WO2012029529A1 - 酵素を用いた卵殻膜の可溶化方法 - Google Patents
酵素を用いた卵殻膜の可溶化方法 Download PDFInfo
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- WO2012029529A1 WO2012029529A1 PCT/JP2011/068418 JP2011068418W WO2012029529A1 WO 2012029529 A1 WO2012029529 A1 WO 2012029529A1 JP 2011068418 W JP2011068418 W JP 2011068418W WO 2012029529 A1 WO2012029529 A1 WO 2012029529A1
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- Prior art keywords
- eggshell membrane
- eggshell
- solubilization
- reducing agent
- solubilized
- Prior art date
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- C12N9/0004—Oxidoreductases (1.)
- C12N9/0012—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7)
- C12N9/0014—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7) acting on the CH-NH2 group of donors (1.4)
- C12N9/0022—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7) acting on the CH-NH2 group of donors (1.4) with oxygen as acceptor (1.4.3)
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- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
- C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
- C12N9/2405—Glucanases
- C12N9/2434—Glucanases acting on beta-1,4-glucosidic bonds
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y104/00—Oxidoreductases acting on the CH-NH2 group of donors (1.4)
- C12Y104/03—Oxidoreductases acting on the CH-NH2 group of donors (1.4) with oxygen as acceptor (1.4.3)
- C12Y104/03013—Protein-lysine 6-oxidase (1.4.3.13), i.e. lysyl-oxidase
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
- C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
- C12Y302/01017—Lysozyme (3.2.1.17)
Definitions
- the present invention relates to a method for solubilizing eggshell membranes using enzymes.
- it is related with the eggshell membrane solubilization method using a proteolytic enzyme, and its use.
- the eggshell membrane wraps egg cells (egg yolk) and egg white in chicken eggs, and physically isolates them from the outside with the eggshell, protecting the eggs from harmful UV rays, oxygen and drying. It also plays an important role in protecting against infection by foreign organisms such as pathogenic bacteria and viruses.
- the eggshell membrane also contains antibacterial substances and antibacterial enzymes such as lysozyme and ⁇ -N-acetylglucosaminidase. Furthermore, eggshell membranes are said to contain other special proteins, and their functionality is attracting attention.
- this invention makes it a subject to provide the eggshell membrane solubilization method, its use, etc. which can eliminate at least one of the said problems which the conventional processing methods (processing by an acid and an alkali, and processing by a proteolytic enzyme) have. To do.
- eggshell membranes can be solubilized very efficiently by using a proteolytic enzyme (protease) in combination with a reducing agent, particularly by allowing the proteolytic enzyme to act in the presence of a reducing agent.
- proteolytic enzyme proteolytic enzyme
- complete solubilization which was difficult with the conventional methods using enzymes, can be achieved, and whether any of acidic protease, neutral protease and alkaline protease is employed, it is mild.
- good solubilization was observed.
- a method for solubilizing eggshell membranes comprising using a proteolytic enzyme and a reducing agent in combination.
- the eggshell membrane solubilization method according to [1] comprising a step of allowing a proteolytic enzyme to act on the eggshell membrane in the presence of a reducing agent.
- the eggshell membrane solubilization method according to [1], comprising the following steps (1) and (2): (1) preparing an eggshell membrane in a solvent; (2) A step of adding a reducing agent and a proteolytic enzyme to the solvent and reacting them.
- [4] The eggshell membrane solubilization method according to [3], wherein the pH of the reaction solution in step (2) is 4.5 to 9.5.
- [5] The eggshell membrane solubilization method according to [3] or [4], wherein the concentration of the reducing agent is 5 mM to 1 M.
- the eggshell membrane solubilization method according to any one of [3] to [6], further comprising the following step (3): (3) The process of filtering the solution after a process (2) and removing a solid substance.
- the eggshell membrane solubilization method according to any one of [1] to [7], wherein the proteolytic enzyme is an alkaline protease or a neutral protease.
- the proteolytic enzyme is one or more enzymes selected from the group consisting of serine endopeptidase, cysteine endopeptidase, metalloendopeptidase, aminopeptidase and aspartate endopeptidase.
- the eggshell membrane solubilization method according to any one of the above.
- proteolytic enzyme is one or more enzymes selected from the group consisting of chymotrypsin, subtilisin, papain, basilolysin, stem bromelain, leucylaminopeptidase, pepsin and trypsin.
- the proteolytic enzyme is biosoak, Proleather FG-F, Papain W40, Protease N, Bromelain F, Ummamizyme G, Samoaase Y100, ProteAX, Protease S, Sumiteam LP500, Deskin C, Protin NY10, Protin PC10, Sumiteam MP
- the eggshell membrane solubilization method according to any one of [1] to [7], which is one or more enzymes selected from the group consisting of Protin AY and Proteinase K.
- the reducing agent is one or more reducing agents selected from the group consisting of sulfite, bisulfite, L-cysteine, N-acetyl-L-cysteine, 2-mercaptoethanol, glutathione, and DTT.
- the eggshell membrane solubilization method according to any one of [1] to [11].
- the eggshell membrane solubilization method according to any one of [1] to [11], wherein the reducing agent is sodium sulfite or sodium bisulfite.
- the eggshell membrane solubilizing agent according to [15] which is a kit comprising a first component containing a proteolytic enzyme and a second component containing a reducing agent.
- [24] [18] to any one of [23] A composition comprising the eggshell membrane soluble material described.
- a eggshell membrane useful component extraction method comprising the following steps (i) and (ii): (I) a solubilization step by the method according to any one of [1] to [13]; (Ii) A step of purifying the solubilized eggshell membranes obtained in the solubilization step.
- An enzyme selected from the group consisting of lysozyme and ⁇ -N-acetylglucosaminidase, or an acidic mucopolysaccharide selected from the group consisting of hyaluronic acid, chondroitin sulfate and dermatan sulfate, wherein the component purified in step (ii) The method for extracting useful components of eggshell membranes according to [26].
- Eggshell membrane useful component extraction method comprising the following steps (i ′) and (ii): (I ′) a solubilization step by the method according to [14]; (Ii) A step of purifying the solubilized eggshell membranes obtained in the solubilization step. [30] The eggshell membrane useful component extraction method according to [29], wherein the component purified in step (ii) is lysyl oxidase. [31] Lysyl oxidase obtained by the method according to [30]. [32] An eggshell membrane extract obtained by the eggshell membrane useful component extraction method according to [26] or [29].
- the result on the left is the result when using Biosork, and the result on the right is when using Pro Leather FG-F.
- Solubilization of eggshell membranes with sodium sulfite and biosoak Solubilization of eggshell membranes using sodium sulfite and Proleather FG-F.
- the figure which shows the relationship between eggshell membrane concentration and solubilization time The left shows the state of the eggshell membrane before and after the reaction.
- On the right is a graph plotting the time required for complete solubilization for each eggshell membrane amount. Solubilization of eggshell membranes when pepsin and reducing agent are used in combination. Solubilization of eggshell membranes when Sumiteam LP500 is used in combination with a reducing agent.
- Solubilization of eggshell membranes when deskin C and a reducing agent are used together. Solubilization of eggshell membranes when protin NY10 and a reducing agent are used in combination. Solubilization of eggshell membranes when protin PC10 and reducing agent are used in combination. Solubilization of eggshell membranes when trypsin and reducing agent are used in combination. Solubilization of eggshell membranes when Sumiteam MP is combined with a reducing agent. Solubilization of eggshell membranes when protin AY and a reducing agent are used in combination. Solubilization of eggshell membranes when proteinase K and a reducing agent are used in combination.
- ACE angiotensin converting enzyme
- Eggshell membrane solubilization method The first aspect of the present invention relates to an eggshell membrane solubilization method. According to the method of the present invention, eggshell membranes can be efficiently solubilized while avoiding the problems of brownish coloration and off-flavor generation due to amino acid degradation. Further, a high solubilization (decomposition) rate can be achieved without performing pretreatment.
- the “egg shell membrane” is a membrane that exists inside the outer shell of avian eggs such as chickens, quails, rib chickens, ducks, geese, and ostriches.
- eggshell membranes are treated and solubilized using a proteolytic enzyme and a reducing agent in combination.
- the state of the eggshell membrane used for the treatment is not particularly limited. For example, after being separated from the outer shell, those subjected to drying treatment (sun drying, hot air drying, vacuum drying, suction drying, freeze drying, etc.) (dried state), those before being subjected to drying treatment (wet state), What was swollen after the drying treatment (wet state) can be used. Moreover, the thing (for example, powder form) to which processes, such as cutting and grinding
- “Combining a proteolytic enzyme and a reducing agent” in the present invention means that the proteolytic enzyme acts on the eggshell membrane while utilizing the action of the reducing agent.
- the timing (time) at which the proteolytic enzyme acts on the eggshell membrane and the timing (time) of using the reducing agent are not particularly limited.
- the action of the reducing agent and the action of the proteolytic enzyme are exhibited simultaneously.
- a proteolytic enzyme is allowed to act on the eggshell membrane in the presence of a reducing agent. In this aspect, for example, the following steps (1) and (2) are performed.
- (1) A step of preparing eggshell membranes in a solvent (2) A step of adding a reducing agent and a proteolytic enzyme to the solvent and reacting them
- the solvent used in step (1) is not particularly limited as long as an enzyme reaction occurs, but preferably a buffer is used to facilitate pH adjustment and maintenance of a desired pH.
- the timing and order of addition of the reducing agent and the proteolytic enzyme are not particularly limited, but preferably the reducing agent and the proteolytic enzyme are added simultaneously or reduced so that the combined effect is sufficiently exerted.
- a proteolytic enzyme is added (preferably added quickly). According to the former method, the addition operation is performed once, which is advantageous in terms of operability.
- a proteolytic enzyme may be allowed to act on the eggshell membrane after being treated with the reducing agent.
- steps (1) and (2 ′) are performed.
- This embodiment is particularly suitable for the purpose of obtaining a solubilized eggshell membrane containing lysyl oxidase that maintains its activity.
- the proteolytic enzyme used in the present invention is not particularly limited as long as efficient solubilization of the eggshell membrane can be achieved.
