• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
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    • 专利摘要:
    MICRORGANISM WITH GREATER PRODUCTIVITY OF L-VALINE AND METHOD FOR THE PRODUCTION OF LVALINE USING THE SAME. The present invention relates to a microorganism with a higher productivity of L-valine and method for the production of L-valine using the same. More particularly, the present invention relates to a mutant strain of Corynebacterium glutamicum that has a resistance to L-valine and its derivatives, in order to present a higher productivity of L-valine and a method for the production of L-valine using the same.
    公开号:BR112014003469B1
    申请号:R112014003469-9
    申请日:2012-02-06
    公开日:2020-11-10
    发明作者:Hye Won Kim；Ji Hye Lee；Soo Youn Hwang；Jong Hyun Kim
    申请人:Cj Cheiljedang Corporation；
    IPC主号:
    专利说明:

    TECHNICAL FIELD
    [001] The present invention relates to a microorganism with higher productivity of L-valine and method for the production of L-valine using the same. BACKGROUND OF THE TECHNIQUE
    [002] L-amino acids are used in human medicine, in particular in the pharmaceutical industry, food industry and animal nutrition or the like. In particular, branched-chain amino acids are three amino acids among the nine essential ones: L-valine, L-leucine and L-isoleucine. Unlike other amino acids, which are metabolized mainly in the liver, branched-chain amino acids are metabolized mainly in muscle tissue and serve as an energy source during exercise. Knowing that branched chain amino acids play an important role in muscle maintenance and growth during exercise, their use is on the rise. Specifically, L-valine has been used as a nutritional component, given the records of high reducing power and better lactation performance in L-valine sows. L-valine has also been used in infusion solutions and amino acid complexes for medical purposes and in food supplements and beverage additives.
    [003] A microorganism used for the production of L-amino acids is the corineform bacteria, particularly Corynebacterium glutamicum. Due to the high importance of corineform bacteria in industrial production, methods of producing L-amino acids through microorganisms are constantly being developed. For example, improvements are being made to improve the method related to stirring and introducing oxygen or compositions of the culture medium, such as the concentration of sugar during fermentation. In order to improve the productivity of L-amino acids of these microorganisms, methods of selection and selection of mutants are widely used. For example, there is a method of selecting and using microorganisms that are resistant to antimetabolites, such as an isoleucine derivative, isoleucine hydroxide (Kisumi M et al., (1972) Journal of Bacteriology 110: 761 -763), a derivative L-valine, 2-thiazole alanine (Tsuchida T et al., (1975) Agricultural and Biological Chemistry, Japan 39: 1319-1322) or a leucine derivative, a-aminobutyrate (Ambe-Ono Y et al., (1996 ) Bioscience Biotechnology Biochemistry 60: 1386-1387) or auxotrophic for metabolites with regulatory relevance and L-amino acid production (Eva Radmacher et al., (2002) Applied and Environmental Microbiology, Vol. 68 p.2246-2250).
    [004] However, one of the branched chain amino acids, L-valine, is biosynthesized in a microorganism from pyruvic acid, through acetolactic acid, dihydroxyvaleric acid and ketoisovaleric acid. These intermediate metabolites are produced through catalytic activities of acetohydroxy acid synthase, acetohydroxy acid isomeroreductase, dihydroxy acid dehydratase and transaminase B. However, these enzymes are also involved in the biosynthesis of L-isoleucine starting from ketobutyric acid and pyruvic acid and L-leucine is also biosynthesized from the intermediate metabolite, ketoisovaleric acid through 2-isopropylmalic acid, 3-isopropylmalic acid and ketoisocaproic acid. Therefore, since the enzymes used in the biosynthetic pathways of branched amino acids, namely L-valine, L-isoleucine and L-leucine are identical, it is difficult to produce just one of the branched chain amino acids through industrial fermentation. Additionally, there is a retroactive inhibition in the final product L-valine or its derivatives, which hinders the production on an industrial scale of L-valine.
