WO2023284853A1 - 一种生产甲萘醌-7的纳豆芽孢杆菌及其应用 - Google Patents
一种生产甲萘醌-7的纳豆芽孢杆菌及其应用 Download PDFInfo
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- WO2023284853A1 WO2023284853A1 PCT/CN2022/105948 CN2022105948W WO2023284853A1 WO 2023284853 A1 WO2023284853 A1 WO 2023284853A1 CN 2022105948 W CN2022105948 W CN 2022105948W WO 2023284853 A1 WO2023284853 A1 WO 2023284853A1
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- WIPO (PCT)
- Prior art keywords
- fermentation
- liquid
- bacillus natto
- strain
- menadione
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Classifications
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- 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
- C12N1/205—Bacterial isolates
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/10—General cosmetic use
-
- 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
- C12R2001/07—Bacillus
Definitions
- the invention relates to the technical field of microorganisms, in particular to a bacillus natto for producing menadione-7 and an application thereof.
- Vitamin K2 (2-methyl-3-all-trans-polypentene-1,4-naphthoquinone) or menaquinones is a family of prenyl derivatives.
- the number of isoprene residues consisting of 5 carbon atoms can be used to distinguish menadione-based compounds.
- the nomenclature is based on the number of prenyl groups, eg "menadione” or "MK" followed by the number of groups added. Although up to 15 prenyl groups have been found in the side chain of menadione, only menadione containing 2 to 13 prenyl groups have been found in human and animal tissues. Demethylated menadione, ie unbound menadione at carbon 2, has also been found.
- MK-7 menaquinone-7
- MK-7 menaquinone-7
- the method of producing MK-7 in the prior art has: (1) chemical synthesis method, this method needs to use organic solvent, not only unfriendly to environment, operator, and organic solvent residue is arranged in the gained product, and cis-trans form in the product
- the coexistence of MK-7 of the structure (2) extract from solid fermented natto, the content of MK-7 in natto is extremely low, and has no market competitiveness; (3) obtained by the method of natural Bacillus natto liquid fermentation, the method cycle Long, low yield.
- the present invention provides a Bacillus natto (Bacillus natto) HDCC00023, which was deposited on February 01, 2021 In the General Microbiology Center of China Committee for Culture Collection of Microorganisms, the preservation number is CGMCC NO.21799.
- menadione-7-containing medicines health products, food, beverages, cosmetics, additives, and feedstuffs.
- a fermented liquid containing the bacillus natto A fermented liquid containing the bacillus natto.
- menadione-7-containing medicines health products, food, beverages, cosmetics, additives, and feedstuffs.
- a fermentation method for producing menadione-7 by using the bacillus natto is a fermentation method for producing menadione-7 by using the bacillus natto.
- the fermentation is carried out in a fermentation medium comprising assimilable carbon and/or nitrogen sources.
- the assimilable carbon source is selected from one or any combination of starch, maltodextrin, glucose, sucrose, lactose, maltose, industrial molasses, glycerin, soybean oil, sorbitol, mannitol; preferably glycerol ,starch.
- the assimilable nitrogen source is selected from yeast extract powder, yeast powder, yeast extract, soybean lecithin, soybean cake powder, cottonseed cake powder, peanut cake powder, gluten powder, corn steep liquor dry powder, soybean meal, peptone , urea, ammonium salt or any combination of several; preferably soybean peptone.
- the fermentation medium further includes inorganic salts selected from trisodium citrate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, ammonium sulfate, calcium carbonate, ferrous sulfate, zinc sulfate, copper sulfate, One or any combination of sodium chloride, potassium chloride, calcium chloride, magnesium sulfate, ferric chloride, manganese sulfate; preferably potassium dihydrogen phosphate, magnesium sulfate, potassium chloride, calcium chloride.
- the seed liquid is fermented in a fermentation medium, and the dissolved oxygen of the fermentation liquid is controlled to be no less than 5% or 5-15%.
- the seed liquid is fermented in a fermentation medium, and the total residual sugar concentration of the fermentation liquid is kept not lower than 1.0% or 1.0-1.5%.
- the seed liquid is fermented in a fermentation medium, and the fermentation temperature is not lower than 10°C, or not lower than 20°C, or 20-60°C, or 20-50°C, or 20-40°C, or 30-50°C, or 30-40°C, or 35-40°C, or 37°C.