- a commercially available enzyme agent may be used as a proteolytic enzyme.
- enzyme agents include biosoak, neurose F3-G, neurose A, protease A “Amano” G, protease N “Amano” G, protease S “Amano” G, papain W-40, promeline F, Protin NY10, Protin PC10, Protin AY, Protin SD-NY10, Protin SD-PC10F, Samoaze PC10F, Protin SD-AC10F, Protin SD-AY10, Proleather FG-F, Protease P “Amano” 3G, Protease M “Amano” G, ProteAX (above, Amano Enzyme), Morsin F (Kikkoman Foods), Sumiteam AP, Sumiteam LP, Sumi
- Protease AL above Yakult Pharmaceutical
- Promod 223LP Protex 7L
- Protex 14L Alkaline Protease GL
- Protex 6L Protex 89L
- Purefect, Purefect OX Properase
- Protex OXG Protex 40L (above, Genencor) Kyowa)
- PTN Neutase, Esperase, Sabinase, Alcalase, Clear Lens Pro
- Everase, Cannase, Polarzyme Flavorzyme
- Protamex Novoran (Novozymes Japan)
- PAPAIN F PAPAIN F.
- eggshell membranes are completely solubilized in a short time when biosoak, proleather FG-F, papain W40, protease N, bromelain F, equinezyme G, samoyase Y100, ProteAX, and protease S are used. did it. Moreover, efficient solubilization of eggshell membranes was also observed when Sumiteam LP500, Deskin C, Protin NY10, Protin PC10, Sumiteam MP, Protin AY, Proteinase K, pepsin, and trypsin were used.
- one or more enzyme agents selected from these enzyme agents or enzymes are employed as proteolytic enzymes.
- the enzymes constituting these enzyme agents include chymotrypsin whose alkaline pH is alkaline and classified as serine endopeptidase, subtilisin whose alkaline pH is alkaline and classified as serine endopeptidase, and optimal pH Is neutral and classified as cysteine endopeptidase, optimal pH range is neutral and metalloendopeptidase is classified as basilolysin, optimal pH range is neutral and cysteine endopeptidase is classified as cysteine endopeptidase, optimal Includes leucylaminopeptidase, which has a neutral pH range and is classified as an aminopeptidase.
- one preferred embodiment of the present invention uses one or more enzymes selected from the group consisting of serine endopeptidase, cysteine endopeptidase, metalloendopeptidase, aminopeptidase and aspartate endopeptidase. More specifically, one or more enzymes selected from the group consisting of chymotrypsin, subtilisin, papain, basilolysin, stem bromelain, leucylaminopeptidase, pepsin and trypsin are used. On the other hand, since many alkaline proteases and neutral proteases have achieved good solubilization (see Examples below), alkaline proteases and neutral proteases are employed as a preferred embodiment.
- eggshell membranes could be completely solubilized in a very short time. Therefore, one or more of these enzyme agents, or enzymes constituting these enzyme agents (that is, chymotrypsin (component of biosoak), subtilisin (component of proleather FG-F) and papain (component of papain W40)) It is particularly preferred to employ one or more types as proteolytic enzymes.
- biosork or chymotrypsin which is a component thereof, that has completely solubilized eggshell membranes in the shortest time is employed as at least one of the proteolytic enzymes.
- the proteolytic enzyme used in the present invention may not be a purified product.
- plant extracts, animal extracts, microorganism-derived culture extracts, or partially purified products thereof can be used as proteolytic enzymes as long as efficient solubilization of eggshell membranes can be achieved.
- reducing agent for example, sulfite or bisulfite is used.
- the salt here is, for example, an alkali metal or alkaline earth metal or ammonium salt (specifically, sodium, potassium, monoethanolamine, etc.). More preferably, a sulfite (for example, sodium sulfite) is used.
- Thiols or phosphines can also be used as the reducing agent.
- thiols include cysteine and its derivatives (for example, N-acetylcysteine), cysteamine and its derivatives (for example, C1-C4 acyl derivatives, more specifically, N-acetylcysteamine, N-propionylcysteamine, and the like.
- Thiolactic acid and its esters eg, thiolactic acid esters such as glycerol monothiolactic acid
- thioglycolic acid and its esters such as thioglycolic acid esters such as monothioglycolate of glycerol or glycol
- thioglycerol and mixtures thereof thioglycerol and mixtures thereof.
- thiols include N-mercaptoalkylamides, N- (mercaptoalkyl) ⁇ -hydroxyalkylamides, N-mono- or N, N-dialkylmercapto-4-butylamides, aminomercaptoalkylamides And alkylaminomercaptoalkylamides, 2-mercaptoethanol.
- N-mercaptoalkylamides for example, N- (mercapto-2-ethyl) gluconamide, ⁇ -mercaptopropionic acid and its derivatives, thiomalic acid, and pantethein can be used.
- N- (mercaptoalkyl) ⁇ -hydroxyalkylamides for example, those described in JP-A-2-104515 can be used.
- N-mono- or N N-dialkylmercapto-4-butylamides, for example, those described in JP-A-2-196711 can be used.
- aminomercaptoalkylamides for example, those described in JP-A-3-170411 can be used.
- alkylamino mercaptoalkylamides for example, those described in JP-A-5-279322 can be used.
- phosphines include tri (hydroxymethyl) phosphine, tri (hydroxypropyl) phosphine, bis (hydroxymethyl) (phenyl) phosphine, allyldiphenylphosphine, benzyldiphenylphosphine, and bis (3,4,5-trimethoxyphenyl).
- Chlorophosphine bis (3,4,5-trimethoxyphenyl) phosphine, benzyloxy (diisopropylamino) methylphosphine, bis (diisopropylamino) chlorophosphine, bis (2-cyanoethyl) phosphine, bis (3,5-di- tert-butylphenyl) chlorophosphine, bis (3,5-di-tert-butylphenyl) phosphine, bis (diethylamino) methylphosphine, bis (diethylamino) chlorophosphine, bis (diethylamino) phenylphosphine, (3,5-dimethyl-4-methoxyphenyl) chlorophosphine, bis (3,5-dimethyl-4-methoxyphenyl) phosphine, bis (3,5-dimethylphenyl) chlorophosphine, bis (3,5-
- a reducing agent that has been found to be well solubilized by its use (see Examples below), ie, sulfite (eg, sodium sulfite), bisulfite (eg, sodium bisulfite), L-cysteine, L-cysteine hydrochloride, N-acetyl-L-cysteine, 2-mercaptoethanol, glutathione (a yeast extract containing glutathione may be used) or DTT is employed.
- sulfite eg, sodium sulfite
- bisulfite eg, sodium bisulfite
- L-cysteine L-cysteine hydrochloride
- N-acetyl-L-cysteine 2-mercaptoethanol
- glutathione a yeast extract containing glutathione may be used
- DTT DTT
- two or more reducing agents may be used in combination as long as the actions and effects necessary for the present invention are obtained.
- the reaction in the step (2) is preferably carried out under weakly acidic pH to weakly alkaline pH conditions (specifically pH 4.5 to 9.5). More preferably, it is carried out under neutral pH conditions.
- the neutral pH condition means a pH of 6.0 to 8.0.
- the reaction is preferably carried out in a reaction solution adjusted to a pH of 7.0 to 7.5.
- the reaction time in step (2) can be arbitrarily set within a range of 10 minutes to 24 hours, for example.
- the eggshell membrane can be solubilized in a short time.
- the reaction time is set so that complete solubilization of the eggshell membrane can be achieved.
- stirring or shaking may be added.
- the temperature conditions are not particularly limited, and may be set within a range that does not hinder the action of the proteolytic enzyme used.
- An example of the temperature condition is 30 ° C. to 80 ° C.
- a preferred temperature condition is 40 ° C to 70 ° C.
- the amount (addition concentration) of the proteolytic enzyme is not particularly limited as long as efficient solubilization of the eggshell membrane is possible.
- the amount of the enzyme in which the concentration of the proteolytic enzyme in the reaction solution is 0.01% (W / W) to 20% (W / W), although the optimum amount used varies depending on the type of enzyme used. Is used.
- the concentration of the proteolytic enzyme in the reaction solution is preferably 0.1% (W / W) to 20% (W / W), more preferably 0.1% (W / W) to 10% (W / W) It is.
- the amount of reducing agent used is not particularly limited as long as the combined effect with the proteolytic enzyme is sufficiently obtained. Although the optimum amount used varies depending on the type of reducing agent to be used, for example, an amount of reducing agent in which the concentration of the reducing agent in the reaction solution is 5 mM to 1 M is used.
- the concentration of the reducing agent in the reaction solution is preferably 10 mM to 500 mM, more preferably 50 mM to 500 mM.
- the eggshell membrane can be completely solubilized in spite of simple operation.
- “Complete solubilization of eggshell membranes” means that the eggshell membranes are decomposed to such an extent that no solid matter is observed by visual observation.
- “complete solubilization of eggshell membranes” is not essential, but setting the conditions so that “complete solubilization of eggshell membranes” is achieved does not waste useful components in eggshell membranes. This is preferable in that it can be extracted and the removal of residues is unnecessary. Therefore, in one embodiment of the present invention, the reaction in the step (2) (or (2 ')) is continued until no solid matter is observed.
- step (2) is finished in a state where the solid content remains, and then the solution is filtered to remove the solid content (step (step (2)). 3)).
- This aspect is useful, for example, for the purpose of obtaining a component that is easily decomposed or deactivated.
- Eggshell membrane solubilizer The second aspect of the present invention relates to an eggshell membrane solubilizer.
- the eggshell membrane solubilizing agent of the present invention is characterized in that it comprises a combination of a proteolytic enzyme and a reducing agent.
- the eggshell membrane solubilizer of the present invention uses a proteolytic enzyme and a reducing agent in combination.
- the eggshell membrane solubilizing agent of the present invention is provided as a compounding agent in which a proteolytic enzyme and a reducing agent are mixed.
