CN1869244A - Production method of 15N stability isotop labeling L-arginine - Google Patents
Production method of 15N stability isotop labeling L-arginine Download PDFInfo
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- CN1869244A CN1869244A CN 200510026243 CN200510026243A CN1869244A CN 1869244 A CN1869244 A CN 1869244A CN 200510026243 CN200510026243 CN 200510026243 CN 200510026243 A CN200510026243 A CN 200510026243A CN 1869244 A CN1869244 A CN 1869244A
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Abstract
The invention relates to a manufacture method for 15N stability isotope mark L-arginine. It uses low sugar flow and fermenting technology to produce L-arginine-15N4, controlling corn steep liquor organic nitrogen source addition level, adding 15N high abundance thallus digest taking the place of corn steep liquor, and directly adding biotin, vitamin B1, vitamin B6, pantothenic acid, nicotinic acid and vitamin compound to improve acid ratio through improving the fermenting compositions. Comparing with the existing technology, the invention solves the decreasing problem of 15N abundance and improves the use factor of 15N.
Description
Technical field
The present invention relates to stable isotope tagged compound production field, relate in particular to and adopt microbial fermentation and biological extraction production
15The method of N stable isotope labeling L-arginine.
Background technology
To the arginic production of L-, there are some research groups that it has been done many research work (microorganism journal, 28 (2): 131~135 (1988) both at home and abroad; 28 (3): 257~264 (1988); 31 (6): 460~465 (1991); Wuxi Light Industry Univ.'s journal, 22 (2): 10~13 (2003); Agri.Biol.Chem., 45 (4): 959~963 (1981); Journal of Bacteriology., 91 (2) 617~621 (1996); European Patent 0~378 223 A1; United States Patent 5,034,319 etc.).But, study about biological synthesis process
15Also lose patent and bibliographical information in the production field of N stable isotope labeling L-arginine.The employing direct fermentation is produced, a large amount of enrichments of target amino acid,
15The easy mark of N stable isotope, but since in the fermentating formula organic nitrogen source be difficult to mark, usually make the L-arginine-
15N
4Abundance descend a lot, do not reach product requirement, so need improve to conventional fermentating formula.
Summary of the invention
The present invention adopt Production by Microorganism Fermentation L-arginine-
15N
4, purpose is to solve
15The problem that the N abundance descends, and improve as far as possible
15The N utilization ratio is to satisfy the products production requirement.
Purpose of the present invention can be achieved through the following technical solutions: a kind of
15The production method of N stable isotope labeling L-arginine is characterized in that, this method utilize the low-glucose addition zymotechnique produce the L-arginine-
15N
4, control corn steep liquor organic nitrogen source addition adds
15Organic nitrogen sources such as N high abundance thalline hydrolyzed solution part instead of corn slurry, directly interpolation comprises vitamin H, vitamins B
1, vitamins B
6, pantothenic acid, nicotinic acid and para-aminobenzoic acid the VITAMIN mixture, improve acid production rate by improving fermentating formula.
This method comprises following processing step:
(1) is suitable for bacterial classification
The bacterial classification that is applicable to L-arginine fermentative production comprises the mutant strain of excellent bacillus, brevibacterium sp;
(2) seed and fermention medium
With the full-synthetic culture medium is minimum medium, adds a small amount of organic nitrogen source, and seed culture medium is mainly filled a prescription as shown in the table:
Explanation | |
The inorganic nitrogen-sourced organic nitrogen source K of carbon source 2HPO 4.3H 2O KH 2PO 4.H 2O MgSO 4.7H 2O urea vitamin H vitamins B 1Vitamins B 6Pantothenic acid nicotinic acid para-aminobenzoic acid | Glucose, 10~50g/L ammonium chloride, 0~15g/L or ammonium sulfate, 0~15g/L corn steep liquor, 0~10mL/L, 1~4g/L, 0.5~3g/L, 0.2~0.8g/L, 1~6g/L, 10~50 μ g/L, 50~500 μ g/L, 50~500 μ g/L, 50~500 μ g/L, 50~500 μ g/L, 50~500 μ g/L |
