JP2018016618A - Angiotensin-converting enzyme inhibitor, composition, production method of the same - Google Patents
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本発明は、アンジオテンシン変換酵素阻害剤、アンジオテンシン変換酵素阻害剤を含有する組成物およびその製造方法に関する。 The present invention relates to an angiotensin converting enzyme inhibitor, a composition containing an angiotensin converting enzyme inhibitor, and a method for producing the same.
２０１５年の国民健康・栄養調査によると、日本人男性の約７割、女性の約５割（年齢４０〜７４才）が高血圧（１４０／９０ｍｍＨｇ以上）であると報告されている。現在、日本高血圧学会などでの高血圧改善の食事指導として減塩が進められていて、塩分を多く含む食品の摂取を抑制する指導がされる場合がある。 According to the 2015 National Health and Nutrition Survey, about 70% of Japanese men and about 50% of women (age 40-74 years) are reported to have high blood pressure (140/90 mmHg or more). Currently, salt reduction is being promoted as a dietary instruction for improving hypertension at the Japanese Society of Hypertension, etc., and there are cases where guidance is given to suppress the intake of foods that contain a large amount of salt.
血圧上昇を抑制する方法の一つに、血圧上昇に関与するアンジオテンシン変換酵素（ＡＣＥ）を阻害することが挙げられる。食品中には、ＡＣＥ阻害活性を有するペプチドが含有されていることが知られ、これらの食品は特定保健用食品として認定され、商品化されているものもある。ラクトトリペプチドを産生する乳酸菌を用いて発酵させた血圧降下活性を有する成分を含む発酵乳製品が特許文献１：特開平１１−１００３２８号公報に開示されている。かつお節由来であるアンギオテンシン変換酵素阻害ペプチドを含む血圧降下剤または血圧降下食品が特許文献２：特開２００１−２４０６００号公報に開示されている。 One method for suppressing an increase in blood pressure is to inhibit angiotensin converting enzyme (ACE) involved in an increase in blood pressure. It is known that foods contain peptides having ACE inhibitory activity, and some of these foods have been certified and commercialized as foods for specified health use. A fermented dairy product containing a component having antihypertensive activity fermented using a lactic acid bacterium producing lactotripeptide is disclosed in Patent Document 1: Japanese Patent Application Laid-Open No. 11-100368. An antihypertensive agent or an antihypertensive food containing an angiotensin converting enzyme inhibitory peptide derived from bonito is disclosed in Japanese Patent Application Laid-Open No. 2001-240600.
食品には多くの栄養分が含まれているため、様々な有益な効果を期待して日常的に食べられている。中には塩分を多く含む食品もあり、高血圧の改善のためにこのような食品を摂取することを制限することは、食生活を大きく変えることになるため困難である。そこで、塩分を含む食品を継続して食べ続けても血圧が上昇しないよう、ＡＣＥ阻害などを示す血圧上昇抑制物質を摂取することが考えられ、血圧上昇抑制物質が含まれる食品を継続して食べるためにも食品の品質を低下させないようにする必要がある。このため、化合物の新たな作用を見出して、ＡＣＥ阻害活性を示す化合物が含まれる組成物を摂取することができるようにするという課題がある。 Since foods contain many nutrients, they are eaten on a daily basis in anticipation of various beneficial effects. Some foods contain a high amount of salt, and it is difficult to restrict the intake of such foods to improve high blood pressure because it will greatly change the diet. Therefore, in order to prevent blood pressure from rising even if the food containing salt is continuously eaten, it is conceivable to take a blood pressure increase-inhibiting substance exhibiting ACE inhibition and the like. Therefore, it is necessary not to deteriorate the quality of food. For this reason, there exists a subject of discovering the new effect | action of a compound and enabling it to take in the composition containing the compound which shows ACE inhibitory activity.
そこで本発明は上記課題を解決すべくなされ、その目的とするところは、新たなアンジオテンシン変換酵素阻害剤を提供すると共に、継続して摂取可能である組成物およびその製造方法を提供することにある。 Accordingly, the present invention has been made to solve the above problems, and an object of the present invention is to provide a new angiotensin converting enzyme inhibitor and a composition that can be continuously ingested and a method for producing the same. .
