CN116323912A - Preparation method of nicotinamide mononucleotide - Google Patents
Preparation method of nicotinamide mononucleotide Download PDFInfo
- Publication number
- CN116323912A CN116323912A CN202180062003.6A CN202180062003A CN116323912A CN 116323912 A CN116323912 A CN 116323912A CN 202180062003 A CN202180062003 A CN 202180062003A CN 116323912 A CN116323912 A CN 116323912A
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- CN
- China
- Prior art keywords
- nicotinamide mononucleotide
- reaction
- buffer
- fructobacillus
- strain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
Abstract
The invention relates to a preparation method of nicotinamide mononucleotide. The present invention provides a method for producing nicotinamide mononucleotide, which comprises a step of reacting a microorganism having nicotinamide mononucleotide productivity in a solution having a pH of 4 to 10.
Description
Technical Field
The present invention relates to a method for producing nicotinamide mononucleotide, which comprises a nicotinamide mononucleotide enrichment reaction step in which a microorganism having nicotinamide mononucleotide production ability is reacted in a solution (e.g., buffer solution or the like) having a pH of 4 to 10.
Background
In recent years, it has been shown to be oldDiseases associated with aging and nicotinamide adenine dinucleotide (nicotinamide adenine dinucleotide; NAD) + ) Amount reduction and NAD + The decrease in the activity of a dependent deacetylase Sirtuin (Sirtuin) has a close relationship (non-patent documents 1 and 2). In addition, it is considered that activation of sirtuin suggests many effects related to prolongation of the life span or health improvement of calorie restriction (non-patent document 2).
NAD + The coenzyme has been known as a redox reaction since long, but in recent years, it has also been known to act as a substrate for polyadenylation-diphosphate ribose polymerase, CD38/CD157, sirtuin, and the like (non-patent document 1). In particular, sirtuin-based slave NAD + The decomposition reaction into nicotinamide promotes deacetylation of a sirtuin-based lysine residue conjugated thereto, and thus participates in various life phenomena related to health and longevity (non-patent documents 1 and 2). NAD is known to accompany aging + Reduced amount and sirtuin activity; on the other hand, as a resynthesis of NAD from nicotinamide + NAD such as nicotinamide ribosyl phosphate transferase (NAMPT), specifically nicotinamide mononucleotide (nicotinamide mononucleotide; NMN) and nicotinamide riboside (nicotinamide riboside; NR), which are the enzyme reaction products of the rate-limiting enzymes + The recruitment of intermediate metabolites is to effectively re-activate sirtuin (non-patent document 1), and further, it is known that the activation of sirtuin causes a wide range of antioxidant actions. Thus, nicotinamide mononucleotide is known to contribute to many biological phenomena associated with extended life and health improvement of calorie restriction, and the like.
Thus, a method for efficiently producing nicotinamide mononucleotide is desired. Hitherto, it has been reported that nicotinamide mononucleotide can be obtained from yeasts having edible experience such as torula yeast (patent document 1), and nicotinamide riboside can be obtained from genetically modified bacteria selected from bacteria of the group consisting of escherichia coli (e.coli), bacillus subtilis (b.subtilis), corynebacterium glutamicum (c.glutamicum), acinetobacter belli (a.bayyi) and rochanterium eutropha (r.euutropha) (patent document 2).
In addition, as a method for producing nicotinamide mononucleotide, a method for producing β -nicotinamide mononucleotide is known which includes a step of reacting a metabolic composition of a microorganism belonging to the genus Aspergillus with β -nicotinamide adenine dinucleotide as a substrate (patent document 3). More specifically, the β -nicotinamide adenine dinucleotide contained in the cultured yeast is produced as nicotinamide mononucleotide by an enzymatic reaction. In the method of the patent, an enzyme must be used for the reaction, and there is a concern about the safety of eating the nicotinamide mononucleotide produced. In addition, the production of nicotinamide mononucleotide cannot be said to be sufficient.