Fermention medium is minimum medium with the full-synthetic culture medium, and high rich thalline hydrolyzed solution partly substitutes corn steep liquor, directly adds somatomedin.Main prescription is as shown in the table:
Explanation | |
The high rich thalline hydrolyzed solution K of the inorganic nitrogen-sourced corn steep liquor of carbon source 2HPO 4.3H 2O | Glucose, 60~140g/L ammonium chloride, 30~50g/L or ammonium sulfate 40~80g/L 0~5mL/L 0~20mL/L 1~4g/L |
KH 2PO 4.H 2O MgSO 4.7H 2The O vitamins B 1Vitamins B 6Pantothenic acid nicotinic acid para-aminobenzoic acid CaCO 3 | 0.5~3g/L 0.2~0.8g/L 50~500 μ g/L 50~500 μ g/L 50~500 μ g/L 50~500 μ g/L 50~300 μ g/L 20~60g/L, branch disappears |
(3) zymotechnique
Be inoculated in the sterilized seed that above-mentioned seed culture medium is housed after the activated inclined plane lawn washed with a small amount of substratum and shake bottle and begin to cultivate, culture condition is: 30~37 ℃ of leavening temperatures, initial pH6.4~6.8, shaking speed 180~220r/min; Seed culture was inoculated in the fermentation shake flask or fermentor tank that above-mentioned fermention medium is housed by 5~10% inoculum sizes after 18~24 hours, shaker fermentation control condition is: 30~37 ℃ of leavening temperatures, initial pH6.4~6.8, patrolling shaking speed 180~220r/min, fermented about 24 hours and improve rotating speed to 220~240r/min, fermented about 48 hours and improve rotating speed to 240~280r/min, fermentation time 72~96 hours; Fermentor tank control condition is: 30~37 ℃ of fermentation initial temperatures, and initial pH6.4~6.8, air flow 0.5~1.5VVM, tank pressure 0.02~0.05Mpa, dissolved oxygen 0.5~90% saturation ratio is by polyethers or silicone defoamer froth breaking; After 18~32 hours middle and later periods of fermentation, improve rotating speed and air flow and guarantee that dissolved oxygen is in 20~50% saturation ratios; Fermentation Whole Process Control pH adds in subacidity
15N labeled urea, ammoniacal liquor or liquefied ammonia are regulated pH6.4~7.0, and stream adds 50% glucose control fermented liquid glucose concn, 10~50g/L, fermentation time 60~72 hours;
(4) separation and Extraction
In the fermented liquid
15The separation of N stable isotope labeling L-arginine is adopted ion exchange method branch to extract and is obtained
15N stable isotope labeling L-arginine solution is caught up with ammonia and is adopted ethanol low temperature crystallization, vacuum-drying to obtain product by vacuum concentration; Adopt special-purpose mass spectrograph of isotropic substance or analysis of spectral method
15The N abundance, purity check adopts ordinary method.
The mutant strain of described brevibacterium sp comprises brevibacterium flavum, and this brevibacterium flavum is meant brevibacterium flavum (Brevobacterium flavum) ATCC14067 mutant strain.
The mutant strain of described Corynebacterium comprises Corynebacterium glutamicum, and this Corynebacterium glutamicum is meant Corynebacterium glutamicum (Corynebacterium glutamicum) ATCC13032, ATCC21831, ATCC21493 or ATCC21659.
The mutant strain of described Corynebacterium comprises Corynebacterium crenatum, and this Corynebacterium crenatum is meant Corynebacterium crenatum (Corynebacterium crenatum) AS1.542 mutant strain, CGMCC preservation bacterial classification.
The present invention utilize the low-glucose addition zymotechnique produce the L-arginine-
15N
4, control corn steep liquor organic nitrogen source addition adds
15Organic nitrogen sources such as N high abundance thalline hydrolyzed solution part instead of corn slurry directly add vitamin H, vitamins B
1, vitamins B
6, VITAMIN mixture such as pantothenic acid, nicotinic acid, para-aminobenzoic acid, improve acid production rate by improving fermentating formula.Can make like this
15The N raw material is utilized effectively, and abundance descends to being unlikely influences the products production requirement.
