CN106755209B - Method for preparing beta-nicotinamide mononucleotide by enzyme method - Google Patents
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- CN106755209B CN106755209B CN201611245619.4A CN201611245619A CN106755209B CN 106755209 B CN106755209 B CN 106755209B CN 201611245619 A CN201611245619 A CN 201611245619A CN 106755209 B CN106755209 B CN 106755209B
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Abstract
The invention relates to a method for preparing beta-nicotinamide mononucleotide by an enzyme method, which takes nicotinamide ribose as a substrate and reacts under the catalysis of nicotinamide ribokinase and/or recombinant cells containing nicotinamide ribokinase to generate the beta-nicotinamide mononucleotide in the presence of a phosphate group donor. The method for preparing beta-nicotinamide mononucleotide by using the enzyme method has important application value. Compared with the existing technology for chemically synthesizing beta-nicotinamide mononucleotide, the method is more environment-friendly and lower in cost, and can provide a product with higher purity, so that the method can be more economically used in the fields of health care products and biological medicines.
Description
Technical Field
The invention relates to a preparation method of beta-nicotinamide mononucleotide, in particular to a biological preparation method of beta-nicotinamide mononucleotide.
Background
Beta-nicotinamide mononucleotide is a health product which is widely researched and focused in recent years, and is also a key intermediate for synthesizing nicotinamide adenine dinucleotide (coenzyme I). Beta-nicotinamide mononucleotide has been reported to have great potential in anti-aging (see J Nutr Sci vitamin (Tokyo) 2016;62(4): 272) 276), treating diabetes (Cell Metab. 2011 Oct 5; 14(4): 528) 536) and the like, and related health care products are sold on the market in Japan and America.
The traditional method for producing beta-nicotinamide mononucleotide is to use nicotinamide ribose as raw material and to use phosphorus oxychloride for phosphorylation to obtain (see chem. Commun. 1999, 729-.
Disclosure of Invention
In view of the above problems, the present invention provides an enzymatic method for preparing beta-nicotinamide mononucleotide, which can produce high purity beta-nicotinamide mononucleotide product at lower cost and in shorter period, and has greatly reduced environmental pollution compared with the traditional method.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a process for preparing beta-nicotinamide mononucleotide by enzyme method features that nicotinamide ribose is used as substrate and reacts under the existance of phosphate donor such as ATP and the catalysis of nicotinamide ribokinase and/or the recombinant cell containing nicotinamide ribokinase to generate beta-nicotinamide mononucleotide.
Preferably, the nicotinamide ribokinase used in the present invention is derived from Saccharomyces cerevisiae (Saccharomyces cerevisiae).
More preferably, the amino acid sequence of nicotinamide ribokinase may have at least 80% identity with sequence 2 of the sequence listing. Further, the amino acid sequence of nicotinamide ribokinase has at least 90% identity with sequence 2 in the sequence table. Furthermore, the amino acid sequence of the nicotinamide ribokinase is completely consistent with the sequence 2 in the sequence table.
According to the invention, the reaction can be carried out in an aqueous phase system at a temperature of 4-50 ℃ and a pH of 5.0-9.0. Preferably, the reaction is carried out in an aqueous system at a temperature of 30 ℃ to 45 ℃ and a pH of 7.5 to 8.5.
More preferably, the reaction is carried out at a temperature of 33 ℃.
More preferably, the reaction is carried out at pH 8.0.
According to a particularly preferred aspect, the reaction is carried out in triethanolamine buffer at pH 8.0.
According to the invention, the reaction is carried out under the catalysis of recombinant cells containing nicotinamide ribokinase, the recombinant cells can be and are preferably microbial cells, and the microorganisms can be and are preferably Escherichia coli, saccharomyces cerevisiae or pichia pastoris and the like.
According to a particular and preferred aspect, the method is carried out as follows: all the raw materials used in the reaction are added into a reaction kettle, mixed evenly and placed at a set temperature for stirring reaction. After the reaction is finished, the beta-nicotinamide mononucleotide product meeting the use requirement can be obtained through purification treatment. One specific purification method is post-treatment including resin separation, according to which beta-nicotinamide mononucleotide products with purity up to 95% or more can be obtained.
By adopting the technical scheme, compared with the prior art, the invention has the following advantages:
the method for preparing beta-nicotinamide mononucleotide by using the enzyme method has important application value. Current chemical methods are very polluting and involve hazardous reagents for storage and use. The product obtained by the chemical reaction has more impurities and is difficult to purify. Compared with the prior art, the enzymatic synthesis method can provide a product with higher purity, is more environment-friendly and convenient for purification, so that the enzymatic synthesis method can be more economically used in the fields of health care products, medicines and the like, and can further expand the application range of the enzymatic synthesis method.
