CN103966276A - Method for synthesizing DL-serine through enzyme catalysis method - Google Patents
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Abstract
The present invention relates to a method for synthesizing DL-serine through an enzyme catalysis method. According to the method, formaldehyde and glycine are adopted as substrates, in the presence of coenzyme and under an effect of a catalyst having serine hydroxymethyl transferase activity or D-threonine aldolase activity, one molecule of the formaldehyde and one molecule of the glycine are converted into one molecule of the single configuration serine, and racemization is performed under an effect of a catalyst having amino acid racemase activity to produce DL-serine, wherein preferably the whole enzyme catalysis reaction process is added with the cofactor so as to promote the enzyme catalysis reaction process. The method has advantages of clever design, simple operation, short production cycle, low production cost, high yield, low environmental protection pressure and the like, and is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to DL amino acid preparing technical field, particularly enzyme catalysis method is prepared DL amino acid technical field, specifically refers to the method for the synthetic DL-serine of a kind of enzyme catalysis method.
Background technology
Serine (Serine) is one of naturally occurring 20 seed amino acids, generally refers to Serine.The optical isomer that DL-serine (DL-Serine) comprises two equivalent is Serine and the D-Ser mixture of 1: 1.DL-serine is the key intermediate of decarboxylase inhibitor benserazide hydrochloride, is also the raw material of synthetic a lot of organic compound simultaneously, and its structural formula is as follows:
Four kinds nothing more than of general amino acid whose production technique: proteolysis extraction method, chemical synthesis, biological fermentation and catalyzed by biological enzyme.Although Serine some protein as sericin in rich content, with silk cocoon clothing hydrolysis, produce Serine, not only raw materials cost is high, and also difficulty of later separation purifying, causes total cost higher.
The production technique of existing DL-serine is to take chemosynthesis as main substantially.
Lu Ximing etc. (Chinese invention patent application publication number CN1339431A) be take vinyl acetate as raw material, in aceticanhydride and acetate system, through chlorination, then react the intermediate 1,1 that obtains DL-serine, 2-triacetoxyl group ethane with excessive sodium acetate, anhydrous.Then through cyaniding, prepare DL-serine.
The method that Zhao Jun equality (Chinese invention patent application publication number CN100999478A) is prepared DL-serine comprises the following steps: that (1) is raw material with acetyl glycine or the sweet ammonia ester of acetyl, the sweet ammonia ester of a part acetyl glycine or acetyl and 37% formaldehyde solution are at alkaline condition, certain temperature reaction certain hour, acidified separation obtains a part DL-serine; (2) with chloracetyl glycine or the sweet ammonia ester of chloracetyl, be raw material: the sweet ammonia ester of chloracetyl glycine or chloracetyl and 37% formaldehyde solution is at alkaline condition, certain temperature reaction certain hour, acidified, hydrolysis, separation obtain two molecule DL-serine.Product yield 50%-70%.
Liao Benren etc. (Chinese invention patent application publication number CN101168513A) invent a kind of method of preparing DL-serine: the amino second eyeball of methylene, paraformaldehyde are joined in ethanol synthesis solvent, under the existence of catalyzer, carry out addition reaction with organic bases triethylamine, obtain 1-methylol-1-methylene aminoacetonitriles, then pass through hydrochloric acid hydrolysis, obtain DL-serine.
Chemical synthesis also has following several technique: fine chemistry industry, and 18 (4), 232-233 (2001) has reported by glycocoll-copper legal system for DL-serine.Glycine and copper sulfate are formed to complex compound under the effect of sodium hydroxide, then react with formalin, then pass through ion-exchange, obtain DL-serine.US Patent No. 4304933 has reported that take acrylonitrile prepares the method for DL-serine as raw material.Chlorine and acrylonitrile addition are obtained to 1,2-dichloro propionitrile, and then under alkaline condition, ammonia solution obtains aziridine-2-sodium formiate, then obtains DL-serine by strong-acid ion exchange resin.