- the fermentation time is not less than 12 hours, or not less than 1 day, or not less than 2 days, or not less than 3 days, or not less than 4 days, or not less than 5 days, or not less than Within 6 days, more preferably 7 days.
- the seed liquid is primary seed liquid or secondary seed liquid.
- the preparation method of the first-level seeds is as follows: take an activated single colony, scrape the colonies, and then inoculate them into a Erlenmeyer flask, shake them on a shaking table, and control the OD value ⁇ 4.0; the preparation method of the second-level seeds For, take first-class seeds, inoculate them into seed tanks, control dissolved oxygen ⁇ 40%, and control OD value ⁇ 6.0.
- the preparation method of the primary seed is as follows: take an activated single colony, scrape the colony, and inoculate it into a conical flask, shake it on a shaker, and control the OD value to ⁇ 4.0, and the culture temperature is not lower than 10°C.
- the incubation time is not less than 0.5h, or not less than 1h, or not less than 2h, or not less than 3h, or not less than 4h, or not less than 5h, or not less than 6h, or not less than Less than 7h, or 8h;
- the preparation method of the secondary seeds is as follows: take the primary seeds, inoculate them into the seed tank, control the dissolved oxygen ⁇ 40%, control the OD value ⁇ 6.0, and the cultivation temperature is not lower than 10°C, or not lower than 20°C.
- the incubation time is not less than 0.5h, or not less than 1h, or not less than 2h, or not less than 3h, or not less than 4h, or not less than 5h, or not less than 6h, or 7h, or 8h.
- the preparation method of the secondary seeds is as follows: take the primary seeds and inoculate them into a seed tank, the pressure of the tank is 0.05Mpa, the dissolved oxygen is controlled to be ⁇ 40%, and the OD value is controlled to be ⁇ 6.0.
- the preparation method of the secondary seeds is as follows: take the primary seeds and inoculate them into a seed tank, the tank pressure is 0.05Mpa, the air flow rate is 1vvm, the dissolved oxygen is controlled to be ⁇ 40%, and the OD value is controlled to be ⁇ 6.0.
- the preparation method of the secondary seeds is as follows: take the primary seeds and inoculate them into the seed tank at a ratio of 0.02-0.2% (V/W). A more preferable ratio is 0.05% (V/W).
- the fermentation medium includes 2% glycerol, 5% soluble starch and 2% soybean peptone according to mass percentage.
- the fermentation method further comprises adding a feed medium.
- the feed medium includes 30% maltodextrin and 10% soybean peptone in terms of mass percentage.
- feeding is initiated when the total sugars drop below 1.5%.
- the seed liquid is inoculated into the fermenter of the liquid fermentation medium at a ratio of 4% (V/W), the set temperature is 37°C, the tank pressure is 0.05Mpa, the air flow rate is 0.7vvm, and the dissolved oxygen drops below 15%. , control the stirring so that the dissolved oxygen is 5-15%.
- V/W the set temperature
- the tank pressure is 0.05Mpa
- the air flow rate is 0.7vvm
- the dissolved oxygen drops below 15%.
- control the stirring so that the dissolved oxygen is 5-15%.
- the bacterial strain of the present invention is obtained by mutagenesis, and the effective transformation rate is significantly improved, and more MK-7 is produced under the condition of consuming very little nutrient;
- the strain (HDCC00023) consumes nutrients more peacefully, and the control of the fermentation process is easier.
- the strain (HDCC00023) has stronger vitality and can realize continuous fermentation production.
- Figure 1 is a comparison of fermentation yield, substrate consumption, and by-product production (viscosity characterization) in 50L tanks of different strains.
- Figure 2 is a comparison of parameters in the fermentation process of 50L tanks of different strains.
- Embodiment 1 strain mutagenesis screening
- the pure MK-7-producing strain (HDCC00001) was isolated from the feces of adults who ate natto all year round.
- the strain was identified as Bacillus natto by 16S RNA sequencing (see SEQ ID NO: 1 for the sequence). Using adult feces as the source of isolation, the strains obtained have higher safety and are more suitable for the production of health care products.
- HDCC00003 bacterial strain glycerol tube thawing solution Take 0.1ml of HDCC00003 bacterial strain glycerol tube thawing solution, inoculate it into 50ml LB liquid medium, cultivate overnight at 37°C, collect the bacteria after centrifugation of the seed solution, resuspend with normal saline, and mutate the bacteria suspension under 15W ultraviolet light for 10s , and then continued mutagenesis for 10 s with a final concentration of 0.2% lithium chloride.