If adopt conventional fermentation process,
15Though N stable isotope labeling L-arginine output is higher relatively,
15The N abundance descends very big, often descends more than 3%, is difficult to reach the high abundance product requirement.Though adopt the full-synthetic culture medium fermentation right
15The influence of N abundance is little, and the acid amount is too low to make but produce
15The N raw material availability is not high.By changing fermentating formula and technology, add
15Organic nitrogen sources such as N high abundance thalline hydrolyzed solution part instead of corn slurry directly add vitamin H, vitamins B
1, vitamins B
6, VITAMIN mixtures such as pantothenic acid, nicotinic acid, para-aminobenzoic acid, the present invention obtains
15N stable isotope labeling L-arginine rate ratio adopts the corresponding raising of full-synthetic culture medium fermentation and acid amount more than 30~90%, and
15N stable isotope labeling L-arginine
15The N abundance descends and can reduce to below 1%, have in addition descend hardly, improved greatly
15The N raw material availability has reduced production cost.Simultaneously, guaranteeing product
15Under the N abundance condition, simplify fermentation and extraction process, because raw material is fully used and has been saved the raw material cost recovery greatly.The present invention can utilize low abundance and high abundance
15The N inorganic raw material satisfies the requirement of different abundance products production.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1
Use bacterial classification for brevibacterium flavum ATCC14067 being the mutant strain TSF11 (Arghx that the bacterium mutagenic and breeding obtains that sets out
r+ D-arg
r+ His
-), the substratum of use comprises slant preservation substratum, slant activation substratum, shake-flask seed and shake flask fermentation substratum.The slant preservation substratum adopts identical with the slant activation substratum with conventional fermentation.
The seed initial formulation of using is as shown in the table:
Explanation | |
Glucose corn steep liquor high abundance Phe thalline hydrolyzed solution K 2HPO 4.3H 2O KH 2PO 4.H 2O MgSO 4.7H 2O urea vitamin H vitamins B 1Vitamins B 6Pantothenic acid nicotinic acid para-aminobenzoic acid | 30g/L 5mL/L 10mL/L 1g/L 1g/L 0.4g/L 2.5g/L, 15N abundance 99.60% 25 μ g/L 200 μ g/L 200 μ g/L 400 μ g/L 400 μ g/L 100 μ g/L |
The fermentation initial formulation of using is as shown in the table:
Explanation | |
Glucosamine sulphate ammonium corn steep liquor high abundance Phe thalline hydrolyzed solution K 2HPO 4.3H 2O KH 2PO 4.H 2O MgSO 4.7H 2The O vitamins B 1 | 120g/L 50g/L, 15N abundance 99.60% 2mL/L 10mL/L 1g/L 1g/L 0.4g/L 200 μ g/L |
Vitamins B 6Pantothenic acid nicotinic acid para-aminobenzoic acid CaCO 3 | 200 μ g/L, 400 μ g/L, 400 μ g/L, 100 μ g/L 40g/L, branch disappears |
Brevibacterium flavum TSF11 is inoculated in activated inclined plane from the preservation inclined-plane, cultivated 24 hours in 31 ℃ of constant incubators, with transfering loop scrape one completely encircle lawn to seed shake the bottle (250mL loading amount a 20mL, connect 2 bottles altogether), 31 ℃, 200rpm were cultivated 20 hours on the patrolling shaking table, get above-mentioned cultured seed liquid and change (500mL loading amount 10mL connects 30 bottles altogether) in the above-mentioned fermentation shake flask over to, add then and divide the CaCO that disappears by 10% inoculum size
3, 31 ℃, 200rpm adjusting rotating speed 220rpm when the top fermentation of patrolling shaking table is cultivated about 24 hours regulate rotating speed 240rpm and end up to fermentation in the time of about 48 hours, and fermentation adds since 24 hours stream
15The N labeled urea began stream in 48 hours and adds glucose, and fermentation culture finished in 72 hours, fermentation is average produce the L-arginine-
15N
4Can reach 16g/L.Fermented liquid adopts 732 Zeo-karb individual plants to separate, adopt ordinary method obtain drying solid L-arginine-
15N
4Product obtains product abundance 98.88% through mass spectroscopy, and abundance descends 0.723%.
If change corn steep liquor in the fermention medium into 0.6, zymotechnique is constant, the average product of fermentation L-arginine-
15N
4Can reach 22g/L, but abundance has only 96.30%, abundance descends 3.31%.If do not add corn steep liquor in the fermention medium, the average product of fermentation L-arginine-
15N
4Have only 8g/L, abundance 99.48%, abundance descends 0.12%.If do not add pantothenic acid, nicotinic acid, vitamins B in the above-mentioned fermention medium
6, vitamins B
1, VITAMIN mixtures such as vitamin H and para-aminobenzoic acid, fermentation is average produce the L-arginine-
15N
4Has only 12g/L.Take all factors into consideration, this invention effect is remarkable.
