CN106755209A - A kind of method that enzyme process prepares β nicotinamide mononucleotides - Google Patents
A kind of method that enzyme process prepares β nicotinamide mononucleotides Download PDFInfo
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- CN106755209A CN106755209A CN201611245619.4A CN201611245619A CN106755209A CN 106755209 A CN106755209 A CN 106755209A CN 201611245619 A CN201611245619 A CN 201611245619A CN 106755209 A CN106755209 A CN 106755209A
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/26—Preparation of nitrogen-containing carbohydrates
- C12P19/28—N-glycosides
- C12P19/30—Nucleotides
- C12P19/305—Pyrimidine nucleotides
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Abstract
The present invention relates to a kind of method that enzyme process prepares β nicotinamide mononucleotides, the method is with niacinamide ribose as substrate, generation β nicotinamide mononucleotides are reacted in the presence of phosphate donor, under the catalysis of the recombinant cell in niacinamide ribokinase and/or containing niacinamide ribokinase.The method that the enzyme process that the present invention is provided prepares β nicotinamide mononucleotides has important application value.Compared with the technology of existing chemical synthesis β nicotinamide mononucleotides, the inventive method is more environmentally-friendly, and cost is lower, and can provide purity product higher, thus can be more economical for health products and biomedicine field.
Description
Technical field
The present invention relates to a kind of preparation method of β-nicotinamide mononucleotide, more particularly to a kind of β-nicotinamide mononucleotide
Biological preparation method.
Background technology
β-nicotinamide mononucleotide is a kind of in recent years by widely studied and concern health products, is also for synthesizing cigarette
Acid amides adenine-dinucleotide（DPN）Key intermediate.It is reported that β-nicotinamide mononucleotide is in anti-aging（Referring to J
Nutr Sci Vitaminol (Tokyo). 2016;62(4):272-276）, treat diabetes（Cell Metab. 2011
Oct 5; 14(4): 528–536）Etc. aspect have great potential, Japan have related health products list marketing to the U.S..
Traditional β-nicotinamide mononucleotide production method is, with niacinamide ribose as raw material, phosphoric acid to be carried out with POCl3
Change is obtained（Referring to Chem. Commun. 1999,729-730）, yield is low, and product purity is low, and uses substantial amounts of organic
Solvent, serious to environmental disruption, wherein POCl3 is to compare relatively hazardous reagent.
The content of the invention
Regarding to the issue above, it is an object of the invention to provide a kind of method that enzyme process prepares β-nicotinamide mononucleotide, should
Method can produce the β-nicotinamide mononucleotide product of high-purity with relatively low cost, shorter cycle, and dirty to environment
Relatively conventional method is contaminated to be greatly reduced.
To reach above-mentioned purpose, the technical solution adopted by the present invention is as follows：
A kind of method that enzyme process prepares β-nicotinamide mononucleotide, the method is supplied with niacinamide ribose as substrate in phosphoric acid such as ATP
In the presence of body, under the catalysis of the recombinant cell in niacinamide ribokinase and/or containing niacinamide ribokinase react generation β-
Nicotinamide mononucleotide.
Preferably, the niacinamide ribokinase used by the present invention comes from saccharomyces cerevisiae（Saccharomyces
cerevisiae）.
It is highly preferred that the amino acid sequence of niacinamide ribokinase can have at least 80% with the sequence 2 in sequence table
Uniformity.Further, the amino acid sequence of niacinamide ribokinase and the sequence 2 in sequence table have at least 90% it is consistent
Property.Further, the amino acid sequence of niacinamide ribokinase is completely the same with sequence 2 in sequence table.
According to the present invention it is possible to make the reaction enter in the aqueous phase system of 4 DEG C ~ 50 DEG C and pH 5.0 ~ 9.0 of temperature
OK.Preferably, make the reaction is carried out in the aqueous phase system of 30 DEG C ~ 45 DEG C and pH 7.5 ~ 8.5 of temperature.
It is highly preferred that making reaction be carried out at 33 DEG C of temperature.
It is highly preferred that making reaction be carried out under pH 8.0.
According to a specific preferred aspect, reaction is set to be carried out in the Triethanolamine buffer of pH 8.0.