- the eggshell membrane solubilizing agent of the present invention is provided in the form of a kit comprising an element containing a proteolytic enzyme (first constituent element) and an element containing a reducing agent (second constituent element). You can also. Two or more types of proteolytic enzymes may be used in combination. Similarly, two or more kinds of reducing agents may be used in combination. In addition, since it is the same as that of the case of the eggshell membrane solubilization method of this invention about a proteolytic enzyme and a reducing agent, the overlapping description is abbreviate
- the eggshell membrane solubilizer of the present invention contains, in addition to active ingredients (proteolytic enzymes and / or reducing agents), excipients, buffers, suspending agents, stabilizers, preservatives, preservatives, physiological saline and the like. You may contain.
- active ingredients proteolytic enzymes and / or reducing agents
- excipients lactose, sorbitol, D-mannitol, sucrose and the like can be used. Phosphate, citrate, acetate, etc. can be used as the buffer.
- Phosphate, citrate, acetate, etc. can be used as the buffer.
- As the stabilizer propylene glycol, ascorbic acid or the like can be used.
- phenol benzalkonium chloride
- benzyl alcohol chlorobutanol
- methylparaben and the like
- benzalkonium chloride paraoxybenzoic acid, chlorobutanol, and the like can be used.
- Egg shell membrane soluble material and composition containing the same Further aspects of the present invention provide an eggshell membrane soluble material obtained by the eggshell membrane solubilization method of the present invention.
- a fully soluble egg shell membrane is provided.
- the eggshell membrane can be solubilized under mild conditions.
- the solubilized eggshell membranes obtained by this method are useful components (including proteins (including enzymes such as lysyl oxidase, lysozyme, ⁇ -N-acetylglucosaminidase, collagen proteins), glycoproteins, peptides ( (Including collagen peptides), glycopeptides, amino acids, hyaluronic acid, chondroitin sulfate, dermatan sulfate and other acidic mucopolysaccharides).
- proteins including enzymes such as lysyl oxidase, lysozyme, ⁇ -N-acetylglucosaminidase, collagen proteins
- glycoproteins including collagen peptides (Including collagen peptides), glycopeptides, amino acids, hyaluronic acid, chondroitin sulfate, dermatan sulfate and other acidic mucopolysaccharides).
- the solubilized eggshell membranes obtained by the method of the present invention comprises one or more components selected from the group consisting of lysozyme, ⁇ -N-acetylglucosaminidase, hyaluronic acid, chondroitin sulfate and dermatan sulfate.
- the solubilized eggshell membranes obtained by the method of the present invention can also be characterized by showing antioxidant activity and / or showing angiotensin converting enzyme inhibitory activity.
- the solubilized eggshell membranes of another embodiment is characterized in that it contains lysyl oxidase.
- the solubilized eggshell membranes containing lysyl oxidase are typically obtained by the eggshell membrane solubilization method including the above steps (1) and (2 ′).
- the present invention also provides a composition containing soluble eggshell membranes.
- the use of the composition of the present invention is not particularly limited, but is preferably a medicine, a quasi-drug, a food or a cosmetic. That is, the present invention provides a pharmaceutical composition, a quasi-drug composition, a food composition, and a cosmetic composition containing a solubilized eggshell membrane as a preferred embodiment.
- Examples of uses or effects of the pharmaceutical composition and quasi-drug composition of the present invention include antioxidant, antibacterial, anti-inflammatory, wound treatment, blood pressure reduction, hair growth, and nutritional support.
- Preparation of the pharmaceutical composition and quasi-drug composition of the present invention can be performed according to a conventional method.
- other pharmaceutically acceptable ingredients for example, carriers, excipients, disintegrants, buffers, emulsifiers, suspending agents, soothing agents, stabilizers, preservatives, preservatives, physiological Saline solution and the like.
- excipient lactose, starch, sorbitol, D-mannitol, sucrose and the like can be used.
- disintegrant starch, carboxymethylcellulose, calcium carbonate and the like can be used. Phosphate, citrate, acetate, etc. can be used as the buffer.
- emulsifier gum arabic, sodium alginate, tragacanth and the like can be used.
- suspending agent glyceryl monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate and the like can be used.
- soothing agent benzyl alcohol, chlorobutanol, sorbitol and the like can be used.
- stabilizer propylene glycol, ascorbic acid or the like can be used.
- preservatives phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methylparaben, and the like can be used.
- preservatives benzalkonium chloride, paraoxybenzoic acid, chlorobutanol and the like can be used.
- the dosage form in the case of formulating is also not particularly limited, and the pharmaceutical composition or pharmaceutical of the present invention can be used as tablets, powders, fine granules, granules, capsules, syrups, injections, external preparations, suppositories, etc.
- An quasi-drug composition can be provided.
- the pharmaceutical composition of the present invention contains an active ingredient in an amount necessary for obtaining an expected therapeutic effect or preventive effect (that is, a therapeutically effective amount).
- the quasi-drug composition of the present invention contains an active ingredient in an amount necessary for obtaining the expected improvement effect, prevention effect and the like.
- the amount of the active ingredient contained in the pharmaceutical composition or quasi-drug composition of the present invention generally varies depending on the dosage form and form, but the amount of the active ingredient is, for example, about 0.1% by weight to achieve a desired dose. Set within the range of about 95% by weight.
- the pharmaceutical composition and quasi-drug composition of the present invention are oral or parenteral (intravenous, intraarterial, subcutaneous, intramuscular, or intraperitoneal injection, transdermal, nasal, transmucosal depending on the dosage form and form. , Application, etc.).
- the “subject” here is not particularly limited, and includes humans and non-human mammals (including pet animals, domestic animals, laboratory animals. Specifically, for example, mice, rats, guinea pigs, hamsters, monkeys, cows, pigs, goats. , Sheep, dogs, cats, chickens, quails, etc.).
- the application subject is a human.
- the dosage and usage of the pharmaceutical composition and quasi-drug composition of the present invention are set so as to obtain the expected effect.
- the symptom, age, sex, weight, etc. of the subject of application are generally considered.
- a person skilled in the art can set an appropriate dose in consideration of these matters.
- the administration schedule for example, once to several times a day, once every two days, or once every three days can be adopted.
- the symptom of the application target, the duration of effect of the active ingredient, and the like can be considered.
- one aspect of the present invention is a food composition containing a solubilized eggshell membrane obtained by the eggshell membrane solubilization method of the present invention.
- the “food composition” in the present invention include general foods (cereals, vegetables, meat, various processed foods, confectionery, milk, soft drinks, alcoholic beverages, etc.), dietary supplements (antioxidants, antibacterials, anti-inflammatorys) , Supplements and nutritional drinks for the purpose of treating wounds, lowering blood pressure, preventing aging, etc.) and food additives.
- a dietary supplement or food additive it can be provided in the form of powder, granule powder, tablet, paste, liquid or the like.
- the amount of eggshell membrane soluble material added can be arbitrarily set according to the purpose. For example, if the food composition of the present invention is expected to have an effect that contributes to the maintenance or promotion of health or the treatment or prevention of a specific disease or condition, a sufficient amount of eggshell membranes can be used to exhibit the effect. It is preferable to contain a solute. The amount added can be determined in consideration of the type of food, the consumer of the food (sex, age, weight, etc.), the effect expected of the food.
- one aspect of the present invention is a cosmetic composition containing a solubilized eggshell membrane obtained by the eggshell membrane solubilization method of the present invention.
- the cosmetic composition of the present invention comprises soluble eggshell membranes and ingredients / bases commonly used in cosmetics (for example, various fats and oils, mineral oil, petrolatum, squalane, lanolin, beeswax, denatured alcohol, dextrin palmitate, Glycerin, glycerin fatty acid ester, ethylene glycol, paraben, camphor, menthol, various vitamins, zinc oxide, titanium oxide, benzoic acid, edetic acid, chamomile oil, carrageenan, chitin powder, chitosan, fragrance, coloring agent, etc.)
- the cosmetic composition include emulsions for face or body, lotions, creams, lotions, essences, oils, packs, sheets, and cleaning agents.
- the addition amount of the solubilized eggshell membranes in the cosmetic composition is not particularly limited.
- a solubilized eggshell membrane may be added so as to be 0.1 wt% to 60 wt%.
- Examples of uses or effects of the cosmetic composition of the present invention include moisture retention, infiltration, prevention of rough skin, beautiful skin, prevention of wrinkles, prevention of sagging and prevention of aging.
- solubilized eggshell membranes of the present invention can also be used in metal ion recovery, moisturizing agents, water-absorbing agents, antibacterial agents, hair restorers and the like.
- Eggshell membrane useful component extraction method The present invention further provides an eggshell membrane useful component extraction method to which the eggshell membrane solubilization method of the present invention is applied.
- the following steps (i) and (ii) are performed.
- Solubilization step by the eggshell membrane solubilization method of the present invention Step of purifying the solubilized eggshell membrane obtained in the solubilization step
- step (ii) purification is performed by appropriately combining filtration, centrifugation, desalting, salting out such as ammonium sulfate precipitation, dialysis, and various chromatography (ion exchange chromatography, hydrophobic chromatography, affinity chromatography, etc.).
- useful components for purification include enzymes such as lysozyme, lysyl oxidase, ⁇ -N-acetylglucosaminidase, and acidic mucopolysaccharides such as hyaluronic acid, chondroitin sulfate, and dermatan sulfate. You may refine
- the eggshell membrane useful component obtained by the method of the present invention can be used as a component used or added to medicines, foods, cosmetics and the like, as in the case of soluble eggshell membranes.
- eggshell membrane Examination of solubilization of eggshell membrane by proteolytic enzyme After breaking egg eggs and taking out egg liquid, eggshell with eggshell membrane is immersed in 4 wt% acetic acid aqueous solution for about 5 to 10 minutes, and eggshell membrane is peeled off by hand Collected. The peeled eggshell membrane was washed with water and thoroughly drained.
- the eggshell membrane was used as a substrate, and it was verified whether the eggshell membrane could be solubilized with existing enzyme agents.
- 15 commercially available enzyme agents (Neurase F3G, Protease M, Protease N, Protease P3G, Protease S, Bromelain F, Proleather FG-F, Peptidase R, Ummamizyme G, Samoaise Y100, ProteAX, Protease A, Papain W40, Bread Using creatine 8AP, biosoak), the reaction was carried out under various pH conditions (pH 4.0 to 13.0).
