CN104878059B - A kind of method for preparing s-adenosylmethionine - Google Patents
A kind of method for preparing s-adenosylmethionine Download PDFInfo
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Abstract
The invention discloses a kind of method for preparing S Ademetionines, including：Using D/L methionine as raw material, fermentation obtains S Ademetionines, and citric acid and phosphate are added into zymotic fluid.Citric acid and phosphate are added into zymotic fluid by the present invention, bacterial strain is made to utilize citric acid and Ruminants animal ATP, in the case where ensureing not significantly improve cost of material, solve the problems, such as that S Ademetionines yield Product yields caused by intracellular ATP concentration is low are low in the prior art, significantly improve the conversion ratio of S Ademetionines yield and L methionine.
Description
Technical field
The present invention relates to biotechnology more particularly to a kind of methods for preparing s-adenosylmethionine.
Background technology
S-adenosylmethionine (S-adenosyl-L-methionine is abbreviated as SAM) is a kind of important physiological activity object
Matter is related to methyl transfer and sulfydryl transfer in its participant's body as methyl donor and the precursor of physiological sulfhydryl compound
A variety of biochemical reactions, for maintain liver plasma membrane proper flow phase and liver function of detoxification have indispensable work
With.
The study found that SAM is hard for intrahepatic cholestasis, liver caused by the hepatopathys such as virus hepatitis, alcoholic liver, fatty liver
A variety of diseases such as change, depression and osteoarthritis have positive therapeutic effect, in countries such as Italy, Germany, Spain
It is approved for prescription medicine and enters clinical practice.
In China, SAM has been enter into 2009 editions national medical insurance catalogues, for the treatment of cholestatic liver disease.In addition, SAM
Also there are the health-care effects such as analgesic, antidepression, be approved by the FDA in the United States and entered market for a kind of novel dietary supplements, sell in year
The amount of selling is more than 1,000,000,000 dollars, and with annual more than 10% speed increase.In recent years, SAM is also used to produce anti-dandruff, only
Itch, subtract the cosmetics of wrinkle, anti-aging, application range is more and more wider.With the increasingly expansion of SAM application ranges, market pair
The demand of SAM is also growing day by day.
There are three types of the main preparation methods of SAM：It is prepared including chemical synthesis, enzymatic synthesis and fermentation.
The raceme that the SAM of chemical synthesis is made of (+)-SAM and two kinds of optical isomers of (-)-SAM, and wherein only
There is (-)-SAM that just there is physiological activity.Due to being difficult to detach (+)-SAM and (-)-SAM, and production cost is higher, therefore, change
Synthesis is learned in the large-scale production of SAM using less.
Prepared by enzymatic synthesis and fermentation is the current main stream approach for mass producing SAM.Both methods is all to utilize to have
S- adenosine first stream propylhomoserin synzyme (abbreviation SAM synzyme) activity biocatalyst (production SAM synzyme strain cell or
SAM synzyme is in itself) it is catalyzed the synthetic reaction of L-Methionine (also referred to as l-methionine) and atriphos (ATP) and produces
Raw s-adenosylmethionine (see reaction equation I).
By reaction equation I it is found that in organism SAM to synthesize yield related with three factors：L-Methionine in organism
The catalysis activity of concentration, the concentration of ATP and SAM synzyme, the catalysis activity of SAM synzyme is by SAM synzyme in organism
Quantity and catalysis activity codetermine；Mg2+And K+It is the co-factor of SAM synzyme, their concentration level can be to SAM synzyme
Catalysis activity have an impact.The research and patent application of SAM are prepared by biological fermentation process in disclosed report, to this
Process optimize so that improve SAM fermentation efficiencies and the method for yield be mainly optimize L-Methionine concentration, promote biology
The expression of internal SAM synzyme improves catalysis activity of SAM synzyme etc. in organism.But L-Methionine and SAM
The utilization ratio of synzyme is also influenced by ATP concentration, when the concentration of L-Methionine and the vigor of SAM synzyme are more than certain
After limit, it will more than, for the ATP concentration levels utilized, excessive L-Methionine and SAM synzyme being caused to obtain in organism
Less than efficiently using.Although also having research to employ adds the method that ATP improves SAM yield into fermentation system, due to ATP
The price is very expensive, production cost can be made significantly to increase, therefore, although this method can effectively improve the fermentation production of SAM
Amount, but it is infeasible to consider from financial cost.
Chinese invention patent application document application No. is 200810020215.4 is disclosed and a kind of is added into zymotic fluid
ATP biosynthesis precursor adenosines or adewosine monophosphate improve SAM fermentation levels to promote the method for ATP concentration in organism, but
Since the price of adenosine or adewosine monophosphate is still higher, the notable rising of production cost can be still caused.