    [005] To solve these problems, several studies have been carried out to develop L-valine-producing microorganisms with resistance to L-valine or derivatives of it for the production of L-valine, and are exemplified through a method of using a microorganism with resistance to D, L-aminobutyric acid (Japanese open patent No. S63-160592), a method of using a microorganism that is resistant to thiazole alanone and auxotrophic to leucine, isoleucine or threonine (Japanese open patent No. S52-116) , method of using a microorganism with resistance to amnioethylcysteine (Japanese patent open no. S58-2678), method of using a microorganism with resistance to L-valine in a medium supplemented with acetic acid and with sensitivity to pyruvic acid in a medium supplemented with glucose (U.S. Patent No. 5,521,074, Korean Patent No. 1995-0005133), method of using a microorganism with polyketide resistance (Korean Patent No. 1996-0016871) or the like.
    [006] However, the L-valine-producing microorganisms currently developed are resistant only to a single material or a limited material of L-valine or derivatives thereof, thus remaining the lack of development of L-valine-producing microorganisms with resistance to various materials involved in retroactive control of L-valine biosynthesis. DISCLOSURE OF THE INVENTION TECHNICAL PROBLEM
    [007] The authors of the present invention endeavored to develop microorganisms capable of producing L-valine in a higher yield than conventional strains. As a result, they found that a mutant strain, obtained from a glutamic acid-producing microorganism, produces L-valine with a high yield and is resistant to numerous derivatives of L-isoleucine and L-valine, specifically, a-aminobutyric acid (ABA ), α-hydroxyvaline (AHV), thiazole alanine (TA) and norvaline (NV), thus completing the present invention. TECHNICAL SOLUTION
    [008] An object of the present invention is to present a mutant strain of Corynebacterium glutamicum producing L-valine, KCCM11201P.
    [009] Another object of the present invention is to present a method of preparing L-valine using the mutant strain. ADVANTAGE EFFECTS OF THE INVENTION
    [010] The corineform microorganism of the present invention has a resistance to L-valine, L-isoleucine and derivatives thereof, thus not being affected by the retroactive inhibition of L-valine, in order to present an increased productivity of L-valine. Therefore, the method of producing L-valine with the microorganism of the present invention is employed to produce L-valine with high efficiency and high yield. DESCRIPTION OF THE FIGURES
    [011] FIG. 1 shows a L-valine biosynthesis pathway as the final product of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION
    [012] In one embodiment, the present invention features a mutant strain of L-valine-producing Corynebacterium glutamicum, KCCM11201P.
    [013] As used today, the term “L-valine means an L-amino acid with a chemical formula (CH3) 2CHCH (NH2) COOH, which is one of the essential amino acids and structurally belongs to the branched chain amino acids, together with L-leucine and L-isoleucine.
    [014] However, the biosynthesis of L-valine in a microorganism is shown in FIG. 1, in which L-valine is biosynthesized from pyruvic acid through acetolactic acid, dihydroxyvaleric acid and ketoisovaleric acid. In addition, the biosynthesis pathway is catalyzed by enzymes, such as acetohydroxy acid synthase, acetohydroxy acid isomeroredutase, dihydroxy acid dehydratase and transaminase B. However, these enzymes are used identically in the biosynthesis pathways of branched amino acids, namely L- valine, L-isoleucine and L-leucine, making it difficult to produce just one of the branched chain amino acids through industrial fermentation. In particular, retroactive inhibition occurs in the final product L-valine or its derivatives, which hinders the production on an industrial scale of L-valine. In solving this problem, the mutant strain of the present invention is a new microorganism that presents resistance to L-valine or derivatives thereof in order to remove the retroactive inhibition, thus presenting a higher productivity of L-valine.
    [015] Preferably, the mutant strain of the present invention may show resistance to valine or derivatives thereof, isoleucine or derivatives thereof.
    [016] As currently used, the term "derivative" means the known compounds that induce retroactive inhibition with respect to the biosynthesis of the final product L-valine in order to reduce the production of L-valine in the micro-organism, and point out as α-aminobutyric acid and derivatives of L-valine, alpha-hydroxyvaline, thiazole alanine and norvaline or similar, as L-isoleucine derivatives, without limitation. Preferably, the mutant strain may be resistant to one or more substances selected from the group consisting of valine, α-aminobutyric acid, alpha-hydroxyvaline, thiazole alanine and norvaline. More preferably, it may show resistance to all of valine, α-aminobutyric acid, alpha-hydroxyvaline, thiazole alanine and norvaline.