According to the present invention, described reaction is carried out under the catalysis of the recombinant cell containing niacinamide ribokinase, described
Recombinant cell can with and preferably microbial cell, wherein microorganism can with and preferably bacillus coli, wine brewing ferment
Female or Pichia pastoris etc..
According to a specific and preferred aspect, methods described is implemented as follows：Whole raw materials used by reaction are added to instead
Answer in kettle, after being well mixed, be placed under design temperature, stirring reaction.After completion of the reaction, can be reached by purification processes
The β of use requirement-nicotinamide mononucleotide product.One specific method of purification through including resin separate including after locate
Reason, according to the method for purification, can obtain the β-nicotinamide mononucleotide product of high purity more than 95%.
The present invention uses above-mentioned technical proposal, has the following advantages that compared to existing technology：
The method that the enzyme process that the present invention is provided prepares β-nicotinamide mononucleotide has important application value.Current chemistry side
It is seriously polluted that method is produced, the involved reactant all dangerous property when storing and using.The product that chemical method reaction is obtained
Product impurity is more, it is difficult to purify.By contrast, can provide purity product higher using enzymatic synthesis method of the invention, it is right
It is more environment-friendly, it is easy to purifying, thus can be more economical for health products, medicine and other fields, and will further expand it
Range of application.
Specific embodiment
Presently preferred embodiments of the present invention is described in detail below so that advantages and features of the invention can be easier to by
It will be understood by those skilled in the art that.
According to the present invention, can there is in enzyme freeze-dried powder form or be present in recombinant cell in niacinamide ribokinase used
In.
The preparation method of niacinamide ribokinase is as follows：
The recombination bacillus coli of niacinamide ribokinase is obtained using molecule clone technology, technique for gene engineering（Or other micro- lifes
Thing bacterium）Expression bacterial strain, then ferments recombination bacillus coli, prepares the recombinant cell containing niacinamide ribokinase, or
Person prepares the freeze-dried powder of niacinamide ribokinase.
Molecule clone technology of the present invention and technique for gene engineering are known.Molecule clone technology can be found in
《Molecular Cloning:A Laboratory guide》The third edition（J. husky nurse Brooker writes, and 2005）.
The expression step for building recombinant bacterial strain of the present invention using technique for gene engineering is as follows：
（1）Genetic fragment according to needed for gene chemical synthesis after Genbank NM_001182967.1 sequence optimisation codons, is connected into
PET30a carriers, two ends add NdeI and BamHI restriction enzyme sites respectively；
（2）Recombinant plasmid transformed is entered into e. coli bl21（DE3）In, expressed using IPTG induction destination proteins, obtain cigarette
The expression of recombinant e. coli bacterial strain of acid amides ribokinase.
Prepared using the expression of recombinant e. coli bacterial strain containing niacinamide ribokinase and contain niacinamide ribokinase
Recombinant cell, or niacinamide ribokinase freeze-dried powder the step of it is as follows：
With 1% ratio by the expression of recombinant e. coli inoculation containing niacinamide ribokinase to 4ml LB liquid mediums
In, 37 DEG C of shaken cultivations（200 rpm）Overnight, overnight culture is taken to be transferred in 50 ml LB liquid mediums with 1% inoculum concentration,
37 DEG C of shaken cultivations（200 rpm）0.6-0.8 is reached to OD600 values, the mM IPTG of final concentration 0.4 is added in 20 DEG C of vibration trainings
Support overnight.Induction is collected by centrifugation cell after terminating（8,000 rpm, 10 min）, buffered with the mmol/L triethanolamines of 5 ml 20
Liquid（pH8.0）Re-suspended cell, obtains the recombinant cell, or the further ultrasonic disruption cell in ice bath, by broken liquid from
The heart（8,000 rpm, 10 min）, collect supernatant and freeze, obtain the freeze-dried powder.
The present invention is described in more detail below in conjunction with specific embodiment.
Embodiment 1：Prepare the recombinant Bacillus coli cells of niacinamide-containing ribokinase
Sequence 1 and sequence 2 in sequence table, gene chemical synthesis niacinamide ribokinase genetic fragment, two ends add respectively
NdeI and BamHI restriction enzyme sites, are connected into pET30a carriers（Suzhou Jin Weizhi Bioisystech Co., Ltd produces）, convert BL21
（DE3）Bacterial strain.