Prior art literature
Patent literature
Patent document 1: international publication No. 2017/200050
Patent document 2: international publication No. 2017/083858
Patent document 3: international publication No. 2019/181961
Non-patent literature
Non-patent document 1: imai, S. & Guarente, l. (2014) Trends Cell biol.,24, 464-471.
Non-patent document 2: guarente, L. (2013) Genes Dev.,27, 2072-2085.
Disclosure of Invention
Technical problem to be solved by the invention
In the previous microbiological methods for producing nicotinamide mononucleotide, there is still room for improvement in production efficiency.
Accordingly, an object of the present invention is to provide a method for producing nicotinamide mononucleotide with high efficiency.
Means for solving the technical problems
As a result of intensive studies, the present inventors have found that the amount of nicotinamide mononucleotide produced increases by reacting a microorganism having a nicotinamide mononucleotide production ability in a reaction solution having a pH of 4.0 to 10.0 (for example, a reaction solution in which the pH is adjusted with a buffer solution, etc.). The present invention has been completed by repeating further studies based on this knowledge.
Item 1. A method of preparing nicotinamide mononucleotide comprising:
and a nicotinamide mononucleotide enrichment reaction step in which a microorganism having nicotinamide mononucleotide production ability is reacted in a reaction solution having a pH of 4 to 10.
The method according to item 2, wherein the microorganism having nicotinamide mononucleotide production ability is a lactic acid bacterium.
The method according to item 3, wherein the reaction solution having a pH of 4 to 10 contains a buffer selected from the group consisting of an acetic acid buffer, a phosphoric acid buffer, a boric acid buffer, a carbonic acid buffer, a Tris buffer, a HEPES buffer, and a MES buffer.
The production method according to any one of items 1 to 3, wherein the lactic acid bacterium is a fructophilic lactic acid bacterium (Fructobalus).
The production method according to any one of items 1 to 4, wherein the lactic acid bacterium is selected from the group consisting of strain Fructobacillus durionis RD011727 (accession number NITE BP-02764), strain Fructobacillus tropaeoil RD012353 (accession number NITE BP-02765), strain Fructobacillus tropaeoil RD012354 (accession number NITE BP-02766) and strain Fructobacillus fructosus NBRC 3516.
Effects of the invention
According to the present invention, by reacting a microorganism having nicotinamide mononucleotide production ability in a reaction solution having a pH of 4 to 10, a target nicotinamide mononucleotide can be easily and efficiently obtained even under very mild conditions at normal temperature and pressure.
Detailed Description
The present invention will be described in detail below.
The present invention provides a method for producing nicotinamide mononucleotide, comprising a nicotinamide mononucleotide enrichment reaction step in which a microorganism having a nicotinamide mononucleotide production ability is reacted in a reaction solution having a pH of 4 to 10 (e.g., a reaction solution in which the pH is adjusted with a buffer solution, etc.).
Microorganism having nicotinamide mononucleotide production ability
The microorganism having nicotinamide mononucleotide productivity used in the present invention is not particularly limited, and examples thereof include yeast, lactic acid bacteria, and the like.
Edible yeast can be used as the yeast. Examples thereof include yeasts belonging to the genus Saccharomyces, kluyveromyces, candida, pichia, and the like, and among them, candida utilis (Candida utipes) belonging to the genus Candida is preferable. More specifically, examples of the candida utilis IAM4264, candida utilis ATCC9950, candida utilis ATCC9550, candida utilis IAM4233, candida utilis AHU3259, and the like can be given.