- the buffer solution in each pH region is as follows.
- pH 4.0 and 5.0 are 100 mM NaOAc buffer
- pH 6.0 is 100 mM MES-NaOH buffer
- pH 7.0 is 100 mM HEPES-NaOH buffer
- pH 8.0 is 100 mM Tris-HCl buffer
- pH 9.0 to 12.0 is 100 mM Glycine-NaOH
- a buffer pH 13.0
- the enzyme amount was 0.1% (w / v)
- the eggshell membrane amount was 1.0% (w / v)
- the reaction temperature was 60 ° C., and incubation was performed for 72 hours.
- FIG. 1 shows the results when biosoak was used as the test enzyme agent. As shown by this result, even if the reaction was carried out for 72 hours, solubilization (decomposition) of the eggshell membrane could not be confirmed visually. Visual solubilization was not observed in the other 14 kinds of enzyme agents.
- eggshell membranes were not solubilized with DTT alone and with the enzyme agent alone, but were solubilized in a short time of 1.5 hours under conditions where DTT and the enzyme agent coexisted. Similar results were obtained when Proleather FG-F was used, but the time required for complete solubilization was longer than that of biosoak (about 2 hours). It is thought that the solubilization was facilitated as a result of the reducing agent cleaving the disulfide bond present in the protein constituting the eggshell membrane. Moreover, since solubilization was inhibited by PMSF which is a serine protease inhibitor, solubilization of eggshell membranes in this test is considered to be due to protease.
- PMSF is a serine protease inhibitor
- the concentrations of sodium sulfite, sodium hydrogen sulfite, L-ascorbic acid, sodium nitrite, sodium nitrate, DTT, and sodium borohydride were tested at 1, 10, and 100 mM.
- the concentrations of L-cysteine hydrochloride, L-cysteine and glutathione were tested at 1, 10, 20, and 50 mM.
- the concentrations of Haithion extract YH-8, Haithion extract YH-15, and Haithion extract YH-D12 were tested at 1, 5, and 10% (w / v).
- the pH conditions of the buffer were 4.0 to 13.0, and the same conditions as described above were used.
- the enzyme amount was 0.1% or 0.5% (w / v)
- the eggshell membrane amount was 1.0% (w / v)
- the reaction temperature was 60 ° C., and the incubation was performed for 6 hours or 12 hours.
- the concentration of sodium sulfite was set to 100 mM, and the test was performed using each buffer solution (100 mM) at pH 4.0 to 13.0.
- pH 4.0-5.5 is NaOAc buffer
- pH 5.5-6.5 is MES-NaOH buffer
- pH 6.5-7.5 is HEPES-NaOH buffer
- pH 7.5-9.0 is Tris-HCl
- pH 9.0 to 12.5 used Glycine-NaOH buffer
- pH 12.5 to 13.0 used KCl-NaOH buffer.
- MES-NaOH buffer pH 6.0
- HEPES-NaOH buffer pH 7.0
- Tris-HCl buffer pH 8.0
- Glycine -It was performed using NaOH buffer (pH 9.0).
- the enzyme amount was 0.1% (w / v)
- the eggshell membrane amount was 1.0% (w / v)
- the reaction temperature was 60 ° C.
- the time required for complete solubilization was measured.
- biosork and proleather FG-F were used as target enzyme agents, and the reaction was stopped by adding PMSF to the solution after the reaction at each pH condition to a final concentration of 1 mM.
- FIG. 3 shows the types of tested reducing agents and the presence or absence of eggshell membrane solubilization (decomposition).
- sulfite and bisulfite showed significant effects at 100 mM concentration.
- When sodium sulfite was used eggshell membrane solubilization was seen efficiently at pH 6.0-8.0. Partial solubilization was observed when L-cysteine was used.
- FIG. 4 shows the results when biosoak was used.
- the horizontal axis represents the reaction pH
- the vertical axis represents the time required for complete solubilization of the eggshell membrane.
- the reaction pH on the horizontal axis indicates not the pH at the time of adjustment but the pH at the time of actual reaction.
- Table 1 shows a correspondence table between pH at the time of adjustment and pH at the time of reaction.
- solubilization occurs efficiently between pH 6.0 and 8.0 in the presence of sodium sulfite. Efficient solubilization of eggshell membranes was observed around pH 7.0 with biosok and other nine enzyme agents including Proleather FG-F. Table 2 shows the order of solubilization of eggshell membranes under the optimum pH conditions for each enzyme agent. * Time required under optimum conditions
- biosork or proleather FG-F was inactivated by adding PMSF, and then subjected to SDS-PAGE (FIG. 5).
- the molecular weight of the solubilized product was distributed between 3.5 and 25 kDa, most of which was around 6 kDa. In addition, a dark band was confirmed around 14 kDa.
- Enzyme concentration dependence in eggshell membrane solubilization We searched for the optimal enzyme concentration in eggshell membrane solubilization. In this test, biosoak was used as the target enzyme. Solubilization was attempted using 50 mM Tris-HCl pH 7.0 as a buffer and adding 200 mM sodium sulfite. The amount of enzyme was 0.01, 0.1, 1.0% (w / v), the amount of eggshell membrane was 10% (w / v), the reaction temperature was 60 ° C., and the time required for complete solubilization was measured. From this test, it was decided to stir during the incubation.
- Solubilization time associated with changes in the amount of eggshell membranes The amount of eggshell membranes was changed, and the amount of solubilization was verified. In this test, biosoak was used as the target enzyme. Solubilization was attempted using 50 mM Tris-HCl pH 7.0 as a buffer and adding 200 mM sodium sulfite. The enzyme amount was 0.1 (w / v), the eggshell membrane amount was 10-50% (w / v), the reaction temperature was 60 ° C., and the time required for complete solubilization was measured. Also in this test, stirring was performed during the incubation. As shown on the left side of FIG. 9, it was possible to completely solubilize even the eggshell membrane amount of 10 to 50%.
- the graph of the solubilization time accompanying eggshell membrane amount is shown on the right of FIG.
- the horizontal axis indicates the amount of eggshell membrane, and the vertical axis indicates the time required for solubilization, and the time required for complete solubilization is plotted for each amount of eggshell membrane.
- the plot is linear, indicating that the decomposition reaction is progressing with the same efficiency.
- Acid protease Sumiteam AP (acid protease from Aspergillus niger, Shin Nippon Chemical), pepsin (Sigma)
- Neutral proteases Sumiteam FP (Aspergillus oryzae-derived neutral protease, Shinnippon Chemical), Sumiteam LP500 (Aspergillus oryzae-derived neutral protease, Shinnippon Chemical), Sumiteam LPL (Aspergillus oryzae-derived neutral protease, Shinnippon Chemical)
- Deskin C unknown, neutral protease, Yamato Kasei), Protin NY10 (Bucillus subtilis-derived neutral protease, Yamato Kasei), Protin PC10 (Bucillus subtilis-derived neutral protease, Yamato Kasei), Trypsin (Trypsin) Roche)
- Alkaline protease Sumiteam MP (Aspergillus sp.-
- sodium sulfite As a reducing agent to be added, sodium sulfite (Kanto Chemical Co., Ltd.) was used and added so that the final concentration was 100 ⁇ m. Buffers include 100 ⁇ mM NaOAc buffer under acidic pH conditions (pH 4.5 or pH4.7), 100 mM Tris-HCl buffer under neutral pH conditions (pH 7.0 or pH 7.5), alkaline pH conditions (pH ⁇ 9.0 or pH 8.7) ), 100 mm mM Glycine-NaOH buffer was used. The added enzyme was performed at a final concentration of 0.1% (w / v). Incubation was performed at 50 ° C. for 24 hours, and the presence or absence of solubilization of the eggshell membrane was examined.
- pepsin In pepsin (FIG. 10), significant solubilization was observed under acidic pH conditions in the presence of a reducing agent. Regarding pepsin, complete solubilization was not achieved, but it can be considered that it can be completely solubilized by increasing the amount of enzyme added.
- the neutral protease in Sumiteam LP500 (Fig. 11), Deskin C (Fig. 12), Protin NY10 (Fig. 13), Protin PC10 (Fig. 14), Trypsin (Fig. 15) Solubilization was seen.
- alkaline protease solubilization was observed in Sumiteam MP (FIG. 16), Protin AY (FIG. 17), and Proteinase K (FIG. 18).
- Biosork and Proleather FG-F were used as the target enzyme agents.
- the amount of enzyme added is 0.1% w / v.
- As buffer solutions 100 mM Tris-HCl pH 7.0 and 100 mM Glycine-NaOH pH 9.0 were used.
- Reducing agents include (1) N-acetyl-L-cysteine (Wako Pure Chemical Industries), (2) 2-mercaptoethanol (Wako Pure Chemical Industries), (3) thioglycolic acid (Wako Pure Chemical Industries), ( 4) Sodium thiosulfate (Wako Pure Chemical Industries) and (5) Thiourea (Wako Pure Chemical Industries) were tested.
- Each reducing agent was added at a final concentration of 1, 10, 100 ⁇ mM, and incubated at 50 ° C. for 24 hours to examine whether or not eggshell membranes were solubilized.
- N-acetyl-L-cysteine (Fig. 19) and 2-mercaptoethanol (Fig. 20) were added and eggshell membranes for both biosoak and proleather FG-F Was solubilized.
- N-acetyl-L-cysteine its solubilization was limited to a part, but it is considered that complete solubilization can be achieved by increasing the amount of enzyme to be added.
- 2-mercaptoethanol is used as the reducing agent, complete solubilization can be achieved.
- Both N-acetyl-L-cysteine and 2-mercaptoethanol are known to cleave disulfide bonds, suggesting that cleavage of disulfide bonds is important and effective for solubilizing eggshell membranes.
- eggshell membranes are known to contain sulfated glycosaminoglycans (GAG) such as dermatan sulfate and chondroitin sulfate and hyaluronic acid. .
- GAG glycosaminoglycans
- These acidic mucopolysaccharides are used in the treatment of arthropathy and cosmetics utilizing water retention. Therefore, if these polysaccharides can be confirmed in the solubilized eggshell membranes obtained by this method, the utility value can be enhanced.