Chinese invention patent application document application No. is 201210285900.6 discloses one kind by fermented and cultured
Citric acid is added in the 15 hours backward culture mediums started to improve the concentration of intracellular ATP, and then improve the side of SAM fermentation levels
Method, but this method is not obvious the improvement effect of SAM fermentation levels：When not adding sodium citrate, SAM fermentation levels are
270.1mg/L；In sodium citrate (2g/L) for adding optimal dose, SAM fermentation levels are 331.5mg/L.By addition citric acid
For SAM fermentation levels before and after sodium it is found that even if under most suitable adding conditional, this method also can only improve the fermentation level of SAM
23%, the effect after sodium citrate addition improves limitation.
Invention content
The present invention provides a kind of method for preparing s-adenosylmethionine, this method can ensure not significantly improving production
In the case of cost, high-efficiency fermenting produces s-adenosylmethionine, improves the yield of s-adenosylmethionine.
A kind of method for preparing s-adenosylmethionine, including：Using D/L- methionine as raw material, fermentation obtains S- adenosine egg ammonia
Acid adds citric acid and phosphate into zymotic fluid.
In above-mentioned fermentation process, citric acid obtains ATP by the krebs cycle pathway in organism, and phosphate is
ADP in organism provides phosphoric acid, and phosphorylation occurs, and obtains ATP, and above-mentioned ATP is both provided to organism and carries out S- adenosine egg ammonia
The preparation of acid, it is ensured that ATP is sufficient in s-adenosylmethionine preparation process, so as to improve s-adenosylmethionine yield.
Preferably, a concentration of 1.0~10mmol/L of the citric acid；Phosphatic a concentration of 0.05~0.50mol/
L。
Further preferably, a concentration of 4.0~6.0mmol/L of the citric acid；Phosphatic a concentration of 0.2~
0.3mol/L。
The phosphate is potassium dihydrogen phosphate.
Citric acid and the phosphatic time for being added into zymotic fluid, to the yield and L-Methionine of final s-adenosylmethionine
Conversion ratio have an impact, preferably, before inoculation, citric acid and phosphate are added in zymotic fluid.Because through reality
It issues after examination and approval now, citric acid and phosphatic addition have facilitation to the growth of bacterial strain.
Thalline in zymotic fluid of the present invention can be the wild mushroom of production S-adenosylmethionine synzyme, can also lead to
It crosses molecule clone technology and prepares the recombination engineering containing S-adenosylmethionine synthase gene.
Preferably, the wild mushroom is saccharomyces cerevisiae or saccharomyces sake, such bacterial strain being capable of high efficient expression S- adenosine first
Methyllanthionine synzyme and enzyme activity height, conducive to the production of s-adenosylmethionine.
Preferably, the temperature of the fermentation is 25~35 DEG C, to ensure that bacterial strain is in optimum growh environment in zymotic fluid,
It is further preferred that 28~30 DEG C.
PH value also has an impact the growth of bacterial strain in zymotic fluid, and meta-acid meta-alkali can reduce S-adenosylmethionine in bacterial strain
The yield and vigor of synzyme, and then reduce the yield of s-adenosylmethionine.Preferably, the pH value of the zymotic fluid is 4.5
~5.5, it is further preferred that pH is 5.0 ± 0.2.
The yield of s-adenosylmethionine can be improved by adding raw material D/L- methionine by several times, preferably, the D/L- eggs ammonia
Sour to add in zymotic fluid by several times, dosage is 2~2.5g/L, adds interval time as 5~6h, and it is 5~6 times to add number.
Compared with prior art, the invention has the advantages that：
Citric acid and phosphate are added into zymotic fluid by the present invention, and bacterial strain is made to utilize citric acid and Ruminants animal ATP,
Ensure do not significantly improve cost of material in the case of, solve in the prior art s-adenosylmethionine yield because intracellular ATP is dense
Spend it is low caused by Product yields it is low the problem of, significantly improve the conversion ratio of s-adenosylmethionine yield and L-Methionine.
Specific embodiment
The invention will be further elaborated With reference to embodiment.
The required all kinds of culture mediums of the present invention are specific as follows：
Solid activated inclined plane culture medium：Glucose 1%, peptone 0.5%, dusty yeast 0.5%, agar 1.8%
Liquid seed culture medium：Glucose 1%, peptone 0.5%, dusty yeast 0.5%
Basic fermentation medium：Glucose 3%, peptone 1.5%, dusty yeast 1%, K2HPO40.5%,
MgCl20.01%, pH 5.0~5.5.