As the lactic acid bacteria, for example, examples of the genus Lactobacillus, leuconostoc, streptococcus, pediococcus, apis, enterococcus, trichosporon, lactobacillus, clostridium, vagococcus, tetragenococcus, atopobium, weissella, oenococcus, fusarium, etc. can be given genus Desemzia, genus Paralactobacter (Paralactobacillus), genus granuliform (Granulatella), genus halophilus (Alkalibacterium), genus Europhilus (Olssella), genus Izomyces (Isobacillus), genus Lactobacillus marinus (Marinilactibacillus), genus Clostridium (Atopas), genus Lactobacilli (Lactooval), genus spear (Picibacterium), genus Lactobacillus fructophilius (Fructobacterium), genus Lactobacilli (Bavaria) genus, genus Bifidobacterium (Bifidobacterium), etc., preferably a fructophilic lactic acid bacterium (Fructobacterium).
Among them, as the genus fructophilic lactic acid bacteria (fructophilic bacteria), fructobacillus durionis, fructobacillus tropaeoil, and Fructobacillus fructosus are exemplified, and Fructobacillus tropaeoil and Fructobacillus fructosus are more preferable.
Examples of more preferred lactic acid bacteria include Fructobacillus durionis RD011727 strain (accession number NITE BP-02764), fructobacillus tropaeoil RD012353 strain (accession number NITE BP-02765), fructobacillus tropaeoil RD012354 strain (accession number NITE BP-02766), fructobacillus fructosus NBRC strain 3516 strain and Fructobacillus durionis NBRC113239 strain, and more preferred examples include Fructobacillus durionis RD011727 strain (accession number NITE BP-02764), fructobacillus tropaeoil RD012353 strain (accession number NITE BP-02765), fructobacillus tropaeoil RD012354 strain (accession number NITE BP-02766) and Fructobacillus fructosus NBRC strain 3516 strain.
In the present invention, 1 or more species can be used singly or in combination from the above microorganism having nicotinamide mononucleotide production ability.
The microorganism having nicotinamide mononucleotide productivity used in the present invention can be a microorganism cultured in a separate culturing step.
The medium for culturing the microorganism is not particularly limited as long as it contains a carbon source, a nitrogen source, and minerals.
Examples of the carbon source include a sugar and a sugar material. Examples of the saccharide include saccharides (monosaccharides, disaccharides, oligosaccharides), polysaccharides, and sugar alcohols. Examples of the sugar include lactose, sucrose, glucose, starch, xylitol, and dextrose. The sugar material may be any organic composition containing sugar, and examples thereof include milk and processed products thereof (skim milk powder, whey, milk powder, condensed milk, etc.), soybean milk and processed products thereof (soybean milk hydrolysate, etc.), cereals, fruits, vegetables, etc. Examples of milk include milk derived from any mammal such as cow, goat, sheep, buffalo, camel, llama, donkey, yak, horse, and reindeer. The sugar may be an isolated sugar or a sugar contained in a sugar material. For example, fructose (sugar) may be in the form of a substance contained in fruits (sugar materials). These carbon sources may be used alone or in combination of 1 or more.
The concentration of the carbon source in the medium is not particularly limited as long as it is appropriately set according to the type of medium, the culture method, and the like, and examples thereof include 0.5 to 15w/w%, preferably 1 to 10w/w%, and more preferably 1.5 to 8.5w/w%.
As the nitrogen source, any inorganic nitrogen source or organic nitrogen source can be used. Examples thereof include proteins such as yeast extract(s) (s.cerevisiae, etc.), meat extract, casein, etc.; peptone (peptone, etc.) and other protein hydrolysates, peptides, etc.; ammonium salts (ammonium citrate, etc.), nitrogen-containing salts such as nitrate, etc. These nitrogen sources may be used alone or in combination of 1 or more.
The concentration of the nitrogen source in the medium is not particularly limited as long as it is appropriately set according to the type of medium, the culture method, and the like, and in the case of a protein, for example, 0.3 to 4w/w%, preferably 0.5 to 3w/w%, and more preferably 1 to 2w/w% can be mentioned; in the case of peptides, for example, 0.1 to 2w/w%, preferably 0.3 to 1.8w/w%, more preferably 0.5 to 1.5w/w%; in the case of the nitrogen-containing salt, for example, 0.03 to 1.5w/w%, preferably 0.05 to 1w/w%, more preferably 0.1 to 0.5w/w% is exemplified.