Embodiment 2
Use bacterial classification for Corynebacterium glutamicum ATCC13032 being the mutant strain CHA156 (Arghx that the bacterium mutagenic and breeding obtains that sets out
r+ D-arg
r+ SG
r), the substratum of use comprises slant preservation substratum, slant activation substratum, shake-flask seed and shake flask fermentation substratum.The slant preservation substratum adopts identical with the slant activation substratum with conventional fermentation.
The seed culture medium that uses is with embodiment 1.The fermentation initial formulation of using changes ammonium sulfate in embodiment 1 fermentating formula into ammonium chloride, and other is constant, and the nitrogenous source abundance that adopts is 5.31%.Zymotechnique is with embodiment 1, fermentation is average produce the L-arginine-
15N
4Can reach 17g/L.
Fermented liquid adopts 732 Zeo-karb individual plants to separate, adopt ordinary method obtain drying solid L-arginine-
15N
4Product obtains product abundance 5.27% through mass spectroscopy, and abundance descends 0.753%.
Claims (5)
1. one kind
15The production method of N stable isotope labeling L-arginine is characterized in that, this method utilize the low-glucose addition zymotechnique produce the L-arginine-
15N
4, control corn steep liquor organic nitrogen source addition adds
15N high abundance thalline hydrolyzed solution part instead of corn slurry, directly interpolation comprises vitamin H, vitamins B
1, vitamins B
6, pantothenic acid, nicotinic acid and para-aminobenzoic acid the VITAMIN mixture, improve acid production rate by improving fermentating formula.
2. according to claim 1 a kind of
15The production method of N stable isotope labeling L-arginine is characterized in that, this method comprises following processing step:
(1) is suitable for bacterial classification
The bacterial classification that is applicable to L-arginine fermentative production comprises the mutant strain of excellent bacillus, brevibacterium sp;
(2) seed and fermention medium
With the full-synthetic culture medium is minimum medium, adds a small amount of organic nitrogen source, and seed culture medium is mainly filled a prescription as shown in the table:
Explanation
The inorganic nitrogen-sourced organic nitrogen source K of carbon source
2HPO
4.3H
2O KH
2PO
4.H
2O MgSO
4.7H
2O urea vitamin H vitamins B
1Vitamins B
6Pantothenic acid nicotinic acid para-aminobenzoic acid
Glucose; 10~50g/L ammonium chloride; 0~15g/L or ammonium sulfate; 0~15g/L corn steep liquor, 0~10mL/L, 1~4g/L, 0.5~3g/L, 0.2~0.8g/L, 1~6g/L, 10~50 μ g/L, 50~500 μ g/L, 50~500 μ g/L, 50~500 μ g/L, 50~500 μ g/L, 50~500 μ g/L
Fermention medium is minimum medium with the full-synthetic culture medium, and high rich thalline hydrolyzed solution partly substitutes corn steep liquor, directly adds somatomedin.Main prescription is as shown in the table:
Explanation
The high rich thalline hydrolyzed solution K of the inorganic nitrogen-sourced corn steep liquor of carbon source
2HPO
4.3H
2O KH
2PO
4.H
2O MgSO
4.7H
2The O vitamins B
1Vitamins B
6Pantothenic acid nicotinic acid para-aminobenzoic acid CaCO
3 Glucose; 60~140g/L ammonium chloride; 30~50g/L or ammonium sulfate 40~80g/L 0~5mL/L 0~20mL/L 1~4g/L 0.5~3g/L 0.2~0.8g/L 50~500 μ g/L 50~500 μ g/L 50~500 μ g/L 50~500 μ g/L 50~300 μ g/L 20~60g/L, branch disappears
(3) zymotechnique
Be inoculated in the sterilized seed that above-mentioned seed culture medium is housed after the activated inclined plane lawn washed with a small amount of substratum and shake bottle and begin to cultivate, culture condition is: 30~37 ℃ of leavening temperatures, initial pH6.4~6.8, shaking speed 180~220r/min; Seed culture was inoculated in the fermentation shake flask or fermentor tank that above-mentioned fermention medium is housed by 5~10% inoculum sizes after 18~24 hours, shaker fermentation control condition is: 30~37 ℃ of leavening temperatures, initial pH6.4~6.8, patrolling shaking speed 180~220r/min, fermented about 24 hours and improve rotating speed to 220~240r/min, fermented about 48 hours and improve rotating speed to 240~280r/min, fermentation time 72~96 hours; Fermentor tank control condition is: 30~37 ℃ of fermentation initial temperatures, and initial pH6.4~6.8, air flow 0.5~1.5VVM, tank pressure 0.02~0.05Mpa, dissolved oxygen 0.5~90% saturation ratio is by polyethers or silicone defoamer froth breaking; After 18~32 hours middle and later periods of fermentation, improve rotating speed and air flow and guarantee that dissolved oxygen is in 20~50% saturation ratios; Fermentation Whole Process Control pH adds in subacidity