Chemical synthesis is prepared DL-serine, relates to reactions steps many, complex process, and overall yield of reaction is on the low side; Raw material or intermediate product have toxicity, not easily separated, cause separation and purification of products difficulty, and unfriendly to environment; Chemical synthesis is prepared DL-serine total cost at present or is higher.
It is generally the Serine that obtains single configuration that biological fermentation process or enzyme catalysis method are prepared Serine, as Hengdian Group Jiayuan Chemical Industry Co., Ltd. (Chinese invention patent application publication number CN102220389A), take glycine and formaldehyde is raw material, by serine hydroxymethyl methyltransgerase, is converted into Serine.In addition, it is raw material that the patent (Chinese invention patent application publication number CN102226207A) of Mitsui KCC application be take glycine and formaldehyde equally, by active bacterium or its handled thing containing D-Thr zymohexase, is converted into D-Ser.If obtain DL-serine, need Serine or D-Ser to extract, then do a step racemization.European patent application EP 0302624A2 has just reported a kind of method of utilizing Serine to obtain DL-serine: in basic solution, add pyridoxal phosphate or salicylic aldehyde and basic cpd, in temperature, surpass under the condition of 150 ℃ and can rapidly Serine racemization be obtained to DL-serine.This reaction conditions is comparatively harsh, and can not prepare with enzyme process the coupling of reacting of Serine.
Therefore, the chemical synthesis all adopting for existing production DL-serine is because of complex process, the feature such as raw materials cost is high, environment is unfriendly, a kind of preparation method of DL-serine need to be provided, its have simple to operate, with short production cycle, production cost is low, yield is high, environmental protection pressure is little, be applicable to the advantages such as large-scale industrial production.
Summary of the invention
The object of the invention is to have overcome above-mentioned shortcoming of the prior art, the method of the synthetic DL-serine of a kind of enzyme catalysis method is provided, the method design of the synthetic DL-serine of this enzyme catalysis method is ingenious, have simple to operate, with short production cycle, production cost is low, yield is high, environmental protection pressure is little, be applicable to the advantages such as large-scale industrial production.
To achieve these goals, the method of the synthetic DL-serine of enzyme catalysis method of the present invention, be characterized in, take formaldehyde and glycine as substrate, under coenzyme exists, there is serine hydroxymethylase (serine hydroxymethyltransferase, SHMT) active catalyzer or have under the active catalyst action of D-Thr zymohexase (aldolase), a part formaldehyde and a part glycine are converted into the Serine of the single configuration of a part, then racemization under the effect with the active catalyzer of amino acid racemase (amino acidracemase), generate DL-serine.
Preferably, the described catalyzer with serine hydroxymethylase activity is selected from the serine hydroxymethylase in (but being not limited to) subtilis source, the serine hydroxymethylase in the serine hydroxymethylase in corynebacterium glutamicum source, intestinal bacteria source or the serine hydroxymethylase in bacillus acidocldarius source.
Preferably, the described catalyzer with serine hydroxymethylase activity is selected from microorganism or its handled thing that (but being not limited to) contains serine hydroxymethylase activity.Described handled thing be selected to described microorganism carry out physical disturbance, ultrasonication, freeze to melt processing, drying treatment, pressurization or reduced pressure treatment, osmotic pressure processing, autodigestion, tensio-active agent are processed, enzyme is processed and the material that obtains and by resulting fixed compound and the described microbial immobilization thing having by the part of the active enzyme of glycine and the synthetic Serine of formaldehyde that contain of above-mentioned processing.
Preferably, the described catalyzer with D-Thr aldolase activity is selected from the D-Thr zymohexase in the D-Thr zymohexase in (but being not limited to) Arthrobacter source, the D-Thr zymohexase in Xanthomonas campestris source or achromobacter source.
Preferably, the described catalyzer with D-Thr aldolase activity is selected from microorganism or its handled thing that (but being not limited to) contains D-Thr aldolase activity.Equally, described handled thing be selected to described microorganism carry out physical disturbance, ultrasonication, freeze to melt processing, drying treatment, pressurization or reduced pressure treatment, osmotic pressure processing, autodigestion, tensio-active agent are processed, enzyme is processed and the material that obtains and by resulting fixed compound and the described microbial immobilization thing having by the part of the active enzyme of glycine and the synthetic Serine of formaldehyde that contain of above-mentioned processing.