Examples of the minerals include manganese (such as manganese sulfate), zinc, iron, sodium (such as sodium acetate), potassium (such as dipotassium hydrogen sulfate and potassium phosphate), magnesium (such as magnesium sulfate), calcium, phosphorus (such as potassium phosphate), sulfur (such as manganese sulfate, potassium hydrogen sulfate and magnesium sulfate), and trace elements. These minerals may be used alone in an amount of 1 kind, or in combination of two or more kinds. Among these minerals, manganese, sodium, magnesium, and potassium are preferable.
The concentration of the mineral in the medium is not particularly limited as long as it is appropriately set according to the type of medium, the culture method, and the like, and in the case of manganese, for example, 0.001 to 0.01w/w%, preferably 0.003 to 0.008w/w%; in the case of sodium, for example, 0.05 to 1.5w/w%, preferably 0.1 to 1w/w%; in the case of magnesium, for example, 0.001 to 0.02w/w%, preferably 0.005 to 0.015w/w%; in the case of potassium, for example, 0.05 to 1w/w%, preferably 0.1 to 0.5w/w% is exemplified.
The medium may contain other components such as vitamins (vitamin B group, etc.), surfactants (nonionic surfactants (Tween, etc.), anionic surfactants (SDS, etc.), antibacterial agents (triclosan, etc.), antibiotics (Monensin, etc.), etc., in addition to the above components. These other components may be used alone or in combination of 1 or more. Among these other components, surfactants are preferable, and nonionic surfactants are more preferable.
The concentration of the other components in the medium is not particularly limited as long as it is appropriately set according to the kind of the other components, the kind of the medium, the culture method, and the like, and in the case of containing the surfactant, the concentration of the surfactant is, for example, 0.01 to 0.5w/w%, preferably 0.05 to 0.3w/w%.
The culture conditions such as the culture temperature and pH are not particularly limited, and may be set in accordance with the microorganism to be used. In general, the cultivation temperature is 21 to 37℃and preferably 25 to 34℃and the pH is 3.0 to 8.0 and particularly preferably 3.5 to 7.0.
The culture may be any of batch culture, fed-batch culture, and continuous culture, but the latter is industrially preferred. The conditions such as stirring and aeration during the culture are not particularly limited, and may be a general method.
The microorganism obtained by the culture can be used as it is or by solid-liquid separation by filtration using filter paper, centrifugal separation, decantation, spiral punching, rolling, drum screen, belt screen, vibrating screen, multiple plate vibrating screen, vacuum dehydration, pressure dehydration, belt press, centrifugal concentration dehydration, multiple disk dehydration or the like, and the cells can be recovered from the culture solution or further washed, and the obtained cells can be used for nicotinamide mononucleotide enrichment reaction. The bacterial cells recovered from the culture solution can be preferably used for nicotinamide mononucleotide enrichment reaction, and the bacterial cells recovered from the culture solution and washed can be more preferably used for nicotinamide mononucleotide enrichment reaction.
The nicotinamide mononucleotide content in the microorganism can be increased by using the microorganism having the nicotinamide mononucleotide production ability obtained in the culturing step in the nicotinamide mononucleotide enrichment reaction step.
Specifically, in the nicotinamide mononucleotide enrichment reaction step, a reaction for enriching nicotinamide mononucleotide is performed by adjusting a reaction solution containing a microorganism having nicotinamide mononucleotide production ability and an appropriate reaction liquid and having a pH of 4 to 10, and maintaining the reaction solution at an appropriate temperature. In the present invention, the pH of the reaction solution refers to the pH at the temperature at which nicotinamide mononucleotide enrichment reaction is performed.