Detailed Description
The following detailed description of the preferred embodiments of the invention is provided to enable those skilled in the art to more readily understand the advantages and features of the invention.
According to the invention, the nicotinamide ribokinase used can be present in the form of an enzyme lyophilized powder or in recombinant cells.
The nicotinamide ribokinase is obtained as follows:
the recombinant escherichia coli (or other microbial bacteria) expression strain of the nicotinamide ribokinase is obtained by utilizing a molecular cloning technology and a genetic engineering technology, and then the recombinant escherichia coli is fermented to prepare recombinant cells containing the nicotinamide ribokinase or prepare freeze-dried powder of the nicotinamide ribokinase.
The molecular cloning and genetic engineering techniques described herein are known. Molecular cloning techniques can be found in molecular cloning, a laboratory manual, third edition (J. SammBruki, 2005).
The expression steps for constructing the recombinant strain of the invention by adopting the genetic engineering technology are as follows:
(1) optimizing codon according to the sequence of Genbank NM-001182967.1, then gene synthesizing the required gene fragment, connecting into pET30a vector, adding NdeI and BamHI enzyme cutting sites at both ends;
(2) and (3) transforming the recombinant plasmid into escherichia coli BL21 (DE 3), and inducing the expression of the target protein by IPTG to obtain the recombinant escherichia coli expression strain of the nicotinamide ribokinase.
The steps of preparing recombinant cells containing nicotinamide ribokinase or freeze-dried powder of nicotinamide ribokinase by using recombinant escherichia coli expression strains containing nicotinamide ribokinase are as follows:
the recombinant E.coli expression strain containing nicotinamide ribokinase was inoculated at a ratio of 1% to 4ml of liquid LB medium, cultured overnight with shaking (200 rpm) at 37 ℃, the overnight culture was taken out and inoculated with 1% inoculum size to 50 ml of liquid LB medium, cultured with shaking (200 rpm) at 37 ℃ until the OD600 value reached 0.6-0.8, and cultured overnight with shaking at 20 ℃ with the addition of 0.4 mM IPTG at the final concentration. After induction, cells are collected by centrifugation (8,000 rpm, 10 min), and the cells are resuspended in 5 ml of 20 mmol/L triethanolamine buffer (pH 8.0) to obtain the recombinant cells, or the cells are further disrupted by ultrasonic waves in an ice bath, the disruption solution is centrifuged (8,000 rpm, 10 min), and the supernatant is collected and lyophilized to obtain the lyophilized powder.
The present invention is described in more detail below with reference to specific examples.
Example 1: preparation of recombinant E.coli cells containing Nicotinamide ribokinase
According to the sequence 1 and the sequence 2 in the sequence table, a nicotinamide ribokinase gene fragment is synthesized, NdeI and BamHI enzyme cutting sites are respectively added at two ends, and a pET30a vector (produced by Jinzhi Biotechnology Ltd. Suzhou) is connected to transform a BL21 (DE 3) strain.
Nicotinamide ribokinase was inoculated into 4ml of liquid LB medium at a ratio of 1%, cultured with shaking (200 rpm) at 37 ℃ overnight, the overnight culture was transferred to 50 ml of liquid LB medium at an inoculum size of 1%, cultured with shaking (200 rpm) at 37 ℃ until the OD600 value reached 0.6-0.8, and cultured with shaking at 20 ℃ overnight with the addition of 0.4 mM IPTG at the final concentration. After induction, cells were collected by centrifugation (8,000 rpm, 10 min), and resuspended in 5 ml of 20 mmol/L triethanolamine buffer (pH 8.0) to obtain recombinant cells containing nicotinamide ribokinase for catalysis.
Example 2: preparation of nicotinamide ribokinase lyophilized powder
The recombinant cells of nicotinamide ribokinase prepared in example 1 were disrupted by ultrasonication in ice bath, the disruption solution was centrifuged (8,000 rpm, 10 min), and the supernatant was collected and lyophilized to obtain lyophilized powder of nicotinamide ribokinase.
Example 3: enzymatic synthesis of beta-nicotinamide mononucleotide by using nicotinamide ribose as substrate
In this example, nicotinamide ribokinase lyophilized powder prepared according to the method of example 2 was used to catalyze the synthesis of beta-nicotinamide mononucleotide.