Preferably, the described catalyzer with amino acid racemase activity is selected from the amino acid racemase in the amino acid racemase in (but being not limited to) pseudomonas putida source, the amino acid racemase in bacillus kaustophilus source or Pseudomonas taetrolens source.
Preferably, the described catalyzer with amino acid racemase activity is selected from microorganism or its handled thing that (but being not limited to) contains amino acid racemase activity.Described handled thing be selected to described microorganism carry out physical disturbance, ultrasonication, freeze to melt processing, drying treatment, pressurization or reduced pressure treatment, osmotic pressure processing, autodigestion, tensio-active agent are processed, enzyme is processed and the material that obtains and by the resulting fixed compound that contains the part with the active enzyme that makes the racemization of single configuration amino acid of above-mentioned processing and described microbial immobilization thing.
Preferably, described coenzyme comprises one or more of pyridoxal phosphate and tetrahydrofolic acid (THFA).Coenzyme mainly refers to pyridoxal phosphate (PLP), tetrahydrofolic acid (THFA) (THFA).While wherein preparing DL-serine with D-Thr zymohexase and amino acid racemase, pyridoxal phosphate is necessary; And when preparing DL-serine with serine hydroxymethylase and amino acid racemase, pyridoxal phosphate and tetrahydrofolic acid (THFA) are all necessary.
Preferably, in whole enzyme-catalyzed reaction, add cofactor to promote the process of enzymic catalytic reaction, described cofactor comprise the activator of enzyme and enzyme protectant one or more.。
More preferably, the protective material of described enzyme comprises one or more of mercaptoethanol, dithiothreitol (DTT) and sodium bisulfite; The activator of described enzyme is divalent-metal ion.
The protective material of enzyme mainly refers to mercaptoethanol, dithiothreitol (DTT), sodium bisulfite etc., be used for preventing or delayed response process in the destruction to enzyme such as oxygen, organic solvent (as formaldehyde), make catalyzed reaction be able to effectively in the time, complete.These not necessarily can not add.
The activator of enzyme mainly refers to divalent-metal ion, can improve the efficiency of enzymic catalytic reaction.Some divalent-metal ion is extremely remarkable to the effect of raising enzymic catalytic reaction, in actual production, must add often.In production, be mainly in catalyzed reaction, to add compound containing divalent-metal ion so that divalent-metal ion to be provided, its water-soluble divalent-metal ion that discharges, for example magnesium chloride, Manganous chloride tetrahydrate, acetic acid brill, ferrous sulfate, calcium chloride etc.
Beneficial effect of the present invention is specifically: it is substrate that the method for the synthetic DL-serine of enzyme catalysis method of the present invention be take formaldehyde and glycine, under coenzyme exists, there is the catalyzer of serine hydroxymethylase activity or having under the catalyst action of D-Thr aldolase activity, a part formaldehyde and a part glycine are converted into the Serine of the single configuration of a part, then racemization under the effect of catalyzer with amino acid racemase activity, generate DL-serine, design ingenious, have simple to operate, with short production cycle, production cost is low, yield is high, environmental protection pressure is little, be applicable to the advantages such as large-scale industrial production.
Embodiment
The present invention is directed to chemical synthesis that existing production DL-serine all adopts because of complex process, the feature such as raw materials cost is high, environment is unfriendly, a kind of brand-new biological enzyme technique is provided.
The present invention specifically, in Production by Enzymes Serine process, directly adds amino acid racemase, and two enzyme one kettle ways are prepared DL-serine, as shown in Scheme 1.
Route 1
It is substrate that formaldehyde and glycine are take in the present invention, by comprising, has the catalyzer of serine hydroxymethylase activity or has the catalyzer of D-Thr aldolase activity and have the catalyzer of amino acid racemase activity and the enzyme catalysis system catalysis High-efficient Production DL-serine of cofactor.