Niacinamide ribokinase strain is inoculated into by 4 ml LB liquid mediums, 37 DEG C of shaken cultivations with 1% ratio（200
rpm）Overnight, overnight culture is taken to be transferred in 50 ml LB liquid mediums, 37 DEG C of shaken cultivations with 1% inoculum concentration（200 rpm）
Reach 0.6-0.8 to OD600 values, add the mM IPTG of final concentration 0.4 in 20 DEG C of shaken cultivations overnight.Induction is centrifuged after terminating and receives
Collection cell（8,000 rpm, 10 min）, with the mmol/L Triethanolamine buffers of 5 ml 20（pH8.0）Re-suspended cell, is contained
The recombinant cell of niacinamide ribokinase is used to be catalyzed.
Embodiment 2：Prepare niacinamide ribokinase freeze-dried powder
By the recombinant cell of obtained niacinamide ribokinase in embodiment 1 in ice bath ultrasonic disruption cell, by broken liquid
Centrifugation（8,000 rpm, 10 min）, collect supernatant and freeze, obtain the freeze-dried powder of niacinamide ribokinase.
Embodiment 3：It is substrate enzymatic clarification β-nicotinamide mononucleotide with niacinamide ribose
In the present embodiment, the niacinamide ribokinase freeze-dried powder for being prepared according to the method for embodiment 2 be used to catalyze and synthesize β-cigarette
Acid amides mononucleotide.
The mmol/L Triethanolamine buffers of 1 L 20 are sequentially added in reaction system（pH8.0）, final concentration 18mM cigarettes
After acid amides ribose, the ATP of final concentration 20mM, the MgCl2 of final concentration 20mM, the g of niacinamide ribokinase freeze-dried powder 5 are well mixed
It is placed in 33 DEG C of water-baths, the h of 300 rpm stirring reactions 24.Reaction is converted after terminating with high performance liquid chromatography detection niacinamide ribose
Rate is more than 90%.Separated through ion exchange resin, the post processing such as lyophilized obtains β-nicotinamide mononucleotide 4.9g after purification, pure
Degree is more than 95%.
The above embodiments merely illustrate the technical concept and features of the present invention, is a kind of preferred embodiment, and its purpose exists
In allowing person skilled in the art to will appreciate that present disclosure and implementing according to this, guarantor of the invention can not be limited with this
Shield scope.The equivalent change or modification that all Spirit Essences of the invention are made, should all cover in protection scope of the present invention
Within.
Sequence table
<110>Suzhou Chinese biotechnology of enzymes Co., Ltd
<120>A kind of method that enzyme process prepares β-nicotinamide mononucleotide
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 723
<212> DNA
<213>Saccharomyces cerevisiae
<400> 1
atgacgagca aaaaagtgat cctggtcgca ctgtccggtt gctcctctag cggcaaaacc 60
actattgcga aactgacggc gtcgctgttt accaaagcta ccctgattca tgaagacgac 120
ttctataaac atgacaacga agtaccggtc gatgccaaat ataacattca aaactgggac 180
agtccggaag cgttggactt taaattgttc gggaaggagt tggatgtaat caaacagacg 240
ggcaaaattg caaccaagct gatccacaac aataacgttg atgatccatt cactaaattc 300
catatcgacc gtcaggtgtg ggatgaactg aaagctaaat acgacagcat taacgacgac 360
aaatacgaag ttgtgattgt cgacggtttt atgatcttca acaacactgg tatttctaag 420
aagttcgatc tgaaaatcct cgttcgtgca ccgtacgaag ttctgaaaaa acgtcgcgcg 480
tctcgtaaag gctaccagac gctggactct ttctgggtag acccgccgta ctatttcgac 540