The yield detection method of s-adenosylmethionine：
The extraction of s-adenosylmethionine：1ml zymotic fluids are taken, 4 DEG C, 6000rpm centrifugation 2min discard supernatant, use 1.4mol/
L, 2ml be pre-chilled perchloric acid processing precipitation 10min, 4 DEG C again, 13000rpm centrifugation 3min after collect supernatant, via hole diameter is
After 0.45 μm of filtering membrane filtration, analyzed with high performance liquid chromatography (HPLC) method；
High performance liquid chromatography (HPLC) method detects the condition of s-adenosylmethionine：
Mobile phase is methanol：Ammonium acetate solution, the two volume ratio be 15: 85, ammonium acetate solution it is a concentration of
0.0185mol/L, pH 3.5, flow rate of mobile phase 1.0mL/min；
Detection wavelength is 254nm, and sample size is 20 μ L, and chromatographic column is 5 μm of (250mm of HYPERSIL ODSZ C18 chromatographic columns
×4.6mm)。
Embodiment 1
Take saccharomyces cerevisiae (Saccharomyces cerevisiae) scribing line of the production SAM synzyme of 4 DEG C of low-temperature preservations
It is inoculated in solid activation medium, after 30 DEG C of overnight incubations, a ring activated strains is taken to be seeded to equipped with 50mL seed cultures
In the 250mL conical flasks of base, rotating speed is placed in as overnight incubation on 200rpm, 28 DEG C of shaking table, is by volume by fresh seeds
5% inoculum concentration inoculation is placed in fermentation tank, and the liquid fermentation medium that volume is 1L is placed in fermentation tank.The liquid fermentation
Culture medium is the basic fermentation medium of the potassium dihydrogen phosphate of the citric acid and 0.05mol/L that are added to 1.0mmol/L.Fermentation tank
Rotating speed of agitator is 150rpm, ventilatory capacity 250m3/ h, cultivation temperature are 28 DEG C, and zymotic fluid pH value is maintained at 5.0.
After thalli growth to mid log phase, D/L- methionine 10g are added into zymotic fluid, are centrifuged after the 40h that ferments
It collects thalline and detects SAM yield as 1.4g/L, effective conversion ratio of L-Methionine is 10% in substrate.
Embodiment 2
The saccharomyces cerevisiae (Saccharomyces cerevisiae) of the production SAM synzyme of 4 DEG C of low-temperature preservations is taken to cross to connect
Kind after 30 DEG C of overnight incubations, takes a ring activated strains to be seeded to equipped with 50mL seed culture mediums in solid activation medium
250mL conical flasks in, be placed in rotating speed for 200rpm, overnight incubation on 28 DEG C of shaking table, be 5% by volume by fresh seeds
Inoculum concentration inoculation be placed in fermentation tank, be placed in fermentation tank volume be 1L liquid fermentation medium.The liquid fermentation is trained
Foster base is the basic fermentation medium of the potassium dihydrogen phosphate of the citric acid and 0.2mol/L that are added to 4.0mmol/L.Fermentation tank stirs
Paddle rotating speed is mixed as 150rpm, ventilatory capacity 250m3/ h, cultivation temperature are 28 DEG C, and zymotic fluid pH value is maintained at 5.0.
After thalli growth to mid log phase, D/L- methionine 10g are added into zymotic fluid, are centrifuged after the 40h that ferments
It collects thalline and detects SAM yield as 1.9g/L, effective conversion ratio of L-Methionine is 14% in substrate.
Embodiment 3
Take saccharomyces cerevisiae (Saccharomyces cerevisiae) scribing line of the production SAM synzyme of 4 DEG C of low-temperature preservations
It is inoculated in solid activation medium, after 30 DEG C of overnight incubations, a ring activated strains is taken to be seeded to equipped with 50mL seed cultures
In the 250mL conical flasks of base, rotating speed is placed in as overnight incubation on 200rpm, 28 DEG C of shaking table, is by volume by fresh seeds
5% inoculum concentration inoculation is placed in fermentation tank, and the liquid fermentation medium that volume is 1L is placed in fermentation tank.The liquid fermentation
Culture medium is the basic fermentation medium of the potassium dihydrogen phosphate of the citric acid and 0.25mol/L that are added to 5mmol/L.Fermentation tank stirs
Paddle rotating speed is mixed as 150rpm, ventilatory capacity 250m3/ h, cultivation temperature are 28 DEG C, and zymotic fluid pH value is maintained at 5.0.
