dissolved oxygen of fermenting process is controlled at about 30%;
(3) 30-m
3Fermentation on the jar
Wash 4 thalline on the slant medium with 40 ml sterilized waters, make bacteria suspension, it is in 30% the 1000 ml triangular flasks that bacteria suspension is connected to the seed culture medium loading amount, cultivates 48 h with the speed oscillation of 180r/min under 28 ℃ of temperature condition on shaking table, makes first order seed; Primary seed solution 1200 ml are seeded in the seed culture medium that loading amount is 70 L/100-L jars, than under 0.8 v/v/min, mixing speed 300 rpm, cultivate 36 h and make secondary seed in 28 ℃ of jar temperature, tank pressure 0.04-0.05 Mpa, ventilation; It is 650 L/1-m that 70 L secondary seed solution move to loading amount
3In the seed culture medium of jar, than under 0.8 v/v/min, mixing speed 200 rpm, cultivate 30 h and make three grades of seeds in 28 ℃ of jar temperature, tank pressure 0.04-0.05 Mpa, ventilation; At last three grades of seed liquor of 700 L are moved into 30-m
3In the fermention medium on the fermentor tank; During the fermentation, a jar gentle tank pressure is controlled at 28 ℃ and 0.04-0.05 Mpa respectively, and the adjusting by mixing speed and air flow is controlled at dissolved oxygen about 30%, and 168 h finish to ferment.
The simple and easy fermentation process of acarbose of the present invention is at first shaking on bottle and the 100-L fermentor tank, the employing actinoplanes (
Actinoplanessp) or other congeneric species bacterial classifications study the carbon source control strategy that its fed-batch fermentation produces acarbose, the concentration that the result shows total reducing sugar controlling concn, the especially maltose in feed supplement stage and glucose has remarkable influence to acarbose synthetic.Based on this, filter out these two key parameters of total reducing sugar and reducing sugar (maltose and glucose) as magnification factor, realized that successfully the industrial fermentation of acarbose from the 100-L jar to the 30-m3 jar amplifies.
Description of drawings
With embodiment the present invention is described in further detail with reference to the accompanying drawings below.
Fig. 1 is at 30-m
3The typical parameter variation tendency figure of acarbose fermenting process on the jar.
Embodiment
The route of synthesis of acarbose shows that maltose and glucose are the precursor of acarbose, and they directly are attached in the molecular structure of acarbose.Therefore, the proportioning of maltose and glucose has important effect in the building-up process of acarbose.For explore maltose and glucose proportioning to actinoplanes (
Actinoplanessp) fermentation produces the influence of acarbose, as the carbon source of supplemented medium, adopts seven kinds of different proportionings with maltose and glucose, its mass ratio is respectively 1:1,1:0,2:1,3:1,4:1,5:1 and 0:1.In shaking bottle fed-batch fermentation process, each shakes bottle is added above proportioning respectively at the 72nd, 96 and 120 h supplemented medium, makes the total sugar concentration of at every turn adding reach 30 g/L, and concrete experimental result and The results of analysis of variance thereof are as shown in table 1.
The proportioning of maltose and glucose is to the influence of acarbose fermentation in table 1 supplemented medium
A: the mass ratio of maltose and glucose in the supplemented medium.
By table 1 as seen, the proportioning of maltose and glucose has remarkable influence to the biosynthesizing of acarbose.Use separately maltose or glucose as supplemented medium under the situation of carbon source, the ultimate capacity of acarbose only is respectively 1535.63 ± 23.22 mg/L and 1137.14 ± 12.05 mg/L.When the proportioning of maltose in the supplemented medium and glucose was 3:1, it is maximum that the output of acarbose reaches, and is 2111.62 ± 14.38 mg/L.According to above experimental result and analysis, can draw actinoplanes (
Actinoplanessp) when shaking bottle batch fermentation and producing acarbose, the best proportioning of maltose and glucose is 3:1 in the supplemented medium.