- the bacterial strain was obtained.
- the highest fermentation level of the shake flask of this bacterial strain was 584 ⁇ g/ml, and the distribution range of the fermentation level of 40 single colony shake flasks was 564 ⁇ 20 ⁇ g/ml.
- the strain has been deposited in the General Microbiology Center of the China Committee for the Collection of Microbial Cultures on February 1, 2021, and the preservation number is CGMCC NO.21799.
- Primary screening fermentation medium 1% glycerol, 0.5% soybean peptone, pH 7.0, sterilized at 121°C for 15 minutes, 3ml/15ml.
- Re-screened fermentation medium glycerin 4%, soybean peptone 1.5%, pH 7.0, sterilized at 121°C for 20 minutes, 30ml/250ml.
- Embodiment 2 original strain (HDCC00001) 50L tank fermentation test
- the pH of LB liquid medium was adjusted to 7.0 before disinfection, and the disinfection conditions were 121-123°C for 30 minutes.
- the pH of LB liquid medium was adjusted to 7.0 before disinfection, and the disinfection conditions were 121-123°C and holding pressure for 30 minutes.
- the formula of the liquid fermentation medium is as follows: 2% glycerin, 5% soluble starch, 2% soybean peptone, the pH is adjusted to 8.0 before disinfection, and the disinfection conditions are 121-123° C., holding pressure for 30 minutes.
- the highest titer of the strain (HDCC00001) was 20.3 ⁇ g/ml when fermented for 3 days, and then the dissolved oxygen rose rapidly, and CER (refers to the carbon dioxide of the culture in the biological fermentation process) release amount) completely dropped to zero, microscopic examination found that a large number of spores were formed, and the potency no longer increased. Through a large amount of feeding, CER rebounded and dissolved oxygen decreased, indicating that the vitality of the bacteria was restored, but the potency still could not be effectively increased, and even fell down. At the same time, the by-products continue to accumulate, resulting in a continuous increase in the viscosity of the feed liquid with the prolongation of the fermentation culture period, resulting in a worse mass transfer effect of the fermentation liquid.
- Embodiment 3 50L tank fermentation test of mutagenic strain (HDCC00003)
- the fermentation cycle of the strain (HDCC00003) can be extended to 4 days, and the highest titer is 124 ⁇ g/ml at this time.
- the carbon and nitrogen sources are consumed rapidly, the dissolved oxygen drops to zero rapidly, the agitator runs at the maximum speed, and the feeding amount increases linearly.
- the results of microscopic examination showed that the increase of feed amount effectively avoided the formation of spores, but the rate of titer growth was still unable to be maintained.
- the effective fermentation period of the strain (HDCC00023) can last for 7 days, and the fermentation titer can maintain continuous growth, reaching a maximum of 526 ⁇ g/ml, successfully expressing the strain Productivity demonstrated in shake flasks.
- strain (HDCC00003) and strain (HDCC00001) strain (HDCC00023) consumed the least nutrient substance and produced the most MK-7 by comparison between titer and cumulative feed.
- the viscosity of the feed liquid is maintained at a level of about 100 cps, which indicates that the formation of by-products is effectively controlled. That is to say, the effective transformation rate of the strain (HDCC00023) was significantly increased and more MK-7 was produced under the condition of consuming very little nutrient.
- the decrease of feed liquid viscosity reduces the difficulty of oxygen entering the fermentation liquid, making it easier to control dissolved oxygen through stirring. It is not necessary to frequently increase the stirring speed to maintain dissolved oxygen.
- the required dissolved oxygen can be achieved by maintaining around 400rpm, and the entire fermentation process dissolves Oxygen is controllable. And because it does not need to run at high speed frequently, the machine loss and energy consumption are also reduced accordingly. Further, since the viscosity of the fermentation broth is reduced, the difficulty of subsequent purification is correspondingly reduced.
- the fluctuation range of pH can reflect the stability of the strain metabolizing nutrients, and the small fluctuation range of pH reflects that the strain (HDCC00023) consumes nutrients more peacefully. Therefore, compared with other strains, the fermentation process of the strain (HDCC00023) Control is easier.