    [017] In general, it is known that the biosynthesis of L-valine is inhibited when L-valine is accumulated at a certain level in the cell. Therefore, the strain with resistance to derivatives releases the inhibition of L-valine and can thus produce even at a high concentration. In accordance with an embodiment of the present invention, the authors of the present invention employed a method of selecting microorganisms capable of producing a high level of L-valine with the derivative. In addition, since L-isoleucine is an amino acid that is produced via the biosynthesis pathway identical to the L-valine biosynthesis pathway, strains capable of producing a high level of L-valine can also be selected by analyzing whether the strains acquire resistance to isoleucine derivatives. In this way, isoleucine derivatives are also used to select strains capable of producing a high level of L-valine.
    [018] According to the present invention, a mutant strain with a high productivity of L-valine is selected from progenitor strains by mutation. In this regard, mutations in the microorganism can be induced through a variety of well-known techniques and any of the physical or chemical mutagenic factors can be employed. Examples of the chemical mutagenic factor suitable for the present invention include N-methyl-N ”-nitro-N-nitrosoguanidine (NTG), diepoxybutane, ethyl methanesulfonate, mustard compounds, hydrazine and nitrous acid, but are not limited to these. In addition, examples of physical mutagenic factors may include ulltraviolet and gamma radiation, but are not limited to these.
    [019] With mutation induction, the parent strain is affected by a mutagenic factor at an intensity sufficient to leave a particular size of surviving populations. The size varies depending on the type of mutagenic factors and depends on the number of mutations induced in the surviving populations at a given death rate. For example, the desired death rate for NTG should leave approximately 10% to 50% of the initial population. Nitrous acid mutagenesis should leave approximately 0.01% to 0.1% of the starting population and ultraviolet mutagenesis should leave approximately 1.0%. In accordance with an embodiment of the present invention, NTG is used to induce mutations in the parent strain in order to prepare a mutant strain with a high productivity of L-valine.
    [020] In an example of the present invention, a Corynebacterium glutamicum KFCC 10661 producing L-glutamic acid (Korean patent application No. 1988-0016543; publication No. 1990-0007948) was used as the parent strain in order to prepare the mutant strain with a increased productivity of L-valine, which is attributed to the property of requiring 1 molecule of glutamic acid during the biosynthesis of L-valine. Therefore, a random mutagenesis was performed on Corynebacterium glutamicum KFCC 10661 producing glutamic acid as a progenitor strain and the microorganism was disseminated in a minimal medium supplemented with the isoleucine derivative, a-aminobutyric acid (ABA) and the valine derivatives, alpha- hydroxyvalin (AHV), thiazole alanine (TA) and norvaline (NV). Subsequently, a mutant strain with a common resistance to derivatives was selected at each concentration of 20 mM, 20 mM, 40 mM and 50 mM, and was designated Corynebacterium glutamicum CA08-0072. In addition, it was confirmed that the production of L-valine from the mutant strain with a common resistance was increased 4 times or more compared to that of the progenitor strain (see Table 1). The mutant strain of Corynebacterium glutamicum CA08-0072 was deposited with the international depository authority, Korean Microorganism Culture Center, located at 361-221, Hongje-1-dong, Seodaemon-gu, Seoul, Korea, on July 13, 2011 , which has been assigned access number KCCM11201P.
    [021] In another embodiment, the present invention features a method of producing L-valine, including the culture phase of the mutant strain in a culture medium.
    [022] Preferably, the method of producing L-valine may further include the step of recovering L-valine from the culture medium of the mutant strain.
    [023] As currently used, the term "culture" means the development of a microorganism under artificially controlled conditions. In the present invention, the culture method of the mutant strain Corynebacterium glutamicum CA08-0072 (KCCM11201P) for the production of L-valine can be conducted using a culture method of Corynebacterium glutamicum well known in the art. Specifically, examples of culture methods include batch culture, continuous culture and semi-batch culture, without being restricted to them. These various methods are presented in, for example, "Biochemical Engineering" (James M. Lee, Prentice-Hall International Editions, pp 138-176, 1991) or the like.