15N labeled urea, ammoniacal liquor or liquefied ammonia are regulated pH6.4~7.0, and stream adds 50% glucose control fermented liquid glucose concn, 10~50g/L, fermentation time 60~72 hours;
(4) separation and Extraction
In the fermented liquid
15The separation of N stable isotope labeling L-arginine is adopted ion exchange method branch to extract and is obtained
15N stable isotope labeling L-arginine solution is caught up with ammonia and is adopted ethanol low temperature crystallization, vacuum-drying to obtain product by vacuum concentration; Adopt special-purpose mass spectrograph of isotropic substance or analysis of spectral method
15The N abundance, purity check adopts ordinary method.
3. according to claim 2 a kind of
15The production method of N stable isotope labeling L-arginine is characterized in that the mutant strain of described brevibacterium sp comprises brevibacterium flavum, and this brevibacterium flavum is meant brevibacterium flavum (Brevobacterium flavum) ATCC14067 mutant strain.
4. according to claim 2 a kind of
15The production method of N stable isotope labeling L-arginine, it is characterized in that, the mutant strain of described Corynebacterium comprises Corynebacterium glutamicum, and this Corynebacterium glutamicum is meant Corynebacterium glutamicum (Corynebacterium glutamicum) ATCC13032, ATCC21831, ATCC21493 or ATCC21659.
5. according to claim 2 a kind of
15The production method of N stable isotope labeling L-arginine, it is characterized in that, the mutant strain of described Corynebacterium comprises Corynebacterium crenatum, and this Corynebacterium crenatum is meant Corynebacterium crenatum (Corynebacterium crenatum) AS1.542 mutant strain, CGMCC preservation bacterial classification.
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101274912B (en) * | 2007-03-30 | 2011-05-11 | 上海化工研究院 | Separation and purification method for 15N-L-histidine |
CN102352390A (en) * | 2011-09-28 | 2012-02-15 | 上海化工研究院 | Fermentation process for producing stable isotope carbon 13 completely labeled L-shaped leucine |
CN103060395A (en) * | 2012-12-19 | 2013-04-24 | 广东环西生物科技股份有限公司 | Method for improving L-arginine fermentation yield and saccharic acid transformation rate |
CN105732436A (en) * | 2016-04-20 | 2016-07-06 | 上海化工研究院 | Method for extracting high-abundance L-arginine-15N4 from high-abundance 15N isotope-labeled L-arginine fermentation liquor |
CN108265095A (en) * | 2017-12-13 | 2018-07-10 | 东莞理工学院 | It is a kind of15N stable isotopes mark the preparation method of 5-methyldeoxycytidine |
-
2005
- 2005-05-27 CN CN 200510026243 patent/CN1869244A/en active Pending
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101274912B (en) * | 2007-03-30 | 2011-05-11 | 上海化工研究院 | Separation and purification method for 15N-L-histidine |
CN102352390A (en) * | 2011-09-28 | 2012-02-15 | 上海化工研究院 | Fermentation process for producing stable isotope carbon 13 completely labeled L-shaped leucine |
CN103060395A (en) * | 2012-12-19 | 2013-04-24 | 广东环西生物科技股份有限公司 | Method for improving L-arginine fermentation yield and saccharic acid transformation rate |
CN105732436A (en) * | 2016-04-20 | 2016-07-06 | 上海化工研究院 | Method for extracting high-abundance L-arginine-15N4 from high-abundance 15N isotope-labeled L-arginine fermentation liquor |
CN108265095A (en) * | 2017-12-13 | 2018-07-10 | 东莞理工学院 | It is a kind of15N stable isotopes mark the preparation method of 5-methyldeoxycytidine |
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