The carbon source control strategy in feed supplement stage is to the influence of acarbose fermentation on the fermentor tank
Osmotic pressure has remarkable influence to the biosynthesizing of acarbose, and osmotic pressure can be regulated by the control of nutrient solution mesostroma concentration, the relation between the carbon source controlling concn that therefore is necessary to study fermented liquid is synthesized with acarbose.For the influence of the total reducing sugar controlling concn of investigating the feed supplement stage to the acarbose fermentation, be the feed supplement carbon source with maltose and the glucose of 3:1, on the 100-L jar, respectively the total sugar concentration in the fermented liquid is controlled at 45-50,60-65,75-80 and 95-100 g/L.Table 2 is the fermentation result under these four kinds of total reducing sugar controlling concn.
The control of the total reducing sugar in feed supplement stage is to the influence of acarbose fermentation on the table 2 100-L fermentor tank
A:0 h adds maltose and glucose (mass ratio is 3:1) in addition and makes its addition is 20 g/L fermented liquids;
B: the concentration of reduced sugar that the feed supplement stage of fermenting process is controlled;
C: the osmotic pressure scope of whole fermentation process.
Can be analyzed by table 2 and to draw, the fermented liquid total reducing sugar controlling concn in feed supplement stage has remarkable influence to the output of acarbose.When total sugar concentration was brought up to 75-80 g/L gradually by 45-50 g/L, acarbose output and nutrient solution osmotic pressure are also corresponding progressively to be improved.Be controlled in total sugar concentration under the culture condition of 75-80 g/L, the output maximum of acarbose is 3746.56 ± 53.08 mg/L, and concentration of reduced sugar and the osmotic pressure in the fermenting process remains on 41-47 g/L and 421-479 mOsm/kg respectively at this moment.When total sugar concentration further was increased to 95-100 g/L, biomass and acarbose output sharply descended, and were respectively 29 PMV and 2963.92 ± 47.24 mg/L.
According to above result, when the fermented liquid total sugar concentration in feed supplement stage was controlled at 75-80 g/L, it was synthetic to be beneficial to acarbose most.Because maltose and glucose are the biosynthetic precursor of acarbose, so the concentration of reduced sugar of feed supplement stage fermentation liquid also needs further research.By adjusting the speed of adding of supplemented medium, the concentration of reduced sugar of fermented liquid is controlled at 35-40,40-45,45-50 and 50-55 g/L respectively, and the experimental result of gained is as shown in table 3.
The control of the reducing sugar in feed supplement stage is to the influence of acarbose fermentation on the table 3 100-L fermentor tank
A: the concentration of W-Gum and glucose in the fermention medium;
B: the osmotic pressure scope of whole fermentation process.
As shown in Table 3, when concentration of reduced sugar was controlled at 45-50 g/L, acarbose output maximum reached 3905.10 ± 52.66 mg/L.In addition, the osmotic pressure under this culture condition remains on 415-467 mOsm/kg, this result and document (Choi BT, Shin CS. Reduced Formation of Byproduct Component C in Acarbose Fermentation by
ActinoplanesSp CKD485-16[J]. Biotechnol Prog, 2003,19 (6): 1677 – 1682.[11] Beunink J, Schedel M, Steiner U. Osmotically controlled fermentation process for the preparation of acarbose. German patent DE 19637591 (US patent 6130072), 1997) conclusion of being reported is consistent.
Acarbose is at 30-m
3Industrial fermentation on the jar amplifies
For industrial microorganism, the optimization and the amplification of its fermenting process have important and practical meanings.In concrete fermentation amplification process, the controlling elements that fermentation parameters such as volume oxygen mass transfer coefficient, oxygen uptake rate, oxyty usually amplify as process.
Experimental result (table 2 and table 3) about carbon source control on the 100-L fermentor tank shows, the total sugar concentration of fermented liquid and concentration of reduced sugar have remarkable influence to acarbose synthetic.Therefore, actinoplanes (
Actinoplanessp) from the 100-L jar to 30-m
3In the fermentation amplification process of jar, filter out these two key parameters of total reducing sugar and reducing sugar as magnification factor.According to the result on the 100-L fermentor tank, actinoplanes (
Actinoplanessp) at 30-m
3In the fermenting process on the jar, the total reducing sugar in feed supplement stage and concentration of reduced sugar are controlled at 75-80 g/L and 45-50 g/L respectively.The DO concentration of fermenting process is controlled at about 30%, and pH is controlled at 7.0-7.2.