1L of 20 mmol/L triethanolamine buffer solution (pH 8.0), 18mM nicotinamide ribose with final concentration, 20mM ATP with final concentration, 20mM MgCl2 with final concentration and 5 g nicotinamide ribokinase lyophilized powder are sequentially added into the reaction system, mixed uniformly and placed in a water bath at 33 ℃, and stirred at 300 rpm for reaction for 24 hours. After the reaction is finished, the conversion rate of nicotinamide ribose is detected to be more than 90% by high performance liquid chromatography. After post-treatment and purification such as ion exchange resin separation, freeze-drying and the like, 4.9g of beta-nicotinamide mononucleotide is obtained, and the purity is higher than 95%.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and are preferred embodiments, which are intended to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the scope of the present invention. All equivalent changes or modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Sequence listing
<110> Suzhou Han enzyme Biotechnology Co., Ltd
<120> method for preparing beta-nicotinamide mononucleotide by enzyme method
<160> 2
<170> PatentIn version 3.5
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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
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<213> Saccharomyces cerevisiae
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Met Thr Ser Lys Lys Val Ile Leu Val Ala Leu Ser Gly Cys Ser Ser
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Ala Thr Leu Ile His Glu Asp Asp Phe Tyr Lys His Asp Asn Glu Val
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Pro Val Asp Ala Lys Tyr Asn Ile Gln Asn Trp Asp Ser Pro Glu Ala
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Phe Thr Lys Phe His Ile Asp Arg Gln Val Trp Asp Glu Leu Lys Ala
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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
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Lys Ile Leu Val Arg Ala Pro Tyr Glu Val Leu Lys Lys Arg Arg Ala
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Ser Arg Lys Gly Tyr Gln Thr Leu Asp Ser Phe Trp Val Asp Pro Pro
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Tyr Tyr Phe Asp Glu Phe Val Tyr Glu Ser Tyr Arg Ala Asn His Ala
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Gln Leu Phe Val Asn Gly Asp Val Glu Gly Leu Leu Asp Pro Arg Lys
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Ser Lys Asn Ile Lys Glu Phe Ile Asn Asp Asp Asp Thr Pro Ile Ala
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Lys Pro Leu Ser Trp Val Cys Gln Glu Ile Leu Lys Leu Cys Lys Asp
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SEQUENCE LISTING
<110> Suzhou Han enzyme Biotechnology Co., Ltd
<120> method for preparing beta-nicotinamide mononucleotide by enzyme method
<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 (4)
1. A method for preparing beta-nicotinamide mononucleotide by an enzymatic method is characterized by comprising the following steps: the method takes nicotinamide ribose as a substrate, and generates beta-nicotinamide mononucleotide by the catalysis of nicotinamide ribokinase and/or recombinant cells containing the nicotinamide ribokinase in the presence of a phosphate group donor, wherein the nicotinamide ribokinase is from saccharomyces cerevisiae, and the amino acid sequence of the nicotinamide ribokinase is consistent with the sequence 2 in a sequence table; carrying out the reaction in a triethanolamine buffer solution with the temperature of 30-40 ℃ and the pH of 7.5-8.5; the phosphate group donor is ATP.
2. The method of claim 1, wherein: all the raw materials used for the reaction are added into a reaction kettle, mixed evenly and placed at a set temperature for stirring reaction.
3. The method of claim 1, wherein: the reaction is carried out under the catalysis of recombinant cells containing nicotinamide ribokinase, and the recombinant cells are microbial cells.