上記の目的を達成するため、本発明のアンジオテンシン変換酵素阻害剤は次の構成を備える。すなわち本発明は、下記（１）〜（２）の理化学的性質を有し、フラン環およびヒドロキシ基を有する構造である物質を基本骨格とする化合物を有効成分として含有することを特徴とする。（１）分子量：２０２、（２）分子式：Ｃ８Ｈ１０Ｏ６。この構成によれば、ＡＣＥ阻害活性を示し、新たなアンジオテンシン変換酵素阻害剤として利用できる。 In order to achieve the above object, the angiotensin converting enzyme inhibitor of the present invention comprises the following constitution. That is, the present invention is characterized by containing, as an active ingredient, a compound having the following physicochemical properties (1) to (2) and having a substance having a structure having a furan ring and a hydroxy group as a basic skeleton. (1) Molecular weight: 202, (2) Molecular formula: C 8 H 10 O 6. According to this structure, it shows ACE inhibitory activity and can be utilized as a new angiotensin converting enzyme inhibitor.
また、本発明において、前記基本骨格が、下記式（１）で示される。
また、本発明において、前記基本骨格が、下記式（２）で示される。
また、本発明において、前記基本骨格が、下記式（３）で示される。
また、本発明において、前記化合物が、前記基本骨格に糖が配位した配糖体である。これによれば、新たなアンジオテンシン変換酵素阻害剤として利用できる。 In the present invention, the compound is a glycoside in which a sugar is coordinated to the basic skeleton. According to this, it can utilize as a new angiotensin converting enzyme inhibitor.
また、本発明において、前記糖が、二糖類である。 In the present invention, the sugar is a disaccharide.
また、本発明において、前記基本骨格に配位した糖が、ゲンチオビオースまたはスクロースである。 In the present invention, the sugar coordinated to the basic skeleton is gentiobiose or sucrose.
また、本発明において、前記化合物が、味噌の抽出物由来であってもよい。これによれば、味噌から抽出される物質であるため、人に対して安全性は問題ない。 In the present invention, the compound may be derived from an extract of miso. According to this, since it is a substance extracted from miso, there is no problem with safety for humans.
また、本発明の組成物は、上記アンジオテンシン変換酵素阻害剤を含有することを特徴とする。これによれば、ＡＣＥ阻害活性を示す物質を継続して摂取可能である。 Moreover, the composition of this invention contains the said angiotensin converting enzyme inhibitor. According to this, the substance showing ACE inhibitory activity can be ingested continuously.
また、本発明において、前記組成物が味噌であってもよい。これによれば、味噌汁や調味料として利用することができ、日々の生活の中で容易に継続して摂取することができる。 In the present invention, the composition may be miso. According to this, it can utilize as miso soup and a seasoning, and can be continuously ingested easily in daily life.
上記の目的を達成するため、本発明の上記アンジオテンシン変換酵素阻害剤を含有する組成物の製造方法は次の構成を備える。すなわち本発明は、米に麹菌を接種して製麹する製麹工程と、前記製麹工程により得られた麹と、大豆とを混合して発酵・熟成する熟成工程とを含むことを特徴とする。この構成によれば、大豆と米麹を用いた発酵物に新たなＡＣＥ阻害活性を示す物質が含まれる。 In order to achieve the above object, a method for producing a composition containing the angiotensin converting enzyme inhibitor of the present invention comprises the following constitution. That is, the present invention includes a koji making process for inoculating rice with koji mold, and koji obtained by the koji making process, and a ripening process for mixing and fermenting soybeans. To do. According to this structure, the substance which shows new ACE inhibitory activity is contained in the fermented material using a soybean and rice bran.
また、本発明において、前記組成物が、味噌であってもよい。これによれば、塩分を含む味噌を製造する際にＡＣＥ阻害活性を示す物質が生成される。 In the present invention, the composition may be miso. According to this, the substance which shows ACE inhibitory activity is produced when manufacturing the miso containing salt.
また、本発明において、前記麹菌が、焼酎製造に用いられる焼酎用の麹菌であってもよい。これによれば、大豆発酵物中に新たなＡＣＥ阻害活性を示す物質がより多く含まれる。 In the present invention, the koji mold may be a koji mold for shochu used for shochu production. According to this, the substance which shows new ACE inhibitory activity is contained more in soybean fermented material.