    [024] The medium used for culture must meet the requirements for the culture of a specific strain. The culture medium of the described Corynebacterium strain (e.g. Manual of Methods for General Bacteriology. American Society for Bacteriology. Washington D.C., USA, 1981). Possible sources of carbon may include sugars and carbohydrates, such as glucose, sucrose, lactose, fructose, maltose, starch and cellulose, oils and fats such as soybean oil, sunflower oil, peanut oil and coconut oil. such as palmitic acid, stearic acid and linoleic acid, alcohols such as glycerol and ethanol and organic acids such as acetic acid. These substances can be used individually or mixed. Possible sources of nitrogen may include peptone, yeast extract, meat extract, malt extract, millhocin, soy and urea flour or inorganic compounds such as ammonium sulfate, ammonium chloride, ammonium phosphate, ammonium carbonate and ammonium nitrate ammonium. The nitrogen sources can be used individually or mixed. Possible sources of phosphorus may include potassium dihydrogen phosphate or dipotassium hydrogen phosphate or the corresponding sodium salts. In addition, the culture medium must include metal salts, such as magnesium sulfate and ferric sulfate, which are necessary for development. In addition to the substances mentioned, essential development substances, such as amino acids and vitamins, can be included. Appropriate precursors can also be added to the culture medium. The referred substances can be suitably added to the culture medium by batch or continuous culture during the same.
    [025] The pH of the culture can be adequately adjusted by adding basic compounds such as sodium hydroxide, potassium and ammonium hydroxide or acidic compounds such as phosphoric acid and sulfuric acid. The formation of air bubbles can be inhibited by using a defoaming agent such as polyglycolic fatty acid ester. To maintain aerobic conditions, oxygen or oxygen-containing gas (eg air) can be injected into the culture. In general, the temperature of the culture medium varies between 20 and 45 ° C. The culture can be continued until the production of L-valine reaches the desired level. This goal is usually achieved within 10 to 160 hours. L-valine can be released into the culture medium or included in the stem cells
    [026] The L-valine production method of the present invention includes the step of recovering L-valine from cells or culture medium. The method of recovering L-valine from cells or culture medium can be performed using a conventional method, known in the art, for example, centrifugation, filtration, anion exchange chromatography, crystallization and HPLC, without being limited to these Law Suit. According to an embodiment of the present invention, a supernatant, obtained by centrifuging the culture medium at low speed and removing the biomass, is separated by ion exchange chromatography. MODE FOR THE INVENTION
    [027] Hereinafter, the present invention will be described in detail with reference to the following examples. However, these examples are illustrative only and it is not intended to limit the invention by these examples. Example 1: Selection of the mutant strain through artificial mutagenesis
    [028] To obtain mutant strains with enhanced L-valine productivity, a microorganism was mutated using the following method.
    [029] Specifically, a parent strain, Corynebacterium glutamicum KFCC 10661 producing glutamic acid (Korean Patent Publication No. 1990-0007948) previously activated by culture in an activation medium for 16 hours, for 14 hours in sowing medium previously sterilized at 121 ° C for 15 minutes. Then 5 ml of culture medium were collected and washed with 100 mM citrate buffer. NTG (N-methyl-N ”-nitro-N-nitrosoguanidine) was added at a final concentration of 200 mg / L. After 20 minutes, the medium was washed with 100 mM phosphate buffer. Strains treated with NTG were spread over minimal media and the death rate was measured. As a result, the death rate was 85%.
    [030] In order to obtain mutant strains with a common resistance to α-aminobutyric acid (ABA, alpha-hydroxyvaline (AHV), thiazole alanine (TA) and norvaline (NV), the strains treated with NTG were spread over minimal medium containing ABA, AHV, TA and NV at a final concentration of 20 mM, 20 mM, 40 mM and 50 mM, respectively, so the strains were grown at 30 ° C for 5 days to obtain a mutant strain with a common resistance to ABA, AHV, TA and NV.
    [031] The mutant strain obtained was designated Corynebacterium glutamicum CA08-0072 and was deposited with the Korean Microorganism Culture Center on July 13, 2011, which was assigned the accession number KCCM11201P.