- a eggshell membrane soluble material was prepared.
- the eggshell membrane was solubilized by adding an enzyme agent to a reaction solution containing 50% (w / v) eggshell membrane (50 mM Tris-HCl pH 7.0, 100 mM sodium sulfite).
- an enzyme agent Proteinase K (Roche), Biosoak, Proleather FG-F, Papain W40 are used.
- the final concentration is 0.01% (w / v)
- the final concentration is 0.1% (w / v).
- the eggshell membrane was completely solubilized by incubation with stirring at 50 ° C. for 12 hours.
- a sample containing no eggshell membrane was prepared.
- hyaluronic acid in each sample was performed using a commercially available hyaluronic acid measurement kit (Seikagaku Corporation). This kit is based on the inhibition method using hyaluronic acid binding protein (HABP), and can specifically detect hyaluronic acid.
- HABP hyaluronic acid binding protein
- the sulfated GAG content in the solubilized eggshell membranes treated with each enzyme agent is shown in FIG. This content is the content per eggshell membrane mass, and the mass measured for the eggshell membrane before treatment with the enzyme agent is used. The content of each sample is obtained by subtracting the control value. As shown in FIG. 21, it is clear that the solubilized eggshell membranes obtained by this experiment contain sulfated GAG (content is 0.53 to 5.4% (w / w) per eggshell membrane weight). Became.
- Fig. 22 shows the hyaluronic acid content in the solubilized eggshell membranes. This content is also the content per eggshell membrane weight, and is obtained by subtracting the control value. As shown by these results, it was found that each eggshell membrane soluble material contained hyaluronic acid (content is 0.026 to 0.11% ⁇ ⁇ ⁇ (w / w) per eggshell membrane weight).
- acidic mucopolysaccharides such as sulfated GAG and hyaluronic acid are present in the solubilized eggshell membranes obtained by this eggshell membrane solubilization method (combination of protease and reducing agent).
- the utility value of acidic mucopolysaccharide is high. Therefore, it can be said that the useful value of this soluble substance is very high.
- an eggshell membrane soluble material was prepared under the condition that a reducing agent and a protease were used in combination.
- the eggshell membrane was solubilized by adding an enzyme agent to a reaction solution containing 100% (w / v) eggshell membrane (100 mM PBS buffer pH 7.4, 100 mM ⁇ ⁇ ⁇ ⁇ ⁇ sodium sulfite).
- an enzyme agent Proteinase K (Roche), Biosoak, Proleather FG-F, Papain W40 are used.
- the final concentration is 0.01% (w / v)
- the final concentration is 0.1% (w / v).
- the eggshell membrane was completely solubilized by incubation with stirring at 50 ° C. for 12 hours.
- a sample containing no eggshell membrane (containing an enzyme agent and a reducing agent) was prepared.
- n-butylamine was added to the solubilized solution to a final concentration of 10 mM and incubated at 37 ° C. for 60 minutes. At this time, if lysyl oxidase is present in the soluble matter, n-butylamine undergoes an oxidation reaction to become n-butyraldehyde.
- n-butyraldehyde was added to a Nash reagent (15% (w / v) ammonium acetate, 0.5% (w / w) acetic acid, 20% (w / w) acetylacetone, Nash, et al. (1953) Biochem. J. 55,416 .).
- Nash reagent 15% (w / v) ammonium acetate, 0.5% (w / w) acetic acid, 20% (w / w) acetylacetone, Nash, et al. (1953) Biochem. J. 55,416 .
- n-butyraldehyde in the reaction solution reacts with the Nash reagent to produce a yellow colored substance. Can be detected. That is, the larger the value of 388 nm, the higher the lysyl oxidase activity.
- a value of 388 nm was measured with a microplate reader using the sample after incubation.
- a soluble eggshell membrane was prepared after the protease treatment.
- a reducing agent solution 100 ⁇ mM PBS buffer pH 7.4, 100 ⁇ mM sodium sulfite
- the eggshell membrane was taken out, washed 5 times with 50 mL distilled water, and finally washed with 500 mL distilled water to remove sodium sulfite.
- lysyl oxidase activity could not be confirmed in any sample of soluble eggshell membranes when a reducing agent and protease were used in combination.
- Lysyl oxidase is an oxidase and may be inactivated by a reducing agent.
- lysyl oxidase liberated in the solution due to the decomposition of protease may be greatly affected by the reducing agent.
- the reducing agent was removed, and then the lysyl oxidase activity could be confirmed in the solubilized eggshell membranes (FIG. 23).
- the activity increased with the lapse of time of protease treatment.
- lysyl oxidase activity was not detected in the control, it can be said that this activity is that of eggshell membrane-derived lysyl oxidase. Lysyl oxidase activity was also confirmed when the enzyme treatment was performed using eggshell membranes that were not treated with the reducing agent, but the activity was about half to one third of that when the reducing agent was treated. Therefore, it can be said that the eggshell membrane treatment with the reducing agent is effective for efficient recovery of lysyl oxidase.
- lysyl oxidase can be efficiently recovered through three steps of (1) treatment of the eggshell membrane with a reducing agent, (2) removal of the reducing agent, and (3) protease treatment.
- a eggshell membrane soluble material was prepared.
- the eggshell membrane was solubilized by adding an enzyme agent to a reaction solution containing 100% (w / v) eggshell membrane (100 mM PBS buffer pH 7.0, 100 mM sodium sulfite). Biosoke, Proleather FG-F, and Papain W40 were used as the target enzyme agents, and added to a final concentration of 0.5% (w / v). After adding the enzyme agent, the eggshell membrane was completely solubilized by incubation at 37 ° C. for 12 hours with stirring. As a control, a sample containing no eggshell membrane (containing an enzyme agent and a reducing agent) was prepared.
- Micrococcus luteus (Wako Pure Chemical Industries) is commonly used as a test bacterium serving as a substrate.
- the bacterial powder was suspended in 100 ⁇ mM PBS buffer pH 7.0 to a final concentration of 0.32 mg / mL.
- 10 ⁇ L of each eggshell membrane soluble material sample was added to a microplate (Nunc), and then 240 ⁇ L of the cell suspension was added to each sample.
- incubation at 37 ° C. was started, and the value of 450 nm was measured every 10 minutes.
- the value of 450 nm decreases. In other words, the faster the value of 450 nm decreases, the higher the lytic activity.
- lytic activity was observed in the solubilized eggshell membranes treated with any enzyme agent. Although there are differences in the degree, the lytic activity is clear. Since no lytic activity was observed in the control, it can be said that this activity was derived from eggshell membranes.
- Oxidative stress such as active oxygen, free radicals and lipid peroxides has been found to be a major factor in cancer, lifestyle-related diseases, and body aging.
- antioxidant substances that prevent oxidative stress vitamin C, vitamin E, ⁇ -carotene, and the like are used.
- protein-derived antioxidant peptides are also attracting attention in terms of their safety.
- a peptide having a cysteine residue such as glutathione exhibits high antioxidant ability. Since about 10% of the amino acids constituting the eggshell membrane are cysteine (cystine), the soluble product can be expected to have a high antioxidant capacity.
- cysteine cysteine
- the antioxidant activity of the solubilized eggshell membranes obtained by this method was measured in order to investigate the possibility of a material having antioxidant ability.
- a eggshell membrane soluble material was prepared.
- the eggshell membrane was solubilized by adding an enzyme agent to a reaction solution containing 100% (w / v) eggshell membrane (100 mM PBS buffer pH 7.0, 100 mM sodium sulfite). Biosoke, Proleather FG-F, and Papain W40 were used as the target enzyme agents, and added to a final concentration of 0.5% (w / v). After adding the enzyme agent, the eggshell membrane was completely solubilized by incubation at 37 ° C. for 12 hours with stirring. As a control, a sample containing no eggshell membrane (containing an enzyme agent and a reducing agent) was prepared.
- antioxidant ability measurement by reduction of copper was performed using an antioxidant ability measuring kit “PAO” (Japan Aging Control Research Laboratories).
- This copper reducing ability test is an antioxidant ability test using a copper ion reduction reaction (Cu 2+ ⁇ Cu + ).
- the value of the antioxidant activity of each solubilized eggshell membrane sample obtained by the above two methods is obtained by subtracting the control value.
- the solubilized eggshell membranes treated with each enzyme agent have free radical scavenging activity.
- the values were 678.3, 521.7, and 415.2 ⁇ mol Trolox equivalent / 100 g for the biosork soluble product, proleather FG-F soluble product, and papain W40 soluble product, respectively.
- the reduction activity of copper could also be confirmed.
- the values of each sample were found to be relatively high values of 3617.1, 2090.8, and 2816.8 ⁇ mol / L for the biosork soluble material, proleather FG-F soluble material, and papain W40 soluble material, respectively.
- the solubilized eggshell membranes obtained by this method have a relatively high antioxidant capacity. Therefore, it can be said that the soluble material is useful as a functional material having an antioxidant ability.
- ACE inhibitory activity of solubilized eggshell membranes Angiotensin-converting enzyme (ACE) plays an extremely important role in the blood pressure regulation mechanism in humans.
- ACE is an enzyme that is greatly related to an increase in blood pressure, such as the production of angiotensin II having a pressor action from angiotensin I in the renin-angiotensin system, which is one of the blood pressure regulation mechanisms.
- food ingredients having an ACE inhibitory action have attracted attention, such as a large number of functional foods (foods for specified health use) aimed at preventing hypertension. Therefore, in this experiment, the ACE inhibitory activity of the solubilized eggshell membranes obtained by this method was measured in order to investigate the possibility of a material having a blood pressure lowering effect.
- a eggshell membrane soluble material was prepared.
- the eggshell membrane was solubilized by adding the enzyme agent to a reaction solution containing 100% (w / v) eggshell membrane (100 mM PBS buffer pH 7.0, 100 mM sodium sulfite). Biosoke, Proleather FG-F, and Papain W40 were used as the target enzyme agents, and added to a final concentration of 0.5% (w / v). After adding the enzyme agent, the eggshell membrane was completely solubilized by incubation with stirring at 37 ° C. for 12 hours. As a control, a sample containing no eggshell membrane (containing an enzyme agent and a reducing agent) was prepared.