また、本発明において、前記麹菌が、アスペルギルス・カワチ（Ａｓｐｅｒｇｉｌｌｕｓ ｋａｗａｃｈｉｉ）であってもよい。これによれば、アスペルギルス・カワチを用いて製造される大豆発酵物中に新たなＡＣＥ阻害活性を示す物質がより多く含まれる。 In the present invention, the koji mold may be Aspergillus kawachii. According to this, the substance which shows new ACE inhibitory activity is contained more in the soybean fermented material manufactured using Aspergillus kawachi.
また、本発明において、前記製麹工程において、前記麹菌が接種された米は、４０℃以上４５℃以下の温度範囲で保持して製麹してもよい。 In the present invention, in the koji making process, the rice inoculated with the koji mold may be kneaded while being held in a temperature range of 40 ° C to 45 ° C.
また、本発明において、前記熟成工程において、４０℃以上５０℃以下の温度範囲で発酵・熟成してもよい。これによれば、一般的な大豆発酵物よりも高温で発酵・熟成されるため、新たなＡＣＥ阻害活性を示す物質がより多く含まれる。 Moreover, in this invention, you may ferment and age | cure | ripen in the temperature range of 40 to 50 degreeC in the said aging process. According to this, since it is fermented and matured at a higher temperature than a general fermented soybean product, more substances that exhibit new ACE inhibitory activity are contained.
本発明によれば、新たなアンジオテンシン変換酵素阻害剤を提供すると共に、継続して摂取可能である組成物およびその製造方法を提供できる。 ADVANTAGE OF THE INVENTION According to this invention, while providing a new angiotensin converting enzyme inhibitor, the composition which can be ingested continuously, and its manufacturing method can be provided.
本実施形態のアンジオテンシン変換酵素（ＡＣＥ）阻害剤は、下記（１）〜（２）の理化学的性質を有し、フラン環およびヒドロキシ基を有する構造である物質を基本骨格とする化合物を有効成分として含有する。
（１）分子量：２０２
（２）分子式：Ｃ８Ｈ１０Ｏ６
The angiotensin converting enzyme (ACE) inhibitor of the present embodiment comprises a compound having the physicochemical properties (1) to (2) below and a substance having a structure having a furan ring and a hydroxy group as a basic skeleton. Contained as.
(1) Molecular weight: 202
(2) Molecular formula: C 8 H 10 O 6
また、フラン環およびヒドロキシ基を有する基本骨格は、下記式（１）で示される構造式である。この基本骨格は、（４−ヒドロキシ−３−メトキシ−５−オキソ−２，５−ジヒドロ−２−フラニル）酢酸メチル（Ｍｅｔｈｙｌ（４−ｈｙｄｒｏｘｙ−３−ｍｅｔｈｏｘｙ−５−ｏｘｏ−２，５−ｄｉｈｙｄｒｏ−２−ｆｕｒａｎｙｌ）ａｃｅｔａｔｅ）である。 The basic skeleton having a furan ring and a hydroxy group is a structural formula represented by the following formula (1). This basic skeleton is methyl (4-hydroxy-3-methoxy-5-oxo-2,5-dihydro-2-furanyl) methyl acetate (Methyl (4-hydroxy-3-methoxy-5-oxo-2,5-dihydro). -2-furanyl) acetate).
また、フラン環およびヒドロキシ基を有する基本骨格は、下記式（２）で示される構造式である。この基本骨格は、（３‐エトキシ‐４‐ヒドロキシ‐５‐オキソ‐２，５‐ジヒドロフラン‐２‐フラニル）酢酸（（３−Ｅｔｈｏｘｙ−４−ｈｙｄｒｏｘｙ−５−ｏｘｏ−２，５−ｄｉｈｙｄｒｏ−２−ｆｕｒａｎｙｌ）ａｃｅｔｉｃ ａｃｉｄ）である。 The basic skeleton having a furan ring and a hydroxy group is a structural formula represented by the following formula (2). This basic skeleton is (3-ethoxy-4-hydroxy-5-oxo-2,5-dihydrofuran-2-furanyl) acetic acid ((3-Ethoxy-4-hydroxy-5-oxo-2,5-dihydro- 2-furanyl) acetic acid).