Concrete, take formaldehyde and glycine as substrate, by thering is the catalyzer of serine hydroxymethylase activity or thering is the effect of the catalyzer of D-Thr aldolase activity, a part formaldehyde and a part glycine are converted into the Serine of the single configuration of a part; Then single configuration Serine, by racemization under the effect of catalyzer with amino acid racemase activity, generates DL-serine.
The production method of DL-serine provided by the invention, specific embodiments is as follows:
(1) in a bio-reactor, add substrate glycine, add the catalyzer that has the catalyzer of serine hydroxymethylase activity or have the catalyzer of D-Thr aldolase activity and have amino acid racemase activity, the catalyzer that has the catalyzer of serine hydroxymethylase activity or have a D-Thr aldolase activity is 1%～10% of substrate weight percent; The catalyzer with amino acid racemase activity is 0.5%～5% of substrate weight percent; The mode adding by stream adds 37% formaldehyde.
(2) in above-mentioned reaction, can add cofactor, described cofactor includes but not limited to pyridoxal phosphate (PLP), tetrahydrofolic acid (THFA) (THFA), divalent metal ion (can from the water-soluble compound with divalent metal ion), mercaptoethanol, dithiothreitol (DTT), sodium bisulfite.
(3) temperature is controlled: control 10～60 ℃ of temperature, preferably temperature is 20～50 ℃, and most preferably temperature is 30～40 ℃;
(4) pH controls: by alkali lye, control pH, controlling pH is 4～10, preferably pH5～9, most preferably pH6～8; As the alkali adding in reaction solution, can make liquid be alkaline material for the alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and ammonium hydroxide, calcium hydroxide, dipotassium hydrogen phosphate, Sodium phosphate dibasic, potassium pyrophosphate, ammonia etc. are dissolved in the water.
(5) process stirring reaction is 5～48 hours, and glycine and formaldehyde transform generation DL-serine.
(6) by change in concentration and the production quality control of substrate glycine in high performance liquid chromatography (HPLC) observation process and product Serine, HPLC analytical procedure is: chromatographic column: Aglent ZRABOX SB-C84.6 * 250mm, 5 μ m; Column temperature: 30 ℃; Flow velocity: 1.0ml/min; Detector: ultraviolet, 334nm; Derivating agent: o-phthalaldehyde(OPA) and N-acetyl-L-cysteine; Derivative program: the derivative program of sample introduction that is applicable to Aglent; Moving phase: the solution that anhydrous sodium acetate, first alcohol and water configure by a certain percentage.
In order more clearly to understand technology contents of the present invention, especially exemplified by following examples, describe in detail.Should be understood that following examples are only for the present invention is described but not for limiting the scope of the invention.
Embodiment 1:
With electronic balance weighing substrate glycine 15g, add 1.5 grams of wet thallus containing serine hydroxymethylase and 0.5g containing the wet thallus of amino acid racemase, join in the reactor that deionized water is housed, add again pyridoxal phosphate 30mg and tetrahydrofolic acid (THFA) 20mg, use deionized water constant volume to 1000mL; By water-bath, circulate, controlling temperature is 30 ℃; Stream adds 37% formalin, and controls pH value 7.5 by 4M aqueous sodium hydroxide solution; Mixing speed 200rpm, HPLC detects glycine transformation efficiency and reaches 99.1%, and the reaction times is 6h.
Conversion fluid after filtration or the centrifugal thalline of removing, then through ultrafiltration except Deproteinization, concentrating under reduced pressure after activated carbon decolorizing, crystallization, 70 ℃ of drying in oven, spend the night, obtain white crystalline powder, odorless, taste sweet, gained Serine product is consistent with the retention time of Serine standard substance in HPLC; In addition, gained Serine product and the infrared spectrum made at KCl crystal wafer of Serine standard substance are consistent.Take this, to confirm the product making be really Serine.Through HPLC, analyze, the DL-serine content of embodiment 1 preparation is 98.9%.Through polarimeter, measuring its specific rotatory power is 0.05.
1H NMR(CDCl
3,400Hz)δ3.84-3.74(m,2H),3.49(dd,J=5.6,4.8Hz,1H);MS(ESI)m/z=106(M
++1).