- the solubilized eggshell membranes were subjected to heat treatment (inactivation of protease) at 100 ° C for 5 minutes, then diluted 25-fold with distilled water, and the ACE inhibitory activity measurement kit “ACE Kit-WST” (Wako Pure Chemicals) ACE inhibitory activity was measured using an industrial).
- This kit is a simple and highly reproducible ACE inhibitory activity measurement kit that detects 3-Hydroxybutyric acid (3HB) excised from 3-Hydroxybutyrylglycyl-glycyl-glycine (3HB-GGG) by enzymatic method.
- the ACE inhibitory activity of each solubilized eggshell membrane sample obtained by this method is obtained by subtracting the control value.
- solubilized eggshell membranes have a relatively high ACE inhibitory ability.
- the inhibition rates were 72.4%, 74.5%, and 63.6% for biosork solubles, proleather FG-F solubles, and papain W40 solubles, respectively.
- solubilized eggshell membranes obtained by this method have high ACE inhibitory activity, and thus have high utility value as a material having a blood pressure lowering effect.
- eggshell membranes can be efficiently solubilized under mild conditions. That is, there are significant advantages in terms of energy costs and raw material costs.
- the soluble eggshell membranes obtained by the method of the present invention include, for example, the pharmaceutical field, the food field, cosmetics (including the concept of skin care), metal ion recovery, moisturizer, water absorbent, antibacterial agent, emulsifier, and hair restorer. Etc. are available.
- the eggshell membrane soluble material of the present invention is used to impart various actions (antibacterial action, water absorption / moisture retention action, rheology adjustment action, coating protection action, etc.).
- the soluble material of the eggshell membrane of the present invention is contained in a polymer material or the like to enhance the stretchability of the material.
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Abstract
Description
[1]タンパク質分解酵素と還元剤を併用することを特徴とする、卵殻膜可溶化方法。
[2]還元剤の共存下、卵殻膜にタンパク質分解酵素を作用させる工程を含む、[1]に記載の卵殻膜可溶化方法。
[3]以下の工程(1)及び(2)を含む、[1]に記載の卵殻膜可溶化方法:
(1)溶媒中に卵殻膜を用意する工程、
(2)前記溶媒に還元剤及びタンパク質分解酵素を添加し、反応させる工程。
[4]工程(2)における反応溶液のpHが4.5~9.5である、[3]に記載の卵殻膜可溶化方法。
[5]前記還元剤の濃度が5mM~1Mである、[3]又は[4]に記載の卵殻膜可溶化方法。
[6]固形物が認められなくなるまで、前記工程(2)の反応を継続する、[3]~[5]のいずれか一項に記載の卵殻膜可溶化方法。
[7]以下の工程(3)を更に含む、[3]~[6]のいずれか一項に記載の卵殻膜可溶化方法:
(3)工程(2)後の溶液を濾過し、固形物を除去する工程。
[8]前記タンパク質分解酵素がアルカリ性プロテアーゼ又は中性プロテアーゼである、[1]~[7]のいずれか一項に記載の卵殻膜可溶化方法。
[9]前記タンパク質分解酵素が、セリンエンドペプチダーゼ、システインエンドペプチダーゼ、メタロエンドペプチダーゼ、アミノペプチダーゼ及びアスパラギン酸エンドペプチダーゼからなる群より選択される一種以上の酵素である、[1]~[7]のいずれか一項に記載の卵殻膜可溶化方法。
[10]前記タンパク質分解酵素がキモトリプシン、サブチリシン、パパイン、バシロライシン、ステムブロメライン、ロイシルアミノペプチダーゼ、ペプシン及びトリプシンからなる群より選択される一種以上の酵素である、[1]~[7]のいずれか一項に記載の卵殻膜可溶化方法。
[11]前記タンパク質分解酵素がビオソーク、プロレザーFG-F、パパインW40、プロテアーゼN、ブロメラインF、ウマミザイムG、サモアーゼY100、ProteAX、プロテアーゼS、スミチームLP500、デスキンC、プロチンNY10、プロチンPC10、スミチームMP、プロチンAY及びプロテイナーゼK(Proteinase K)からなる群より選択される一種以上の酵素である、[1]~[7]のいずれか一項に記載の卵殻膜可溶化方法。
[12]前記還元剤が、亜硫酸塩、亜硫酸水素塩、L-システイン、N-アセチル-L-システイン、2-メルカプトエタノール、グルタチオン及びDTTからなる群より選択される一種以上の還元剤である、[1]~[11]のいずれか一項に記載の卵殻膜可溶化方法。
[13]前記還元剤が亜硫酸ナトリウム又は亜硫酸水素ナトリウムである、[1]~[11]のいずれか一項に記載の卵殻膜可溶化方法。
[14]以下の工程(1)及び(2’)を含む、[1]に記載の卵殻膜可溶化方法:
(1)溶媒中に卵殻膜を用意する工程、
(2’)前記溶媒に還元剤を添加して反応させた後、還元剤を除去し、次いでタンパク質分解酵素を添加し、反応させる工程。
[15]タンパク質分解酵素と還元剤を組合せてなる、卵殻膜可溶化剤。
[16]タンパク質分解酵素と還元剤を含有することを特徴とする、[15]に記載の卵殻膜可溶化剤。
[17]タンパク質分解酵素を含有する第1構成要素と、還元剤を含有する第2構成要素とからなるキットであることを特徴とする、[15]に記載の卵殻膜可溶化剤。
[18][1]~[13]のいずれか一項に記載の卵殻膜可溶化方法で得られる、卵殻膜可溶物。
[19]リゾチーム、β-N-アセチルグルコサミニダーゼ、ヒアルロン酸、コンドロイチン硫酸及びデルマタン硫酸からなる群より選択される一以上の成分を含む、[18]に記載の卵殻膜可溶物。
[20]抗酸化活性及びアンジオテンシン変換酵素阻害活性からなる群より選択される一以上の活性を示す、[18]に記載の卵殻膜可溶物。
[21][14]に記載の卵殻膜可溶化方法で得られる、卵殻膜可溶物。
[22]リジルオキシダーゼを含む、[21]に記載の卵殻膜可溶物。
[23]卵殻膜の完全な可溶物である、[18]~[22]のいずれか一項に記載の卵殻膜可溶物
[24][18]~[23]のいずれか一項に記載の卵殻膜可溶物を含む組成物。
[25]医薬、医薬部外品、食品又は化粧料である、[24]に記載の組成物。
[26]以下の工程(i)及び(ii)を含む、卵殻膜有用成分抽出方法:
(i)[1]~[13]のいずれか一項に記載の方法による可溶化工程;
(ii)前記可溶化工程で得られた卵殻膜可溶物を精製する工程。
[27]工程(ii)で精製される成分が、リゾチーム及びβ-N-アセチルグルコサミニダーゼからなる群より選択される酵素、又はヒアルロン酸、コンドロイチン硫酸及びデルマタン硫酸からなる群より選択される酸性ムコ多糖である、[26]に記載の卵殻膜有用成分抽出方法。
[28][27]に記載の方法で得られるリゾチーム、β-N-アセチルグルコサミニダーゼ、ヒアルロン酸、コンドロイチン硫酸又はデルマタン硫酸。
[29]以下の工程(i’)及び(ii)を含む、卵殻膜有用成分抽出方法:
(i’)[14]に記載の方法による可溶化工程;
(ii)前記可溶化工程で得られた卵殻膜可溶物を精製する工程。
[30]工程(ii)で精製される成分がリジルオキシダーゼである、[29]に記載の卵殻膜有用成分抽出方法。
[31][30]に記載の方法で得られるリジルオキシダーゼ。
[32][26]又は[29]に記載の卵殻膜有用成分抽出方法で得られる卵殻膜抽出物。
本発明の第一の局面は卵殻膜の可溶化方法に関する。本発明の方法によれば、茶褐色の着色やアミノ酸分解による異臭発生の問題を回避しつつ、卵殻膜を効率的に可溶化できる。また、前処理を行わなくとも高い可溶化(分解)率を達成できる。
(1)溶媒中に卵殻膜を用意する工程
(2)前記溶媒に還元剤及びタンパク質分解酵素を添加し、反応させる工程
(1)溶媒中に卵殻膜を用意する工程