また、フラン環およびヒドロキシ基を有する基本骨格は、下記式（３）で示される構造式である。この基本骨格は、５−（ヒドロキシメチル）−３，４−ジメトキシ−２−フランカルボン酸（５−（Ｈｙｄｒｏｘｙｍｅｔｈｙｌ）−３，４−ｄｉｍｅｔｈｏｘｙ−２−ｆｕｒｏｉｃ ａｃｉｄ）である。 The basic skeleton having a furan ring and a hydroxy group is a structural formula represented by the following formula (3). This basic skeleton is 5- (hydroxymethyl) -3,4-dimethoxy-2-furancarboxylic acid (5- (Hydroxymethyl) -3,4-dimethyl-2-furoic acid).
式（１）〜式（３）に示す構造式を基本骨格とする化合物としては、式（１）〜式（３）に示す構造式内にあるヒドロキシ基の水素が置換基で置換された化合物である。置換基の一例として糖があり、式（１）〜式（３）の化合物をアグリコンとし、アグリコンに糖が結合した配糖体が挙げられる。糖は二糖類であってもよく、糖の一例として、ゲンチオビオース（分子式：Ｃ１２Ｈ２２Ｏ１１）、スクロース（分子式：Ｃ１２Ｈ２２Ｏ１１）がある。 As a compound having the structural formula shown in formula (1) to formula (3) as a basic skeleton, a compound in which hydrogen of a hydroxy group in the structural formula shown in formula (1) to formula (3) is substituted with a substituent It is. An example of the substituent is sugar, and examples thereof include glycosides in which the compounds of formulas (1) to (3) are aglycones and the sugars are bound to aglycones. The sugar may be a disaccharide, and examples of the sugar include gentiobiose (molecular formula: C 12 H 22 O 11 ) and sucrose (molecular formula: C 12 H 22 O 11 ).
また、本実施形態のＡＣＥ阻害剤は、味噌の抽出物由来であってもよい。上記の理化学的性質を有し、フラン環およびヒドロキシ基を有する構造である物質を基本骨格とする化合物が含まれる味噌から溶媒を用いて抽出することで、抽出物には上記化合物が含まれる。この抽出物を用いて本実施形態のＡＣＥ阻害剤が得られる。抽出物をそのまま用いてもよいが、その他の物質も抽出されるため、上記化合物を得るために分離、精製してもよい。味噌の抽出に用いられる溶媒は水を用いるが、溶媒は特に限定されない。また、食べることが可能な味噌から抽出される物質であるため、人に対して安全性は問題ない。 Moreover, the ACE inhibitor of this embodiment may be derived from the extract of miso. By extracting from a miso containing a compound having the above physicochemical properties and having a structure having a furan ring and a hydroxy group as a basic skeleton, the extract contains the above compound. The ACE inhibitor of this embodiment is obtained using this extract. The extract may be used as it is, but since other substances are also extracted, it may be separated and purified to obtain the above compound. Although the solvent used for the extraction of miso uses water, the solvent is not particularly limited. Moreover, since it is a substance extracted from miso that can be eaten, there is no problem with safety for humans.
本実施形態のＡＣＥ阻害剤は、食品、飲料、飼料、食品添加物、医薬品、医薬部外品、サプリメント等の組成物に含められることによって、ＡＣＥ阻害活性を含有する組成物を提供することができる。ＡＣＥ阻害剤をそのまま食品や飲料、飼料に混ぜてもよく、カプセルなどに封入して所要量混入させるようにすればよい。また、医薬品、医薬部外品に用いる場合には、賦形剤、結合剤、崩壊剤、溶解補助剤、コーティング剤等の製剤に用いる公知の補助剤を用いて製剤することが可能である。 The ACE inhibitor of this embodiment can provide a composition containing ACE inhibitory activity by being included in a composition such as food, beverage, feed, food additive, pharmaceutical product, quasi-drug, and supplement. it can. The ACE inhibitor may be mixed as it is with food, beverages, and feed, or may be encapsulated in a capsule or the like and mixed in a required amount. Moreover, when using for a pharmaceutical and a quasi-drug, it can formulate using well-known adjuvants used for formulation, such as an excipient | filler, binder, a disintegrating agent, a solubilizing agent, and a coating agent.