After thalli growth to mid log phase, D/L- methionine 10g are added into zymotic fluid, are centrifuged after the 40h that ferments
It collects thalline and detects SAM yield as 2.2g/L, effective conversion ratio of L-Methionine is 16% in substrate.
Embodiment 4
Take saccharomyces cerevisiae (Saccharomyces cerevisiae) scribing line of the production SAM synzyme of 4 DEG C of low-temperature preservations
It is inoculated in solid activation medium, after 30 DEG C of overnight incubations, a ring activated strains is taken to be seeded to equipped with 50mL seed cultures
In the 250mL conical flasks of base, rotating speed is placed in as overnight incubation on 200rpm, 28 DEG C of shaking table, is by volume by fresh seeds
5% inoculum concentration inoculation is placed in fermentation tank, and the liquid fermentation medium that volume is 1L is placed in fermentation tank.The liquid fermentation
Culture medium is the basic fermentation medium of the potassium dihydrogen phosphate of the citric acid and 0.3mol/L that are added to 6mmol/L.Fermentation tank stirs
Paddle rotating speed is mixed as 150rpm, ventilatory capacity 250m3/ h, cultivation temperature are 28 DEG C, and zymotic fluid pH value is maintained at 5.0.
After thalli growth to mid log phase, D/L- methionine 10g are added into zymotic fluid, are centrifuged after the 40h that ferments
It collects thalline and detects SAM yield as 2.0g/L, effective conversion ratio of L-Methionine is 15% in substrate.
Embodiment 5
Take saccharomyces cerevisiae (Saccharomyces cerevisiae) scribing line of the production SAM synzyme of 4 DEG C of low-temperature preservations
It is inoculated in solid activation medium, after 30 DEG C of overnight incubations, a ring activated strains is taken to be seeded to equipped with 50mL seed cultures
In the 250mL conical flasks of base, rotating speed is placed in as overnight incubation on 200rpm, 28 DEG C of shaking table, is by volume by fresh seeds
5% inoculum concentration inoculation is placed in fermentation tank, and the liquid fermentation medium that volume is 1L is placed in fermentation tank.The liquid fermentation
Culture medium is the basic fermentation medium of the potassium dihydrogen phosphate of the citric acid and 0.50mol/L that are added to 10mmol/L.Fermentation tank
Rotating speed of agitator is 150rpm, ventilatory capacity 250m3/ h, cultivation temperature are 28 DEG C, and zymotic fluid pH value is maintained at 5.0.
After thalli growth to mid log phase, D/L- methionine 10g are added into zymotic fluid, are centrifuged after the 40h that ferments
It collects thalline and detects SAM yield as 1.6g/L, effective conversion ratio of L-Methionine is 12% in substrate.
Comparative example 1
Take saccharomyces cerevisiae (Saccharomyces cerevisiae) scribing line of the production SAM synzyme of 4 DEG C of low-temperature preservations
It is inoculated in solid activation medium, after 30 DEG C of overnight incubations, a ring activated strains is taken to be seeded to equipped with 50mL seed cultures
In the 250mL conical flasks of base, rotating speed is placed in as overnight incubation on 200rpm, 28 DEG C of shaking table, is by volume by fresh seeds
5% inoculum concentration inoculation is placed in fermentation tank, and the liquid fermentation medium that volume is 1L is placed in fermentation tank.The liquid fermentation
Culture medium is the basic fermentation medium for being not added with citric acid and potassium dihydrogen phosphate.Fermentation tank rotating speed of agitator is 150rpm, is led to
Tolerance is 250m3/ h, cultivation temperature are 28 DEG C, and zymotic fluid pH value is maintained at 5.0.
After thalli growth to mid log phase, D/L- methionine 10g are added into zymotic fluid, are centrifuged after the 40h that ferments
It collects thalline and detects SAM yield as 0.9g/L, effective conversion ratio of L-Methionine is 6.7% in substrate.
Comparative example 1 is compared with Examples 1 to 5, it is known that：Citric acid and phosphate are added in the fermentation medium,
The fermentation yield of SAM can be made to improve 56%~120%, the conversion ratio of substrate L-Methionine is increased to 10~17% from 6.7%.