The pH of the reaction solution in the nicotinamide mononucleotide enrichment reaction step is preferably 4.8 to 9.2, more preferably 5.8 to 9.2, still more preferably 6.8 to 9.2, 6.8 to 8.2, or 7.8 to 9.2.
In the case of using strain Fructobacillus tropaeoil RD012353 (accession number NITE BP-02765) as a microorganism having nicotinamide mononucleotide producing ability, the pH of the reaction solution in the nicotinamide mononucleotide enrichment reaction step may be preferably 4.8 to 9.2, more preferably 5.8 to 8.2, still more preferably 6.8 to 8.2, and still more preferably 7.8 to 8.2.
When strain Fructobacillus durionis RD011727 (accession number NITE BP-02764) is used as a microorganism having nicotinamide mononucleotide producing ability, the pH of the reaction solution in the nicotinamide mononucleotide enrichment reaction step is preferably 5.8 to 8.2, more preferably 5.8 to 8.2, and still more preferably 6.8 to 8.2.
When strain Fructobacillus fructosus NBRC3516 is used as a microorganism having nicotinamide mononucleotide productivity, the pH of the reaction solution in the nicotinamide mononucleotide enrichment reaction step may be preferably 4.8 to 9.2, more preferably 5.8 to 9.2, still more preferably 6.8 to 9.2, still more preferably 7.8 to 9.2, and still more preferably 7.8 to 8.2.
The reaction liquid may be used without any particular limitation as long as the pH of the reaction liquid can be adjusted to the above range. For example, when the microorganism obtained by the culture is directly used for the nicotinamide mononucleotide enrichment reaction, the reaction liquid is a medium used for culturing a microorganism having the ability to produce nicotinamide mononucleotide. When the microorganism obtained by the culture is recovered from the culture solution, more preferably, is used for the nicotinamide mononucleotide enrichment reaction after further washing, examples of the reaction liquid include water (including a pH adjuster used in the reaction, adjusted to an optimum pH range), a buffer solution, an organic solvent, and a mixture of 2 or more of them.
Examples of the buffer include acetate buffer, phosphate buffer, borate buffer, carbonate buffer, citrate buffer, tris buffer, HEPES buffer, and MES buffer, and 1 or a combination of two or more of these buffers may be used.
More specifically, KHC can be exemplified 8 H 4 O 4 -NaOH(pH4.0)、CH 3 COOH-CH 3 COONa(pH4.0)、MES-NaOH(pH5.0)、CH 3 COOH-CH 3 COONa(pH5.0)、KH 2 PO 4 -K 2 HPO 4 (pH6.0)、MES-NaOH(pH6.0)、KH 2 PO 4 -K 2 HPO 4 (pH7.0)、PIPES-NaOH(pH7.0)、HEPES-NaOH(pH8.0)、H 3 BO 4 -NaOH(pH8.0)、CHES-NaOH(pH9.0)、H 3 BO 4 -NaOH(pH9.0)、H 2 CO 3 -NaHCO 3 (pH 10.0), CHES-NaOH (pH 10.0). Among them, CH is preferable 3 COOH-CH 3 COONa、KH 2 PO 4 -K 2 HPO 4 、H 3 BO 4 NaOH, more preferably KH 2 PO 4 -K 2 HPO 4 。
Examples of the organic solvent include aromatic compounds such as benzene and benzonitrile, ketones such as acetone, acetylacetone and methyl ethyl ketone, aliphatic esters such as ethyl acetate, butyl acetate, ethyl butyrate and ethyl formate, ethers such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran and 1, 4-dioxane, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, alcohols such as 1, 2-propanediol, 1, 2-butanediol, 1, 3-butanediol, 1, 4-butanediol, 2, 3-butanediol, 1, 2-hexanediol, 1, 6-hexanediol, 1, 2-pentanediol, 1, 5-pentanediol, 2-methyl-2, 4-pentanediol and 3-methyl-1, 5-pentanediol, and alcohols having a linear or branched alkyl group having 1 to 7 carbon atoms such as cyclohexanol, 3-methoxy-3-methyl-1-butanol and 3-methoxy-1-butanol, and the like, and the organic solvents may be used singly or in combination of two or more thereof.