Embodiment 2:
With electronic balance weighing substrate glycine 30g, add 2.5 grams of wet thallus containing D-Thr zymohexase and 1.5g containing the wet thallus of amino acid racemase, join in the reactor that deionized water is housed, add again pyridoxal phosphate 40mg and anhydrous magnesium sulfate 150mg, use deionized water constant volume to 1000mL; By water-bath cycle control temperature, it is 40 ℃; Stream adds 37% formalin, and controls pH value 6.8 by 4M aqueous sodium hydroxide solution; Mixing speed 220rpm, after the reaction times is 17h, HPLC detects glycine transformation efficiency and reaches 99.5%.
Conversion fluid after filtration or the centrifugal thalline of removing, then through ultrafiltration except Deproteinization, concentrating under reduced pressure after activated carbon decolorizing, crystallization, 70 ℃ of drying in oven, spend the night, obtain white crystalline powder, odorless, taste sweet, gained Serine product is consistent with the retention time of Serine standard substance in HPLC; In addition, gained Serine product and the infrared spectrum made at KCl crystal wafer of Serine standard substance are consistent.Take this, to confirm the product making be really Serine.Through HPLC, analyze, the DL-serine content of embodiment 2 preparations is 99.1%.Through polarimeter, measuring its specific rotatory power is 0.01.Spectral data is shown in embodiment 1.
Embodiment 3:
With electronic balance weighing substrate glycine 60g, add 100mL to contain the broken cytosol of thalline of serine hydroxymethylase, join in the reactor that deionized water is housed, then add pyridoxal phosphate 75mg and tetrahydrofolic acid (THFA) 40mg, use deionized water constant volume to 1000mL; By water-bath, circulate, controlling temperature is 50 ℃; Stream adds 37% formalin, and controls pH value 8.0 by 4M aqueous sodium hydroxide solution; Mixing speed 300rpm, after reaction 26h, HPLC detects glycine transformation efficiency and reaches 98%, and the specific rotatory power that polarimeter records reaction solution is+14.5 °; Now in reaction solution, add 3g to contain the wet thallus continuation reaction of amino acid racemase, after 12h, glycine transformation efficiency reaches 99.7% again, and reaction solution specific rotatory power is 0.03.
Conversion fluid after filtration or the centrifugal thalline of removing, then through ultrafiltration except Deproteinization, concentrating under reduced pressure after activated carbon decolorizing, crystallization, 70 ℃ of drying in oven, spend the night, obtain white crystalline powder, odorless, taste sweet, gained Serine product is consistent with the retention time of Serine standard substance in HPLC; In addition, gained Serine product and the infrared spectrum made at KCl crystal wafer of Serine standard substance are consistent.Take this, to confirm the product making be really Serine.Through HPLC, analyze, the DL-serine content of embodiment 3 preparations is 99.3%.Through polarimeter, measuring its specific rotatory power is 0.02.Spectral data is shown in embodiment 1.
Therefore, beneficial effect of the present invention is specifically: the synthetic method of DL-serine provided by the present invention have simple to operate, with short production cycle, production cost is low, yield is high, environmental protection pressure is little, be applicable to the advantages such as large-scale industrial production.The present invention has following innovative point:
(1) raw material is easy to get and is with low cost: glycine and formaldehyde are the simplest industrial chemicals, 20 yuan of left and right of glycine per kilogram, 37% formaldehyde, 1500 yuan of left and right per ton.
(2) technique is simple: all raw materials and enzyme single step reaction in a reactor can make the DL-serine of DL, does not relate to intermediate steps and reaction, greatly simplified technical process, and plant factor is high.
(3) environmental protection pressure is little: the synthetic method of DL-serine provided by the present invention is biological catalysis, and reaction conditions is gentle, environmentally friendly, meets the development trend of Modern Green chemical industry, is applicable to industrialized production.
To sum up, the method design of the synthetic DL-serine of enzyme catalysis method of the present invention is ingenious, have simple to operate, with short production cycle, production cost is low, yield is high, environmental protection pressure is little, be applicable to the advantages such as large-scale industrial production.