gaattcgttt acgaaagcta tcgcgctaac cacgcccagc tgtttgttaa cggtgacgtg 600
gaaggtctgt tagacccgcg taagtccaaa aacattaaag agtttattaa cgatgatgac 660
actccgattg ctaaaccgct gtcctgggtt tgccaggaaa tcctgaaact gtgcaaagat 720
taa 723
<210> 2
<211> 240
<212> PRT
<213>Saccharomyces cerevisiae
<400> 2
Met Thr Ser Lys Lys Val Ile Leu Val Ala Leu Ser Gly Cys Ser Ser
1 5 10 15
Ser Gly Lys Thr Thr Ile Ala Lys Leu Thr Ala Ser Leu Phe Thr Lys
20 25 30
Ala Thr Leu Ile His Glu Asp Asp Phe Tyr Lys His Asp Asn Glu Val
35 40 45
Pro Val Asp Ala Lys Tyr Asn Ile Gln Asn Trp Asp Ser Pro Glu Ala
50 55 60
Leu Asp Phe Lys Leu Phe Gly Lys Glu Leu Asp Val Ile Lys Gln Thr
65 70 75 80
Gly Lys Ile Ala Thr Lys Leu Ile His Asn Asn Asn Val Asp Asp Pro
85 90 95
Phe Thr Lys Phe His Ile Asp Arg Gln Val Trp Asp Glu Leu Lys Ala
100 105 110
Lys Tyr Asp Ser Ile Asn Asp Asp Lys Tyr Glu Val Val Ile Val Asp
115 120 125
Gly Phe Met Ile Phe Asn Asn Thr Gly Ile Ser Lys Lys Phe Asp Leu
130 135 140
Lys Ile Leu Val Arg Ala Pro Tyr Glu Val Leu Lys Lys Arg Arg Ala
145 150 155 160
Ser Arg Lys Gly Tyr Gln Thr Leu Asp Ser Phe Trp Val Asp Pro Pro
165 170 175
Tyr Tyr Phe Asp Glu Phe Val Tyr Glu Ser Tyr Arg Ala Asn His Ala
180 185 190
Gln Leu Phe Val Asn Gly Asp Val Glu Gly Leu Leu Asp Pro Arg Lys
195 200 205
Ser Lys Asn Ile Lys Glu Phe Ile Asn Asp Asp Asp Thr Pro Ile Ala
210 215 220
Lys Pro Leu Ser Trp Val Cys Gln Glu Ile Leu Lys Leu Cys Lys Asp
225 230 235 240
SEQUENCE LISTING
<110>Suzhou Chinese biotechnology of enzymes Co., Ltd
<120>A kind of method that enzyme process prepares β-nicotinamide mononucleotide
<130> 2010
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 723
<212> DNA
<213>Saccharomyces cerevisiae
<400> 1
atgacgagca aaaaagtgat cctggtcgca ctgtccggtt gctcctctag cggcaaaacc 60
actattgcga aactgacggc gtcgctgttt accaaagcta ccctgattca tgaagacgac 120
ttctataaac atgacaacga agtaccggtc gatgccaaat ataacattca aaactgggac 180
agtccggaag cgttggactt taaattgttc gggaaggagt tggatgtaat caaacagacg 240
ggcaaaattg caaccaagct gatccacaac aataacgttg atgatccatt cactaaattc 300
catatcgacc gtcaggtgtg ggatgaactg aaagctaaat acgacagcat taacgacgac 360
aaatacgaag ttgtgattgt cgacggtttt atgatcttca acaacactgg tatttctaag 420
aagttcgatc tgaaaatcct cgttcgtgca ccgtacgaag ttctgaaaaa acgtcgcgcg 480
tctcgtaaag gctaccagac gctggactct ttctgggtag acccgccgta ctatttcgac 540
gaattcgttt acgaaagcta tcgcgctaac cacgcccagc tgtttgttaa cggtgacgtg 600
gaaggtctgt tagacccgcg taagtccaaa aacattaaag agtttattaa cgatgatgac 660
actccgattg ctaaaccgct gtcctgggtt tgccaggaaa tcctgaaact gtgcaaagat 720
taa 723
<210> 2
<211> 240
<212> PRT
<213>Saccharomyces cerevisiae
<400> 2
Met Thr Ser Lys Lys Val Ile Leu Val Ala Leu Ser Gly Cys Ser Ser
1 5 10 15
Ser Gly Lys Thr Thr Ile Ala Lys Leu Thr Ala Ser Leu Phe Thr Lys
20 25 30
Ala Thr Leu Ile His Glu Asp Asp Phe Tyr Lys His Asp Asn Glu Val
35 40 45
Pro Val Asp Ala Lys Tyr Asn Ile Gln Asn Trp Asp Ser Pro Glu Ala
50 55 60
Leu Asp Phe Lys Leu Phe Gly Lys Glu Leu Asp Val Ile Lys Gln Thr
65 70 75 80
Gly Lys Ile Ala Thr Lys Leu Ile His Asn Asn Asn Val Asp Asp Pro
85 90 95
Phe Thr Lys Phe His Ile Asp Arg Gln Val Trp Asp Glu Leu Lys Ala
100 105 110
Lys Tyr Asp Ser Ile Asn Asp Asp Lys Tyr Glu Val Val Ile Val Asp
115 120 125
Gly Phe Met Ile Phe Asn Asn Thr Gly Ile Ser Lys Lys Phe Asp Leu
130 135 140
Lys Ile Leu Val Arg Ala Pro Tyr Glu Val Leu Lys Lys Arg Arg Ala
145 150 155 160
Ser Arg Lys Gly Tyr Gln Thr Leu Asp Ser Phe Trp Val Asp Pro Pro
165 170 175