The pH adjustor may be appropriately selected so as to be capable of adjusting to an optimum pH during the reaction, and examples thereof include inorganic acids such as hydrochloric acid, organic acids such as citric acid, inorganic bases such as hydroxides such as sodium hydroxide and potassium hydroxide, and organic bases such as organic amines, and 1 or a combination of these compounds may be used singly or in combination.
The reaction temperature in the nicotinamide mononucleotide enrichment reaction step of the present invention is, for example, 10 to 55 ℃, preferably 15 to 45 ℃, more preferably 20 to 37 ℃, and even more preferably 20 to 35 ℃. The reaction time is, for example, 0.1 to 48 hours, preferably 1 to 24 hours, more preferably 3 to 20 hours.
The nicotinamide mononucleotide enrichment reaction can be performed by suspending, standing, stirring or shaking a microorganism having a nicotinamide mononucleotide production ability in the above-described reaction liquid.
Microorganisms containing nicotinamide mononucleotide obtained by the nicotinamide mononucleotide enrichment reaction can be directly dried by freeze drying, shelf drying, spray drying, or the like to obtain bacterial powder, which can be blended as an additive to food or an active ingredient of cosmetics or pharmaceuticals.
The microorganism containing nicotinamide mononucleotide obtained by the nicotinamide mononucleotide enrichment reaction can also be recovered by solid-liquid separation from a buffer solution by centrifugation, membrane filtration, or the like. The collected cells are dried directly by, for example, shelf drying or freeze drying, and are prepared into a cell powder, which can be blended as an additive to foods or as an active ingredient of cosmetics or pharmaceuticals.
Examples
The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
Test example 1
[1-1]Culture of Fructobacillus tropaeoil RD012353 strain
A strain Fructobacillus tropaeoil RD012353 (accession number NITE BP-02765) of lactic acid bacteria belonging to the genus Lactobacillus as fructophilic lactic acid bacteria having nicotinamide mononucleotide production ability was inoculated into 3ml of MRS medium (preculture medium) prepared by Difco corporation, and the culture was allowed to stand at 30℃for 24 hours for expansion. The resulting culture broth was inoculated into 100ml of MRS medium (main culture medium) so that OD660 became 0.02, and cultured with shaking at 30℃for 12 hours.
The obtained culture solution was subjected to centrifugal separation, and cells were recovered. The recovered cells were washed with 100ml of a 0.85w/w% KCl aqueous solution. The washed cells were subjected to centrifugal separation again to recover the cells.
[1-2]Nicotinamide mononucleotide enrichment reaction procedure (NMN enrichment reaction)
The cells recovered in the above-mentioned [1-1] were suspended in 20ml of the following reaction liquid, respectively, to prepare a reaction liquid, and the reaction liquid was allowed to stand at 25℃for 8 hours to conduct NMN enrichment reaction. The pH of the reaction solution in the NMN enrichment reaction is shown in Table 1.
The reaction liquids used in the NMN enrichment reaction are shown below. The reaction liquids having pH3.0 and pH11.0 were used for comparison.
Comparative example 1:0.1M citrate buffer (pH 3.0)
Example 1:0.1M acetate buffer (pH 4.0)
Example 2:0.1M acetate buffer (pH 5.0)
Example 3:0.1M phosphate buffer (pH 6.0)
Example 4:0.1M phosphate buffer (pH 7.0)
Example 5:0.1M phosphate buffer (pH 8.0)
Example 6:0.1M boric acid buffer (pH 9.0)
Example 7:0.1M carbonate buffer (pH 10.0)
Comparative example 2:0.1M phosphate buffer (pH 11.0)
After the completion of the reaction, the cells were collected by centrifugation. The recovered cells were washed with 100ml of a 0.85w/w% KCl aqueous solution. The washed cells were subjected to centrifugal separation again to recover the cells.