(2’)前記溶媒に還元剤を添加して反応させた後、還元剤を除去し、次いでタンパク質分解酵素を添加し、反応させる工程
本発明の第2の局面は卵殻膜可溶化剤に関する。本発明の卵殻膜可溶化剤はタンパク質分解酵素と還元剤を組合せてなる点に特徴を有する。換言すれば、本発明の卵殻膜可溶化剤ではタンパク質分解酵素と還元剤を併用する。典型的には、タンパク質分解酵素と還元剤とを混合した配合剤として本発明の卵殻膜可溶化剤が提供されることになる。一方、例えば、タンパク質分解酵素を含有する要素(第1構成要素)と、還元剤を含有する要素(第2構成要素)とからなるキットの形態で本発明の卵殻膜可溶化剤を提供することもできる。2種類以上のタンパク質分解酵素を併用してもよい。同様に2種類以上の還元剤を併用してもよい。尚、タンパク質分解酵素と還元剤については、本発明の卵殻膜可溶化方法の場合と同様であるため、重複する説明は省略する。
本発明の更なる局面は本発明の卵殻膜可溶化方法で得られる卵殻膜可溶物を提供する。好ましい一態様として、卵殻膜の完全な可溶物が提供される。本発明の卵殻膜可溶化方法によれば、温和な条件で卵殻膜を可溶化することができる。従って、当該方法により得られる卵殻膜可溶物は、卵殻膜に含まれる有用成分(タンパク質(リジルオキシダーゼ、リゾチーム、β-N-アセチルグルコサミニダーゼ等の酵素、コラーゲンタンパク質を含む)、糖タンパク質、ペプチド(コラーゲンペプチドを含む)、糖ペプチド、アミノ酸、ヒアルロン酸、コンドロイチン硫酸、デルマタン硫酸等の酸性ムコ多糖等)を多く含有する。一態様では、本発明の方法により得られる卵殻膜可溶物は、リゾチーム、β-N-アセチルグルコサミニダーゼ、ヒアルロン酸、コンドロイチン硫酸及びデルマタン硫酸からなる群より選択される一以上の成分を含む。また、本発明の方法により得られる卵殻膜可溶物を、抗酸化活性を示すこと及び/又はアンジオテンシン変換酵素阻害活性を示すことによって特徴付けることもできる。一方、他の一態様の卵殻膜可溶物はリジルオキシダーゼを含む点が特徴的である。リジルオキシダーゼを含む当該卵殻膜可溶物は、典型的には、上記工程(1)及び(2’)を含む卵殻膜可溶化方法によって得られる。
本発明は更に、本発明の卵殻膜可溶化方法を応用した卵殻膜有用成分抽出方法を提供する。本発明の卵殻膜有用成分抽出方法では、以下の工程(i)及び(ii)を行う。
(i)本発明の卵殻膜可溶化方法による可溶化工程
(ii)前記可溶化ステップで得られた卵殻膜可溶物を精製する工程
鶏卵を割卵して卵液を取り出した後、卵殻膜付きの卵殻を4重量%酢酸水溶液に5~10分程度浸漬させ、手で卵殻膜を剥がして採取した。剥がし取った卵殻膜を水洗いし、十分に水気を切ったものを使用した。
酵素剤単独では卵殻膜の可溶化は見られなかったため、還元剤との組み合わせによる効果を検証した。本試験では対象酵素剤としてビオソークおよびプロレザーFG-Fを用いた。緩衝液として100 mM Glycine-NaOH pH 9.0を用い、10 mM DTTを添加した、または添加していない条件にて可溶化を試みた。酵素量は0.1% (w/v)、卵殻膜量は1.0% (w/v)、反応温度は60℃でインキュベーションした。図2は、試験酵素剤としてビオソークを用いた場合の結果を示している。図2が示すように、DTT単独および酵素剤単独では卵殻膜の可溶化は見られないが、DTTと酵素剤が共存する条件下では1.5時間という短時間での可溶化が見られた。また、プロレザーFG-Fを用いた場合も同様の結果が得られたが、完全可溶化に要する時間はビオソークよりも長かった(約2時間)。卵殻膜を構成する蛋白質中に存在するジスルフィド結合を還元剤が開裂させた結果、可溶化を容易にしたと考えられる。また、セリンプロテアーゼ阻害剤であるPMSFによって可溶化が阻害されたことから、当試験での卵殻膜の可溶化はプロテアーゼによるものであると考えられる。
安全性とコスト面を考慮し、食品添加物から卵殻膜の可溶化を可能にする還元剤を探索した。まず、ビオソークを試験酵素剤として用い、10種の還元剤(亜硫酸ナトリウム、亜硫酸水素ナトリウム、L-アスコルビン酸、L-システイン塩酸塩、亜硝酸ナトリウム、硝酸ナトリウム、L-システイン、グルタチオン、DTT、水素化ホウ素ナトリウム、ハイチオンエキスYH-8、ハイチオンエキスYH-15、ハイチオンエキスYH-D12)を各々添加し、可溶化を試みた。亜硫酸ナトリウム、亜硫酸水素ナトリウム、L-アスコルビン酸、亜硝酸ナトリウム、硝酸ナトリウム、DTT、水素化ホウ素ナトリウムの濃度は1、10、100 mMを試験した。L-システイン塩酸塩、L-システイン、グルタチオンの濃度は1、10、20、50 mMを試験した。ハイチオンエキスYH-8、ハイチオンエキスYH-15、ハイチオンエキスYH-D12の濃度は1、5、10% (w/v)を試験した。緩衝液のpH条件は4.0~13.0でそれぞれ行い、前述と同じものを用いた。酵素量は0.1% または0.5% (w/v)、卵殻膜量は1.0% (w/v)、反応温度は60℃とし、6時間または12時間インキュベーションした。亜硫酸ナトリウム存在下におけるpH変化による分解能の比較では、亜硫酸ナトリウムの濃度を100mMとし、pH 4.0~13.0の各緩衝液(100 mM)を用いて試験を行った。ビオソークおよびプロレザーFG-Fを用いた試験においては、pH 4.0~5.5はNaOAcバッファー、pH 5.5~6.5はMES-NaOHバッファー、pH 6.5~7.5はHEPES-NaOHバッファー、pH 7.5~9.0はTris-HClバッファー、pH 9.0~12.5はGlycine-NaOHバッファー、pH 12.5~13.0はKCl-NaOHバッファーを用いた。他の13種類の酵素剤を用いた試験では、NaOAcバッファー(pH 4.0、5.0)、MES-NaOHバッファー(pH 6.0)、HEPES-NaOHバッファー(pH 7.0)、Tris-HClバッファー(pH 8.0)、Glycine-NaOHバッファー(pH 9.0)を用いて行った。酵素量は0.1% (w/v)、卵殻膜量は1.0% (w/v)、反応温度は60℃でインキュベーションを行い、完全な可溶化に要する時間を測定した。分解パターンの確認では、ビオソークおよびプロレザーFG-Fを対象酵素剤とし、各pH条件にて反応後の溶液にPMSFを終濃度1 mMとなるように添加することで反応を停止し、各サンプルをSDS-PAGEに供した。図3は、試験した還元剤の種類と添加による卵殻膜可溶化(分解)の有無を示している。食品添加物では亜硫酸塩と亜硫酸水素塩が100 mMの濃度条件で顕著な効果を示した。亜硫酸ナトリウムを用いた場合、卵殻膜の可溶化はpH 6.0~8.0において効率よく見られた。L-システインを使用した場合、一部可溶化を認めた。
卵殻膜可溶化において、至適な亜硫酸ナトリウム濃度の探索を行った。本試験では対象酵素剤としてビオソークおよびプロレザーFG-Fを用いた。緩衝液として50 mM Tris-HCl pH 7.0を用い、10~1000 mM 亜硫酸ナトリウムを添加した、または添加していない条件にて可溶化を試みた。酵素量は0.1% (w/v)、卵殻膜量は1.0% (w/v)、反応温度は60℃でインキュベーションを行い、完全な可溶化に要する時間を測定した。図6に示すように、ビオソーク、プロレザーFG-Fともに至適な亜硫酸ナトリウム濃度は200 mMであった。一方で、10~1000 mMの広い濃度条件下で可溶化可能であることも確認できた。尚、ビオソーク及びプロレザーFG-Fを用いた場合の卵殻膜の可溶化の結果をそれぞれ図7及び図8に示す。
卵殻膜可溶化において、至適な酵素濃度の探索を行った。本試験では対象酵素剤としてビオソークを用いた。緩衝液として50 mM Tris-HCl pH 7.0を用い、200 mM 亜硫酸ナトリウムを添加した条件にて可溶化を試みた。酵素量は0.01、0.1、1.0% (w/v)、卵殻膜量は10% (w/v)、反応温度は60℃でインキュベーションを行い、完全な可溶化に要する時間を測定した。また、本試験からインキュベーション中に撹拌することにした。表3に示すように、ビオソークを用いた場合、1.0%濃度では45分、0.1%濃度では60分で完全に可溶化することが分かった。一方、0.01%濃度では可溶化は見られなかった。本試験から卵殻膜量を10% (w/v)としているにもかかわらず、可溶化時間は1% (w/v)のときよりも短縮された。おそらく撹拌の影響が大きいと考えられる。用いる酵素量に関して、1.0%と0.1%ではそれほど大きな違いはないといえる。コスト面を考慮した場合、0.1%での使用がより効率的と思われる。
卵殻膜の量を変化させ、どこまでの量を可溶化可能か検証した。本試験では対象酵素剤としてビオソークを用いた。緩衝液として50 mM Tris-HCl pH 7.0を用い、200 mM 亜硫酸ナトリウムを添加した条件にて可溶化を試みた。酵素量は0.1 (w/v)、卵殻膜量は10~50% (w/v)、反応温度は60℃でインキュベーションを行い、完全な可溶化に要する時間を測定した。また、本試験でもインキュベーション中に撹拌した。図9左に示すように、10~50%の卵殻膜量であっても完全に可溶化することが可能であった。また図9右には、卵殻膜量に伴う可溶化時間のグラフを示す。横軸は卵殻膜量、縦軸は可溶化に要した時間を示しており、各卵殻膜量で完全可溶化に要する時間をプロットしている。10~40%の卵殻膜量ではプロットが直線にのることから、同効率で分解反応が進んでいることを示している。
15種類の市販酵素剤のうち10種類の酵素剤において、還元剤、特に亜硫酸ナトリウムの共存下で卵殻膜の可溶化が見られた。これら10種類の酵素剤の中には中性およびアルカリ性プロテアーゼが含まれていた。本実験では酸性プロテアーゼによる卵殻膜の分解能を実証することを目的とし、複数の酸性プロテアーゼを用いて分解能の有無を検証した。また、新たな中性およびアルカリ性プロテアーゼを用いた実験も並行して行った。
(1)酸性プロテアーゼ:スミチームAP(Aspergillus niger由来酸性プロテアーゼ、新日本化学)、ペプシン(Sigma)