- Embodiment 5 mutagenic strain (HDCC00023) 30 tons (T) tank fermentation test
- the pH of LB liquid medium was adjusted to 7.0 before disinfection, and the disinfection conditions were 121-123°C for 30 minutes.
- the pH of LB liquid medium was adjusted to 7.0 before disinfection, and the disinfection conditions were 121-123°C and holding pressure for 30 minutes.
- the formula of the liquid fermentation medium is as follows: 2% glycerin, 5% soluble starch, 2% soybean peptone, the pH is adjusted to 8.0 before disinfection, and the disinfection conditions are 121-123° C., holding pressure for 30 minutes.
- the results of fermentation culture show that after the strain (HDCC00023) is scaled up to 30T scale, the process is stable and controllable, with good reproducibility, the effective fermentation period can last for more than 7 days, and the fermentation titer reaches 384 ⁇ g/ml.
- the titer of the strain (HDCC00023) is much higher than that of the strain (HDCC00003) and the strain (HDCC00001), the fermentation titer can maintain continuous growth, the formation of by-products is effectively controlled, the growth and metabolism are mild, and the whole fermentation
- the dissolved oxygen in the process is controllable, the feeding control of nutrients is easier, the process stability is good, and it is suitable for industrial scale-up. It fundamentally solves the key problems of difficult amplification (poor repeatability of process control), low effective substrate conversion rate and high production cost in the process of MK-7 industrialization, and reduces the difficulty of purification of fermentation broth.
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Abstract
Description
Claims (12)
- 一种纳豆芽孢杆菌(Bacillus natto)HDCC00023,于2021年02月01日保藏于中国微生物菌种保藏管理委员会普通微生物中心,保藏编号为CGMCC NO.21799。
- 一种如权利要求1所述纳豆芽孢杆菌的用途,其特征在于:用于制备甲萘醌-7;或者,用于制备含甲萘醌-7的药品、保健品、食品、饮料、化妆品、添加剂、饲料中的一个或多个。
- 一种含有如权利要求1所述纳豆芽孢杆菌的发酵液。
- 一种如权利要求3所述发酵液的用途,其特征在于:用于制备甲萘醌-7;或者,用于制备含甲萘醌-7的药品、保健品、食品、饮料、化妆品、添加剂、饲料中的一个或多个。
- 一种用如权利要求1所述纳豆芽孢杆菌生产甲萘醌-7的发酵方法。
- 如权利要求5所述的发酵方法,其特征在于:包括在含有可同化的碳源和/或氮源的发酵培养基里,进行发酵。
- 如权利要求6所述的发酵方法,其特征在于:所述可同化的碳源选自淀粉、麦芽糊精、葡萄糖、蔗糖、乳糖、麦芽糖、工业糖蜜、甘油、豆油、山梨醇、甘露醇之一或者任意几种的组合;优选为甘油、淀粉。
- 如权利要求6所述的发酵方法,其特征在于:所述可同化的氮源选自酵母抽提粉、酵母粉、酵母膏、大豆卵磷脂、黄豆饼粉、棉籽饼粉、花生饼粉、麸质粉、玉米浆干粉、豆粕、蛋白胨、尿素、铵盐之一或者任意几种的组合;优选为大豆蛋白胨。
- 如权利要求6所述的发酵方法,其特征在于:所述发酵培养基还包括无机盐,所述无机盐选自柠檬酸三钠、磷酸二氢钾、磷酸氢二钾、硫酸铵、碳酸钙、硫酸亚铁、硫酸锌、硫酸铜、氯化钠、氯化钾、氯化钙、硫酸镁、氯化铁、硫酸锰之一或任意几种的组合;优选为磷酸二氢钾、硫酸镁、氯化钾、氯化钙。
- 如权利要求5~9所述的发酵方法,其特征在于:取种子液在发酵培养基中发酵,控制发酵液的溶氧为不低于5%或者5~15%。
- 如权利要求5~9所述的发酵方法,其特征在于:取种子液在发酵培养基中发酵,维持发酵液的总残糖浓度不低于1.0%或者1.0~1.5%。
- 如权利要求5~9所述的发酵方法,其特征在于:取种子液在发酵培养基中发酵,发酵温度不低于10℃,或者不低于20℃,或者为20~60℃,或者为20~50℃,或者为20~40℃,或者为30~50℃,或者为30~40℃,或者为35~40℃,或者为37℃。
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