[1-3]Nicotinamide Mononucleotide (NMN) amount measurement
The cells recovered in the above-mentioned [1-1] and the cells recovered in the above-mentioned [1-2] were suspended in 20ml of ion-exchanged water, and after adding glass beads in equal amounts, the cells were crushed by a bead mill. The disrupted cells were separated by centrifugation, and the supernatant (disrupted cell extract) was recovered.
The recovered supernatant was analyzed by HPLC analysis under the following analysis conditions, and the Nicotinamide Mononucleotide (NMN) production amount in the recovered cells was measured. The relative value of NMN production in the cells recovered in the above-mentioned [1-2] was derived, assuming that NMN production in the cells recovered in the above-mentioned [1-1] was 100 (NMN enrichment reaction was not performed). The results are shown in Table 1.
(MRS Medium composition)
2w/w% glucose
1w/w% protease peptone
1w/w% beef extract
0.5w/w% yeast extract
0.2w/w% ammonium citrate
0.1w/w% Tween 80
0.5w/w% sodium acetate
0.01w/w% magnesium sulfate
0.005w/w% manganese sulfate
0.2w/w% dipotassium hydrogen phosphate
(HPLC analysis conditions)
Column: daisoPak SP-100-5-ODS-P (4.6X106 mm). Times.2 roots)
Column temperature: 25 DEG C
Eluent: 75mM ammonium phosphate aqueous solution (pH 6.0)
Flow rate: 0.6ml/min
A detector: UV detector (260 nm)
Detection time: 15.1 minutes
TABLE 1
As shown in table 1, the NMN productivity can be significantly improved by reacting the cultured cells in a solution having a pH of 4 to 10.
TestExample 2
[2-1]Fructobacillus
durionis
Culture of RD011727 strain
A strain Fructobacillus durionis RD011727 (accession number NITEBP-02764) of lactic acid bacteria belonging to the genus Lactobacillus as fructophilic lactic acid bacteria having nicotinamide mononucleotide production ability was inoculated into 3ml of MRS medium (preculture medium) prepared by Difco corporation, and the culture was allowed to stand at 30℃for 24 hours for expansion. The resulting culture broth was inoculated into 100ml of MRS medium (main culture medium) so that OD660 became 0.02, and cultured with shaking at 30℃for 12 hours.
The obtained culture solution was subjected to centrifugal separation, and cells were recovered. The recovered cells were washed with 100ml of a 0.85w/w% KCl aqueous solution. The washed cells were subjected to centrifugal separation again to recover the cells.
[2-2]Nicotinamide mononucleotide enrichment reaction procedure (NMN enrichment reaction)
NMN enrichment was performed in the same manner as in [1-2] of test example 1, except that the bacterial cells recovered in [2-1] and the reaction liquids used in examples 1 to 7 of test example 1 were used. The pH of the reaction liquid in the NMN enrichment reaction was the same as that of the reaction liquid, as shown in Table 2.
[2-3]Nicotinamide Mononucleotide (NMN) amount measurement
NMN was measured in the same manner as in [1-3] of test example 1, except that the cells recovered in [2-1] and the cells recovered in [2-2] were used. The relative value of NMN production in the cells recovered in the above-mentioned [2-2] was derived, assuming that NMN production in the cells recovered in the above-mentioned [2-1] was 100 (NMN enrichment reaction was not performed). The results are shown in Table 2.
TABLE 2
As shown in table 2, the NMN productivity can be significantly improved by reacting the cultured cells in a solution having a pH of 4 to 10.