30-m shown in Figure 1
3Actinoplanes on the jar (
Actinoplanessp) thalli growth of fermenting process and the synthetic variation tendency of product show, the metabolic characteristics of thalline substantially to the 100-L jar on similar.Under this amplification scheme, (168 h) acarbose output reaches 4327 mg/L when putting jar, but also is higher than the acarbose output on the 100-L jar.This amplification process is only chosen total reducing sugar and these two parameters of reducing sugar magnification factor as the acarbose industrial fermentation, therefore is easy to operate implementation procedure control by feed supplement.30-m
3Acarbose output on the fermentor tank is higher than the output that present document is reported, proves that further this strategy is simple and obvious results is amplified strategy.
The final purpose of fermentation engineering is to realize industrial microorganism large-scale industrialization fermentative production.Generally speaking, the research of industrial fermentation process can be divided into this three phases of lab scale, pilot scale and amplification.But, in concrete fermentation amplification process, often exist " scale effect ", promptly along with the expansion of fermentation scale, optimization knot that can't the repeated experiments chamber stage.When just being to amplify, the reason that bioprocess amplifies difficulty can not accomplish simultaneously that geometricsimilarity, hydrokinematics phase Sihe hydrokinetics are similar.Some important factors that production is exerted an influence when lab scale is studied are not observed, and this factor is when exactly becoming key factor when amplifying, the failure that will cause whole process to amplify.Therefore, how efficiently to filter out the responsive magnification factor in the reactor, particularly crucial to the successful realization that fermenting process amplifies.
Claims (4)
1. easy fermentation process of acarbose, adopt actinoplanes (
Actinoplanessp) or the bacterial classification of congeneric species be fermented bacterium, the substratum of employing comprises slant medium, seed culture medium and fermention medium,
Fermentation step comprises:
(1) shake flask fermentation
Every cultured fresh inclined-plane washes thalline with 10 ml sterilized waters, make bacteria suspension, it is in 12% the 250ml triangular flask, under 28 ℃ of temperature condition that the 1ml bacteria suspension is connected to the seed culture medium loading amount, on shaking table, cultivate 48 h, make shake-flask seed liquid with the speed oscillation of 180r/min; By 10% inoculum size cultured shake-flask seed liquid being connected to the fermention medium loading amount is in 12% the 250 ml triangular flasks, cultivates 168 h with the speed oscillation of 180r/min under 28 ℃ of temperature condition;
(2) fermentation on the 100-L jar
Wash 4 thalline on the slant medium with 40 ml sterilized waters, make bacteria suspension, it is in 30% the 1000ml triangular flask that bacteria suspension is connected to the seed culture medium loading amount, cultivates 48 h with the speed oscillation of 180r/min under 28 ℃ of temperature condition on shaking table; With shake-flask seed liquid 3000 ml inoculation value loading amounts is in the fermention medium of 60 L/100-L jars, and culture condition is jar temperature 28 ℃, a tank pressure 0.04-0.05 MPa, by the adjusting of mixing speed and air flow, the dissolved oxygen of fermenting process is controlled at about 30%;
(3) 30-m
3Fermentation on the jar
Wash 4 thalline on the slant medium with 40 ml sterilized waters, make bacteria suspension, it is in 30% the 1000 ml triangular flasks that bacteria suspension is connected to the seed culture medium loading amount, cultivates 48 h with the speed oscillation of 180r/min under 28 ℃ of temperature condition on shaking table, makes first order seed; Primary seed solution 1200 ml are seeded in the seed culture medium that loading amount is 70 L/100-L jars, than under 0.8 v/v/min, mixing speed 300 rpm, cultivate 36 h and make secondary seed in 28 ℃ of jar temperature, tank pressure 0.04-0.05 Mpa, ventilation; It is 650 L/1-m that 70 L secondary seed solution move to loading amount
3In the seed culture medium of jar, than under 0.8 v/v/min, mixing speed 200 rpm, cultivate 30 h and make three grades of seeds in 28 ℃ of jar temperature, tank pressure 0.04-0.05 Mpa, ventilation; At last three grades of seed liquor of 700 L are moved into 30-m
3In the fermention medium on the fermentor tank; During the fermentation, a jar gentle tank pressure is controlled at 28 ℃ and 0.04-0.05 Mpa respectively, and the adjusting by mixing speed and air flow is controlled at dissolved oxygen about 30%, and 168 h finish to ferment.