4. The method of claim 3, wherein: the microorganism is Escherichia coli, Saccharomyces cerevisiae or Pichia pastoris.
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| Application Number | Priority Date | Filing Date | Title |
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| 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 |
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| CN201611245619.4A CN106755209B (en) | 2016-12-29 | 2016-12-29 | Method for preparing beta-nicotinamide mononucleotide by enzyme method |
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| CN106755209B true CN106755209B (en) | 2021-07-23 |
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| JP6949002B6 (en) | 2015-08-05 | 2021-11-17 | メトロ インターナショナル バイオテック，エルエルシー | Nicotinamide mononucleotide derivatives and their use |
| GB2542881B (en) | 2015-10-02 | 2020-01-01 | Carr Andrew | Crystal forms of ß-nicotinamide mononucleotide |
| CN117887788A (en) | 2017-09-29 | 2024-04-16 | 三菱化学株式会社 | Method for producing nicotinamide mononucleotide |
| US11180521B2 (en) | 2018-01-30 | 2021-11-23 | Metro International Biotech, Llc | Nicotinamide riboside analogs, pharmaceutical compositions, and uses thereof |
| CN108949865A (en) * | 2018-08-17 | 2018-12-07 | 尚科生物医药（上海）有限公司 | One step enzyme method of immobilized whole-cell catalysis preparation β-nicotinamide mononucleotide |
| US10618927B1 (en) | 2019-03-22 | 2020-04-14 | Metro International Biotech, Llc | Compositions and methods for modulation of nicotinamide adenine dinucleotide |
| US11939348B2 (en) | 2019-03-22 | 2024-03-26 | Metro International Biotech, Llc | Compositions comprising a phosphorus derivative of nicotinamide riboside and methods for modulation of nicotinamide adenine dinucleotide |
| EP4059571A4 (en) * | 2019-10-11 | 2023-11-15 | National University Corporation Shizuoka University | Lactic acid bacteria that produce nicotinamide riboside, and lactic acid bacteria that produce nicotinamide mononucleotide and nicotinamide riboside |
| CN111424064A (en) * | 2020-04-20 | 2020-07-17 | 比瑞博生物科技(北京)有限公司 | High-purity NMN preparation process based on enzyme method |
| CN111593083A (en) * | 2020-05-29 | 2020-08-28 | 江苏易诺维生物医学研究院有限公司 | Method for preparing beta-nicotinamide mononucleotide |
| CN113755413B (en) * | 2020-06-04 | 2023-09-05 | 苏州华赛生物工程技术有限公司 | Recombinant microorganism for producing beta-nicotinamide mononucleotide and method for producing NMN by using same |
| CN111549012B (en) * | 2020-06-08 | 2022-05-13 | 石家庄创组生物科技有限公司 | Ribose kinase mutant and application thereof |
| CN111635917A (en) * | 2020-06-11 | 2020-09-08 | 辽宁天华生物药业有限公司 | Preparation method of beta-nicotinamide ribodinucleotide |
| WO2021253362A1 (en) * | 2020-06-19 | 2021-12-23 | 邦泰生物工程(深圳)有限公司 | Method for preparing nicotinamide mononucleotide by using nicotinamide as raw material |
| CN111705096A (en) * | 2020-06-29 | 2020-09-25 | 上海舒泽生物科技研究所 | Method for producing beta-nicotinamide mononucleotide by enzyme conversion method |
| CN112159831B (en) * | 2020-09-30 | 2022-06-03 | 湖州颐盛生物科技有限公司 | Method for preparing nicotinamide mononucleotide |
| CN112522232B (en) * | 2020-12-07 | 2023-04-07 | 内蒙古金达威药业有限公司 | Synthetic method of nicotinamide ribokinase and nicotinamide mononucleotide |
| CN112869164B (en) * | 2021-03-02 | 2023-04-07 | 获嘉天众生物技术有限公司 | Preparation method of broccoli extract with high content of beta-Nicotinamide Mononucleotide (NMN) |
| CN113122594B (en) * | 2021-04-13 | 2023-04-25 | 百瑞全球有限公司 | Method for preparing mononucleotide of nicotinic acid or derivative thereof and biological product thereof |
| MX2023013903A (en) | 2021-05-27 | 2023-12-11 | Metro Int Biotech Llc | Crystalline solids of nicotinic acid mononucleotide and esters thereof and methods of making and use. |
| CN113481262B (en) * | 2021-06-29 | 2022-09-16 | 康盈红莓(中山)生物科技有限公司 | NMN semisynthesis method with participation of adenosine |
| CN113881738A (en) * | 2021-09-09 | 2022-01-04 | 武汉生命奥义生物科技有限公司 | Biocatalytic high-purity NMN production process |
| CN113755353B (en) * | 2021-10-19 | 2023-02-28 | 风火轮(上海)生物科技有限公司 | Saccharomyces cerevisiae for preparing NMN |
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| CN108368493A (en) * | 2015-06-11 | 2018-08-03 | 新南创新私人有限公司 | Enzymatic system and method for synthesizing nicotinamide mononucleotide and niacin mononucleotide |
| CN105755019A (en) * | 2016-03-07 | 2016-07-13 | 华南师范大学 | Nicotinamide mononucleotide adenylyl transferase gene and application thereof |
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- 2016-12-30 WO PCT/CN2016/113623 patent/WO2018120069A1/en active Application Filing
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| CN106755209A (en) | 2017-05-31 |
| WO2018120069A1 (en) | 2018-07-05 |
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