Comparative example 2
Take saccharomyces cerevisiae (Saccharomyces cerevisiae) scribing line of the production SAM synzyme of 4 DEG C of low-temperature preservations
It is inoculated in solid activation medium, after 30 DEG C of overnight incubations, a ring activated strains is taken to be seeded to equipped with 50mL seed cultures
In the 250mL conical flasks of base, rotating speed is placed in as overnight incubation on 200rpm, 28 DEG C of shaking table, is by volume by fresh seeds
5% inoculum concentration inoculation is placed in fermentation tank, and the liquid fermentation medium that volume is 1L is placed in fermentation tank.The liquid fermentation
Culture medium is the basic fermentation medium for adding 5mmol/L citric acids.Fermentation tank rotating speed of agitator is 150rpm, and ventilatory capacity is
250m3/ h, cultivation temperature are 28 DEG C, and zymotic fluid pH value is maintained at 5.0.
After thalli growth to mid log phase, D/L- methionine 10g are added into zymotic fluid, are centrifuged after the 40h that ferments
It collects thalline and detects SAM yield as 1.2g/L, effective conversion ratio of L-Methionine is 8.9% in substrate.
Comparative example 3
Take saccharomyces cerevisiae (Saccharomyces cerevisiae) scribing line of the production SAM synzyme of 4 DEG C of low-temperature preservations
It is inoculated in solid activation medium, after 30 DEG C of overnight incubations, a ring activated strains is taken to be seeded to equipped with 50mL seed cultures
In the 250mL conical flasks of base, rotating speed is placed in as overnight incubation on 200rpm, 28 DEG C of shaking table, is by volume by fresh seeds
5% inoculum concentration inoculation is placed in fermentation tank, and the liquid fermentation medium that volume is 1L is placed in fermentation tank.The liquid fermentation
Culture medium is the basic fermentation medium added with potassium dihydrogen phosphate 0.25mol/L.Fermentation tank rotating speed of agitator is 150rpm, is led to
Tolerance is 250m3/ h, cultivation temperature are 28 DEG C, and zymotic fluid pH value is maintained at 5.0.
After thalli growth to mid log phase, D/L- methionine 10g are added into zymotic fluid, are centrifuged after the 40h that ferments
It collects thalline and detects SAM yield as 1.1g/L, effective conversion ratio of L-Methionine is 8.2% in substrate.
Claims (7)
1. a kind of method for preparing s-adenosylmethionine, including：Using D/L- methionine as raw material, fermentation obtains S- adenosine egg ammonia
Acid, which is characterized in that citric acid and phosphate are added into zymotic fluid；
A concentration of 4.0~6.0mmol/L of the citric acid；Phosphatic a concentration of 0.2~0.3mol/L.
2. the method as described in claim 1, which is characterized in that the phosphate is potassium dihydrogen phosphate.
3. the method as described in claim 1, which is characterized in that before inoculation, citric acid and phosphate are added in zymotic fluid.
4. the method as described in claim 1, which is characterized in that the bacterial strain is the wild of production S-adenosylmethionine synzyme
Bacterium or engineering bacteria.
5. the method as described in claim 1, which is characterized in that the temperature of the fermentation is 25~30 DEG C.
6. the method as described in claim 1, which is characterized in that the pH value of the zymotic fluid is 4.5~5.5.
7. the method as described in claim 1, which is characterized in that the D/L- methionine is added in zymotic fluid by several times, is added
It measures as 2~2.5g/L, adds interval time as 5~6h, it is 5~6 times to add number.
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| CN105483190B (en) * | 2015-10-23 | 2019-08-13 | 山东金城生物药业有限公司 | The engineered method for improving s-adenosyl-L-methionine yield of genes of brewing yeast |
| CN106349311B (en) * | 2016-08-23 | 2018-04-13 | 北京金阳利康医药有限公司 | The method that S Ademetionines are extracted from yeast fermentation broth |
| CN112375797B (en) * | 2020-10-23 | 2022-05-24 | 内蒙古拜克生物有限公司 | Preparation method of adenosylmethionine butanedisulfonate with health-care function |
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| CN101012470B (en) * | 2007-01-25 | 2010-06-16 | 华东理工大学 | Method for zymolytic production of S-adenosine methionine |
| CN102776258A (en) * | 2012-08-13 | 2012-11-14 | 苏州大学 | Fermentation method for coproduction of S-adenosyl-L-methionine and glutathione |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101012470B (en) * | 2007-01-25 | 2010-06-16 | 华东理工大学 | Method for zymolytic production of S-adenosine methionine |
| CN102776258A (en) * | 2012-08-13 | 2012-11-14 | 苏州大学 | Fermentation method for coproduction of S-adenosyl-L-methionine and glutathione |
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| Title |
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| 腺苷蛋氨酸发酵条件及发酵培养基的优化;陈小龙等;《中国生物工程杂志》;20041130;第24卷(第11期);全文 * |
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