In this specification sheets, the present invention is described with reference to its specific embodiment.But, still can make various modifications and conversion obviously and not deviate from the spirit and scope of the present invention.Therefore, specification sheets is regarded in an illustrative, rather than a restrictive.
Claims (10)
1. the method for the synthetic DL-serine of an enzyme catalysis method, it is characterized in that, take formaldehyde and glycine as substrate, under coenzyme exists, there is the catalyzer of serine hydroxymethylase activity or having under the catalyst action of D-Thr aldolase activity, a part formaldehyde and a part glycine are converted into the Serine of the single configuration of a part, then racemization under the effect of catalyzer with amino acid racemase activity, generates DL-serine.
2. enzyme catalysis method according to claim 1 synthesizes the method for DL-serine, it is characterized in that, the described catalyzer with serine hydroxymethylase activity is selected from the serine hydroxymethylase in subtilis source, the serine hydroxymethylase in the serine hydroxymethylase in corynebacterium glutamicum source, intestinal bacteria source or the serine hydroxymethylase in bacillus acidocldarius source.
3. the method for the synthetic DL-serine of enzyme catalysis method according to claim 1, is characterized in that, the described catalyzer with serine hydroxymethylase activity is selected from microorganism or its handled thing that contains serine hydroxymethylase activity.
4. enzyme catalysis method according to claim 1 synthesizes the method for DL-serine, it is characterized in that, the described catalyzer with D-Thr aldolase activity is selected from the D-Thr zymohexase in the D-Thr zymohexase in Arthrobacter source, the D-Thr zymohexase in Xanthomonas campestris source or achromobacter source.
5. the method for the synthetic DL-serine of enzyme catalysis method according to claim 1, is characterized in that, the described catalyzer with D-Thr aldolase activity is selected from microorganism or its handled thing that contains D-Thr aldolase activity.
6. enzyme catalysis method according to claim 1 synthesizes the method for DL-serine, it is characterized in that, the described catalyzer with amino acid racemase activity is selected from the amino acid racemase in the amino acid racemase in pseudomonas putida source, the amino acid racemase in bacillus kaustophilus source or Pseudomonas taetrolens source.
7. the method for the synthetic DL-serine of enzyme catalysis method according to claim 1, is characterized in that, the described catalyzer with amino acid racemase activity is selected from microorganism or its handled thing that contains amino acid racemase activity.
8. the method for the synthetic DL-serine of enzyme catalysis method according to claim 1, is characterized in that, described coenzyme comprises one or more of pyridoxal phosphate and tetrahydrofolic acid (THFA).
9. enzyme catalysis method according to claim 1 synthesizes the method for DL-serine; it is characterized in that; in whole enzyme-catalyzed reaction, add cofactor to promote the process of enzymic catalytic reaction, described cofactor comprise the activator of enzyme and enzyme protectant one or more.
10. the method for the synthetic DL-serine of enzyme catalysis method according to claim 9, is characterized in that, the protective material of described enzyme comprises one or more of mercaptoethanol, dithiothreitol (DTT) and sodium bisulfite; The activator of described enzyme is divalent-metal ion.
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| CN108384818A (en) * | 2018-05-18 | 2018-08-10 | 南京大学 | A kind of method that enzymatic conversion method prepares D-His |
| WO2020043077A1 (en) * | 2018-08-29 | 2020-03-05 | 北京科技大学 | Method for preparing l-threo/erythro-p-methylsulfonylphenyl serine and enzyme for method |
| CN110872585A (en) * | 2018-08-29 | 2020-03-10 | 北京科技大学 | L- β -hydroxy- α -amino acid synthetase cyclized by SpyTag/Spycatcher and application thereof |
| CN110373440A (en) * | 2019-07-23 | 2019-10-25 | 长兴制药股份有限公司 | The method of one pot of enzyme process preparation DL-serine |
| CN110373440B (en) * | 2019-07-23 | 2022-03-01 | 长兴制药股份有限公司 | Method for preparing DL-serine by one-pot enzyme method |
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