Tyr Tyr Phe Asp Glu Phe Val Tyr Glu Ser Tyr Arg Ala Asn His Ala
180 185 190
Gln Leu Phe Val Asn Gly Asp Val Glu Gly Leu Leu Asp Pro Arg Lys
195 200 205
Ser Lys Asn Ile Lys Glu Phe Ile Asn Asp Asp Asp Thr Pro Ile Ala
210 215 220
Lys Pro Leu Ser Trp Val Cys Gln Glu Ile Leu Lys Leu Cys Lys Asp
225 230 235 240
Claims (10)
1. a kind of method that enzyme process prepares β-nicotinamide mononucleotide, it is characterised in that：The method with niacinamide ribose as substrate,
In the presence of phosphate donor, under the catalysis of the recombinant cell in niacinamide ribokinase and/or containing niacinamide ribokinase
Reaction generation β-nicotinamide mononucleotide.
2. method according to claim 1, it is characterised in that：Described phosphate donor is ATP.
3. method according to claim 1, it is characterised in that：Described niacinamide ribokinase comes from saccharomyces cerevisiae.
4. method according to claim 3, it is characterised in that：The amino acid sequence and sequence of described niacinamide ribokinase
Sequence 2 in list has at least 80% uniformity.
5. method according to claim 4, it is characterised in that：The amino acid sequence and sequence of described niacinamide ribokinase
Sequence 2 in list has at least 90% uniformity.
6. method according to claim 1, it is characterised in that：Make described reaction in temperature for 30 ~ 40 DEG C and pH are
Carried out in 7.5 ~ 8.5 aqueous phase system.
7. method according to claim 6, it is characterised in that：Described reaction is set to be carried out in Triethanolamine buffer.
8. method according to claim 7, it is characterised in that：Whole raw materials used by described reaction are added to reaction
In kettle, after being well mixed, it is placed under design temperature, stirring reaction.
9. method according to claim 1, it is characterised in that：Described reaction is in the restructuring containing niacinamide ribokinase
Carried out under the catalysis of cell, described recombinant cell is microbial cell.
10. method according to claim 9, it is characterised in that：Described microorganism is bacillus coli, wine brewing ferment
Female or Pichia pastoris.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611245619.4A CN106755209B (en) | 2016-12-29 | 2016-12-29 | Method for preparing beta-nicotinamide mononucleotide by enzyme method |
| PCT/CN2016/113623 WO2018120069A1 (en) | 2016-12-29 | 2016-12-30 | METHOD FOR ENZYMATICALLY PREPARING β-NICOTINAMIDE MONONUCLEOTIDE |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611245619.4A CN106755209B (en) | 2016-12-29 | 2016-12-29 | Method for preparing beta-nicotinamide mononucleotide by enzyme method |
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| Publication Number | Publication Date |
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| CN106755209A true CN106755209A (en) | 2017-05-31 |
| CN106755209B CN106755209B (en) | 2021-07-23 |
Family
ID=58929022
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| CN201611245619.4A Active CN106755209B (en) | 2016-12-29 | 2016-12-29 | Method for preparing beta-nicotinamide mononucleotide by enzyme method |
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| WO (1) | WO2018120069A1 (en) |
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| CN106755209B (en) | 2021-07-23 |
| WO2018120069A1 (en) | 2018-07-05 |
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