(2)中性プロテアーゼ:スミチームFP(Aspergillus oryzae由来中性プロテアーゼ、新日本化学)、スミチームLP500(Aspergillus oryzae由来中性プロテアーゼ、新日本化学)、スミチームLPL(Aspergillus oryzae由来中性プロテアーゼ、新日本化学)、デスキンC(由来は不明、中性プロテアーゼ、大和化成)、プロチンNY10(Bucillus subtilis由来中性プロテアーゼ、大和化成)、プロチンPC10(Bucillus subtilis由来中性プロテアーゼ、大和化成)、トリプシン(Trypsin)(Roche)
(3)アルカリ性プロテアーゼ:スミチームMP(Aspergillus sp.由来アルカリ性プロテアーゼ、新日本化学)、プロチンAY(Bucillus licheniformis由来アルカリ性プロテアーゼ、大和化成)、プロテナーゼK(Proteinase K)(Roche)
上記の通り、プロテアーゼによる効率的な卵殻膜の可溶化には還元剤の添加が有効であることが示された。これまでに、卵殻膜の可溶化を可能にする還元剤として、亜硫酸ナトリウム(関東化学株式会社)、亜硫酸水素ナトリウム(和光純薬工業)、L-システイン(Sigma Aldrich)、DTT(和光純薬工業)の4種類が確認された。以下では、新たに数種類の還元剤を用いて可溶化試験を行った。
卵殻膜にはコラーゲン様蛋白質以外に、デルマタン硫酸やコンドロイチン硫酸といった硫酸化グリコサミノグリカン(GAG)と、ヒアルロン酸が存在することが知られている。これら酸性ムコ多糖は関節症の治療や、保水性を活かした化粧品に利用されている。したがって、本法によって得られる卵殻膜可溶物中にこれらの多糖類が確認できれば、その利用価値を高めることができる。そこで本実験では、今回得られた卵殻膜可溶物を用いて、硫酸化GAGとヒアルロン酸の同定を試みた。
卵殻膜にはリジルオキシダーゼ(EC 1.4.3.13)が存在することが知られている。当酵素はタンパク質中のリジン残基のε-アミノ基を酸化的に脱アミノすることでアルデヒド(アリシン残基)を生成し、コラーゲンやエラスチン等のタンパク質の架橋化反応に関与する。この架橋化反応は、表皮の弾性や伸張性などの機能発現だけではなく、組織の構築に必要不可欠な特異的プロセスである。したがって、本法によって得られる卵殻膜可溶物中からリジルオキシダーゼ活性を同定できれば、その利用価値をさらに高めることになる。そこで本実験では、卵殻膜可溶物を用いて、リジルオキシダーゼ活性の検出を試みた。
卵殻膜には、リゾチーム(EC 3.2.1.17)やβ-N-アセチルグルコサミニダーゼ(EC 3.2.1.96)といった溶菌(抗菌)活性を持つ酵素が存在している。本法によって得られる卵殻膜可溶物中にこれらの酵素が存在しておれば、当可溶物の利用範囲を拡大できる。当実験では、卵殻膜可溶物を用いて溶菌活性の有無を検証した。
癌、生活習慣病、身体の老化において、活性酸素、フリーラジカル、過酸化脂質などの酸化ストレスが大きな要因であることが明らかにされている。酸化ストレスを防ぐ抗酸化物質として、ビタミンC、ビタミンE、β-カロテンなどが利用されている一方で、タンパク質に由来する抗酸化ペプチドも、その安全性の面から注目されている。特に、グルタチオンのようにシステイン残基を持つペプチドは高い抗酸化能を示す。卵殻膜を構成するアミノ酸のうち約10%はシステイン(シスチン)であることから、その可溶物は高い抗酸化能を持つことが期待できる。本実験では、本法によって得られる卵殻膜可溶物について、抗酸化能を持つ素材としての可能性を探るため、その抗酸化活性を測定した。
ヒトの血圧調節機構においてアンジオテンシン変換酵素(ACE)は極めて重要な役割を持っている。ACEは血圧調節メカニズムの一つであるレニン-アンジオテンシン系において、アンジオテンシンIから昇圧作用を有するアンジオテンシンIIを生成するなど、血圧上昇に大きく関係している酵素である。近年、高血圧予防を目的とした機能食品(特定保健用食品)が多く販売されるなど、ACE阻害作用を有する食品成分が注目を集めている。そこで本実験では、本法で得られる卵殻膜可溶物について、血圧降下作用を有する素材としての可能性を探るため、そのACE阻害活性を測定した。
本明細書の中で明示した論文、公開特許公報、及び特許公報などの内容は、その全ての内容を援用によって引用することとする。
Claims (32)
- タンパク質分解酵素と還元剤を併用することを特徴とする、卵殻膜可溶化方法。
- 還元剤の共存下、卵殻膜にタンパク質分解酵素を作用させる工程を含む、請求項1に記載の卵殻膜可溶化方法。
- 以下の工程(1)及び(2)を含む、請求項1に記載の卵殻膜可溶化方法:
(1)溶媒中に卵殻膜を用意する工程、
(2)前記溶媒に還元剤及びタンパク質分解酵素を添加し、反応させる工程。 - 工程(2)における反応溶液のpHが4.5~9.5である、請求項3に記載の卵殻膜可溶化方法。
- 前記還元剤の濃度が5mM~1Mである、請求項3又は4に記載の卵殻膜可溶化方法。
- 固形物が認められなくなるまで、前記工程(2)の反応を継続する、請求項3~5のいずれか一項に記載の卵殻膜可溶化方法。
- 以下の工程(3)を更に含む、請求項3~6のいずれか一項に記載の卵殻膜可溶化方法:
(3)工程(2)後の溶液を濾過し、固形物を除去する工程。 - 前記タンパク質分解酵素がアルカリ性プロテアーゼ又は中性プロテアーゼである、請求項1~7のいずれか一項に記載の卵殻膜可溶化方法。
- 前記タンパク質分解酵素が、セリンエンドペプチダーゼ、システインエンドペプチダーゼ、メタロエンドペプチダーゼ、アミノペプチダーゼ及びアスパラギン酸エンドペプチダーゼからなる群より選択される一種以上の酵素である、請求項1~7のいずれか一項に記載の卵殻膜可溶化方法。
- 前記タンパク質分解酵素がキモトリプシン、サブチリシン、パパイン、バシロライシン、ステムブロメライン、ロイシルアミノペプチダーゼ、ペプシン及びトリプシンからなる群より選択される一種以上の酵素である、請求項1~7のいずれか一項に記載の卵殻膜可溶化方法。
- 前記タンパク質分解酵素がビオソーク、プロレザーFG-F、パパインW40、プロテアーゼN、ブロメラインF、ウマミザイムG、サモアーゼY100、ProteAX、プロテアーゼS、スミチームLP500、デスキンC、プロチンNY10、プロチンPC10、スミチームMP、プロチンAY及びプロテイナーゼK(Proteinase K)からなる群より選択される一種以上の酵素である、請求項1~7のいずれか一項に記載の卵殻膜可溶化方法。
- 前記還元剤が、亜硫酸塩、亜硫酸水素塩、L-システイン、N-アセチル-L-システイン、2-メルカプトエタノール、グルタチオン及びDTTからなる群より選択される一種以上の還元剤である、請求項1~11のいずれか一項に記載の卵殻膜可溶化方法。
- 前記還元剤が亜硫酸ナトリウム又は亜硫酸水素ナトリウムである、請求項1~11のいずれか一項に記載の卵殻膜可溶化方法。
- 以下の工程(1)及び(2’)を含む、請求項1に記載の卵殻膜可溶化方法:
(1)溶媒中に卵殻膜を用意する工程、
(2’)前記溶媒に還元剤を添加して反応させた後、還元剤を除去し、次いでタンパク質分解酵素を添加し、反応させる工程。 - タンパク質分解酵素と還元剤を組合せてなる、卵殻膜可溶化剤。
- タンパク質分解酵素と還元剤を含有することを特徴とする、請求項15に記載の卵殻膜可溶化剤。
- タンパク質分解酵素を含有する第1構成要素と、還元剤を含有する第2構成要素とからなるキットであることを特徴とする、請求項15に記載の卵殻膜可溶化剤。
- 請求項1~13のいずれか一項に記載の卵殻膜可溶化方法で得られる、卵殻膜可溶物。
- リゾチーム、β-N-アセチルグルコサミニダーゼ、ヒアルロン酸、コンドロイチン硫酸及びデルマタン硫酸からなる群より選択される一以上の成分を含む、請求項18に記載の卵殻膜可溶物。
- 抗酸化活性及びアンジオテンシン変換酵素阻害活性からなる群より選択される一以上の活性を示す、請求項18に記載の卵殻膜可溶物。
- 請求項14に記載の卵殻膜可溶化方法で得られる、卵殻膜可溶物。
- リジルオキシダーゼを含む、請求項21に記載の卵殻膜可溶物。
- 卵殻膜の完全な可溶物である、請求項18~22のいずれか一項に記載の卵殻膜可溶物
- 請求項18~23のいずれか一項に記載の卵殻膜可溶物を含む組成物。
- 医薬、医薬部外品、食品又は化粧料である、請求項24に記載の組成物。
- 以下の工程(i)及び(ii)を含む、卵殻膜有用成分抽出方法:
(i)請求項1~13のいずれか一項に記載の方法による可溶化工程;
(ii)前記可溶化工程で得られた卵殻膜可溶物を精製する工程。 - 工程(ii)で精製される成分が、リゾチーム及びβ-N-アセチルグルコサミニダーゼからなる群より選択される酵素、又はヒアルロン酸、コンドロイチン硫酸及びデルマタン硫酸からなる群より選択される酸性ムコ多糖である、請求項26に記載の卵殻膜有用成分抽出方法。
- 請求項27に記載の方法で得られるリゾチーム、β-N-アセチルグルコサミニダーゼ、ヒアルロン酸、コンドロイチン硫酸又はデルマタン硫酸。
- 以下の工程(i’)及び(ii)を含む、卵殻膜有用成分抽出方法:
(i’)請求項14に記載の方法による可溶化工程;
(ii)前記可溶化工程で得られた卵殻膜可溶物を精製する工程。 - 工程(ii)で精製される成分がリジルオキシダーゼである、請求項29に記載の卵殻膜有用成分抽出方法。
- 請求項30に記載の方法で得られるリジルオキシダーゼ。
- 請求項26又は29に記載の卵殻膜有用成分抽出方法で得られる卵殻膜抽出物。
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CN107569518A (zh) | 2018-01-12 |
CN103069000A (zh) | 2013-04-24 |
US20130224830A1 (en) | 2013-08-29 |
JP5985394B2 (ja) | 2016-09-06 |
JPWO2012029529A1 (ja) | 2013-10-28 |
EP2612922A4 (en) | 2015-12-23 |
US10526423B2 (en) | 2020-01-07 |
EP2612922A1 (en) | 2013-07-10 |
CN105671018A (zh) | 2016-06-15 |
JP2016152816A (ja) | 2016-08-25 |
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