2. the easy fermentation process of acarbose according to claim 1 is characterized in that, slant medium (g/L): glucose 20; Peptone 5; KCl 0.5; K
2HPO
41.0; MgSO
40.5; Agar 20; PH 7.0-7.2.
3. the easy fermentation process of acarbose according to claim 1 is characterized in that, seed culture medium (g/L): W-Gum 10; Glucose 20; Corn steep liquor 20; Soybean cake powder 10; KH
2PO
41.0; MgSO
41.0; CaCO
320; PH 7.0-7.2.
4. the easy fermentation process of acarbose according to claim 1 is characterized in that, fermention medium (g/L): W-Gum 30; Glucose 50; Corn steep liquor 10; Soybean cake powder 20; Sodium Glutamate 1.0; FeCl
30.5; K
2HPO
41.0; CaCO
32.0; PH 7.0-7.2.
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Cited By (5)
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|---|---|---|---|---|
| CN102978261A (en) * | 2012-08-24 | 2013-03-20 | 河北华荣制药有限公司 | High malt syrup and method for improving acarbose fermentation unit by using high malt syrup |
| CN103088089A (en) * | 2013-01-10 | 2013-05-08 | 伊犁川宁生物技术有限公司 | Method for fermenting acarbose |
| CN110541017A (en) * | 2019-10-12 | 2019-12-06 | 山东鲁抗医药股份有限公司 | Method for improving production of acarbose |
| CN112048532A (en) * | 2020-09-18 | 2020-12-08 | 山东鲁抗医药股份有限公司 | Method for producing acarbose by fermentation |
| CN112575046A (en) * | 2020-12-31 | 2021-03-30 | 苏州第四制药厂有限公司 | Acarbose fermentation method for reducing acarbose impurity C yield |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102978261A (en) * | 2012-08-24 | 2013-03-20 | 河北华荣制药有限公司 | High malt syrup and method for improving acarbose fermentation unit by using high malt syrup |
| CN102978261B (en) * | 2012-08-24 | 2019-04-05 | 河北华荣制药有限公司 | A kind of high maltose syrup and the method using its raising acarbose fermentation unit |
| CN103088089A (en) * | 2013-01-10 | 2013-05-08 | 伊犁川宁生物技术有限公司 | Method for fermenting acarbose |
| CN103088089B (en) * | 2013-01-10 | 2014-07-16 | 伊犁川宁生物技术有限公司 | Method for fermenting acarbose |
| CN110541017A (en) * | 2019-10-12 | 2019-12-06 | 山东鲁抗医药股份有限公司 | Method for improving production of acarbose |
| CN110541017B (en) * | 2019-10-12 | 2021-04-06 | 山东鲁抗医药股份有限公司 | Method for improving production of acarbose |
| CN112048532A (en) * | 2020-09-18 | 2020-12-08 | 山东鲁抗医药股份有限公司 | Method for producing acarbose by fermentation |
| CN112048532B (en) * | 2020-09-18 | 2022-07-15 | 山东鲁抗医药股份有限公司 | Method for producing acarbose by fermentation |
| CN112575046A (en) * | 2020-12-31 | 2021-03-30 | 苏州第四制药厂有限公司 | Acarbose fermentation method for reducing acarbose impurity C yield |
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| Publication number | Publication date |
|---|---|
| CN102220396B (en) | 2013-07-24 |
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