    [032] The media used in examples 1 and 2 have the following compositions.
    [033] <Means of activation>
    [034] Beef extract 1%, polypeptone 1%, sodium chloride 0.5%, yeast extract 1%, agar 2%, pH 7.2
    [035] <Sowing medium>
    [036] Glucose 5%, Bact peptone 1%, sodium chloride 0.25%, yeast extract 1%, urea 0.4%, pH 7.2
    [037] <Minimum means>
    [038] Glucose 1.0%, ammonium sulfate 0.4%, magnesium sulfate 0.04%, potassium dihydrogen phosphate 0.1%, urea 0.1%, thiamine 0.001%, biotin 200 yg ZL, 2% agar, pH 7.0 Example 2: L-valine productivity analysis of the mutant L-valine producing strain
    [039] Corynebacterium glutamicum CA08-0072 (KCCM11201P) with a common resistance to high concentrations of ABA, AHV, TA and NV, obtained in example 1, was grown according to the following method in order to analyze the productivity of L-valine of this .
    [040] The parent strain Corynebacterium glutamicum KFCC 10661 and the mutant strain were both inoculated in 250 ml Erlenmeyer flasks containing 25 ml of seed medium and were grown at 30 ° C for 20 hours with agitation at 200 rpm to obtain the sowing culture medium. Then, 1 ml of each culture medium was inoculated into 250 ml Erlenmeyer flasks containing 24 ml of the following production medium and were grown at 30 ° C for 72 hours with agitation at 200 rpm to produce L-valine.
    [041] The production medium used in the present example 2 has the following composition.
    [042] <Means of production>
    [043] Glucose 5%, ammonium sulfate 2%, potassium dihydrogen phosphate 0.1%, magnesium sulfate heptahydrate 0.05%, millhocin 2.0%, biotin 200 jug / L, pH 7.2
    [044] Once the culture was completed, high-speed liquid chromatography was performed to determine the amounts of L-valine produced. The concentrations of L-valine in the culture medium of the experimental strains are summarized in Table 1 below. Table 1
    [045] Comparison of the productivity of L-valine from Corynebacterium glutamicumCA08-0072 (KCCM11201P)

    [046] As shown in Table 1, the parent strain, Corynebacterium glutamicum KFCC 10661 produced 0.5 g / L of L-valine, but the mutant strain, Corynebacterium glutamicum CA08-0072 according to the present invention produced 2.1 g / L of L-valine, indicating that its L-valine productivity is about 4 times higher than that of the parent strain.
    [047] The previous result suggests that the mutant strain with resistance to L-valine, L-isoleucine and their derivatives is not affected by retroactive inhibition, thus producing L-valine with high efficiency and high yield.
    权利要求:
    Claims (6)
    [0001]
    1. Corynebacterium glutamicum mutant strain characterized by being a producer of L-valine, KCCM11201P.
    [0002]
    Mutant strain KCCM11201P according to claim 1, characterized in that the mutant strain has resistance to L-valine, L-isoleucine and their derivatives.
    [0003]
    Mutant strain KCCM11201P according to claim 2, characterized in that the L-isoleucine derivative is α-aminobutyric acid (ABA), and the L-valine derivative is α-hydroxyvaline (AHV), thiazole alanine (TA) and norvaline (NV).
    [0004]
    4. L-valine production method, characterized in that it comprises the culture of KCCM11201P as defined in claim 1 by a culture medium.
    [0005]
    Method according to claim 4, characterized in that it further includes the recovery of L-valine from the KCCM11201P culture medium.
    [0006]
    Method according to claim 4, characterized in that the culture is carried out under aerobic conditions, at a temperature between 20 to 45 ° C for 10 to 160 hours.
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    法律状态:
    2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-07-16| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2020-08-11| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-11-10| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 06/02/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    KR10-2011-0081146|2011-08-16|
    KR1020110081146A|KR101117022B1|2011-08-16|2011-08-16|A microorganism having enhanced l-valine production and process for preparing l-valine using the same|
    PCT/KR2012/000856|WO2013024947A1|2011-08-16|2012-02-06|Microorganism having enhanced l-valine productivity and method for producing l-valine using the same|
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