Test example 3
[3-1]Fructobacillus
fructosus
Cultivation of NBRC3516 strain
A strain Fructobacillus fructosus NBRC3516 of lactic acid bacteria belonging to the genus fructophilic lactic acid bacteria having nicotinamide mononucleotide productivity was inoculated into 3ml of MRS medium (preculture medium) prepared by Difco, and subjected to stationary expansion culture at 30℃for 24 hours. The resulting culture broth was inoculated into 100ml of MRS medium (main culture medium) so that OD660 became 0.02, and cultured with shaking at 30℃for 12 hours.
The obtained culture solution was subjected to centrifugal separation, and cells were recovered.
[3-2]Nicotinamide mononucleotide enrichment reaction procedure (NMN enrichment reaction)
NMN enrichment was performed in the same manner as in [1-2] of test example 1, except that the bacterial cells recovered in [3-1] and the reaction liquids used in examples 1 to 6 of test example 1 were used. The pH of the reaction liquid in the NMN enrichment reaction was the same as that of the reaction liquid, as shown in Table 3.
[3-3]Nicotinamide Mononucleotide (NMN) amount measurement
NMN was measured in the same manner as in [1-3] of test example 1, except that the cells recovered in [3-1] and the cells recovered in [3-2] were used. The relative value of NMN production in the cells recovered in the above-mentioned [3-2] was derived, assuming that NMN production in the cells recovered in the above-mentioned [3-1] was 100 (NMN enrichment reaction was not performed). The results are shown in Table 3.
TABLE 3
As shown in table 3, the NMN productivity can be significantly improved by reacting the cultured cells in a solution having a pH of 4 to 10.
Test example 4
The same operations as in test examples 1 to 3 were performed except that the reaction liquid used in the NMN enrichment reaction was changed to a buffer described below (the pH of the reaction liquid in the NMN enrichment reaction was the same as that of the reaction liquid, as shown in table 4), and the relative values of the NMN production amounts were derived. The results are shown in Table 4.
The reaction solution (buffer) used in the NMN enrichment reaction is shown below.
Examples 21, 24, 27:0.1M MES buffer (pH 5.0)
Examples 22, 25, 28:0.1M HEPES buffer (pH 7.0)
Examples 23, 26, 29:0.1M Tris buffer (pH 9.0)
TABLE 4
As shown in table 4, by reacting the cultured cells in a solution having a pH of 4 to 10, the NMN productivity can be significantly improved regardless of the type of buffer.
Test example 5
The same procedure as in test example 3 was carried out except that ion-exchanged water was used as the reaction liquid used in the NMN enrichment reaction, and a 24 wt% NaOH aqueous solution was used, and the reaction was carried out while adjusting the pH during the reaction to 7 (the pH of the reaction liquid in the NMN enrichment reaction is shown in table 5), to obtain the relative value of the NMN production. The results are shown in Table 5.
TABLE 5
Claims (5)
1. A method for preparing nicotinamide mononucleotide, comprising the steps of:
and a nicotinamide mononucleotide enrichment reaction step in which a microorganism having nicotinamide mononucleotide production ability is reacted in a reaction solution having a pH of 4 to 10.
2. The method according to claim 1, wherein the microorganism having nicotinamide mononucleotide production ability is a lactic acid bacterium.
3. The method according to claim 1 or 2, wherein the reaction solution having a pH of 4 to 10 comprises a buffer selected from the group consisting of an acetic acid buffer, a phosphoric acid buffer, a boric acid buffer, a carbonic acid buffer, a Tris buffer, a HEPES buffer, and a MES buffer.
4. The process according to any one of claims 1 to 3, wherein the lactic acid bacterium is a fructophilic lactic acid bacterium (Fructobalus).
5. The process according to any one of claims 1 to 4, wherein the lactic acid bacterium is selected from the group consisting of strain Fructobacillus durionis RD011727 having accession number NITE BP-02764, strain Fructobacillus tropaeoil RD012353 having accession number NITE BP-02765, strain Fructobacillus tropaeoil RD012354 having accession number NITE BP-02766 and strain Fructobacillus fructosus NBRC 3516.
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