また、ＡＣＥ阻害剤が生成して含有されるように製造した組成物自体を、ＡＣＥ阻害剤を含む組成物としてもよい。そして、組成物は味噌であってもよい。本実施形態のＡＣＥ阻害剤を混合したＡＣＥ阻害剤を含む味噌、もしくは、ＡＣＥ阻害剤が生成し、含有されるように製造した味噌をそのままＡＣＥ阻害剤を含む味噌としてもよい。味噌は塩分を含む食品ではあるものの、本実施形態のＡＣＥ阻害活性を示す物質が含まれるため、味噌自体がＡＣＥ阻害活性を示し、食品として日常的に摂取し続けることができる。 Further, the composition itself produced so that the ACE inhibitor is generated and contained may be a composition containing the ACE inhibitor. And the composition may be miso. The miso containing the ACE inhibitor mixed with the ACE inhibitor of this embodiment, or the miso produced so that the ACE inhibitor is produced and contained may be used as it is as the miso containing the ACE inhibitor. Although miso is a food containing salt, since the substance showing the ACE inhibitory activity of the present embodiment is included, the miso itself shows the ACE inhibitory activity and can be continuously ingested as a food.
本実施形態のＡＣＥ阻害剤を含有する組成物の製造方法は、米に麹菌を接種して製麹する製麹工程と、製麹工程により得られた麹と、大豆とを混合して発酵・熟成する熟成工程とを含む。これにより、ＡＣＥ阻害活性が高い組成物が得られ、この組成物を用いて抽出した抽出物から本実施形態のＡＣＥ阻害活性を示す化合物を得ることができる。特に本実施形態の組成物の製造方法により味噌を製造でき、製造される味噌中に本実施形態のＡＣＥ阻害活性を示す化合物が含まれる。 The method for producing a composition containing an ACE inhibitor according to the present embodiment comprises a koji making process in which rice is inoculated with koji mold, koji obtained by the koji making process, and soybeans are mixed and fermented. An aging step for aging. Thereby, a composition with high ACE inhibitory activity is obtained, and the compound which shows the ACE inhibitory activity of this embodiment can be obtained from the extract extracted using this composition. In particular, miso can be produced by the method for producing the composition of the present embodiment, and the produced miso contains a compound that exhibits the ACE inhibitory activity of the present embodiment.
本実施形態のＡＣＥ阻害活性を示す化合物が含まれる味噌は、一般的な味噌を製造する際には使用されない麹菌を用いて製造され、焼酎を製造する際に用いられる焼酎用の麹菌を用いて製造される。麹菌のうち、製麹工程における米麹の製造に適したアスペルギルス・カワチ（Ａｓｐｅｒｇｉｌｌｕｓ ｋａｗａｃｈｉｉ）であることが好ましい。製麹工程における製麹温度は一般的な味噌用の麹菌の製麹温度より高く、４０℃以上４５℃以下の範囲であることが好ましい。この温度範囲において一定時間保持して製麹する。製麹温度を高くすることで、ＡＣＥ阻害活性を示す上記化合物の量を増加させることができ、味噌中のＡＣＥ阻害活性が高くなる。 The miso containing the compound showing the ACE inhibitory activity of the present embodiment is produced using koji mold that is not used when producing general miso, and using the koji mold for shochu used when producing shochu. Manufactured. Among Aspergillus oryzae, Aspergillus kawachii suitable for the production of rice bran in the koji making process is preferable. The koji-making temperature in the koji-making process is higher than the koji-making temperature of a common miso-use koji mold, and is preferably in the range of 40 ° C to 45 ° C. Holding in this temperature range for a certain period of time, ironmaking is performed. By increasing the koji-making temperature, the amount of the above compound exhibiting ACE inhibitory activity can be increased, and the ACE inhibitory activity in miso is increased.
麹と、大豆とを混合して発酵・熟成する熟成工程における発酵・熟成温度の範囲は４０℃以上５０℃以下である。発酵・熟成温度を一般的な味噌の製造時よりも高い４０℃以上５０℃以下の範囲にすることで、ＡＣＥ阻害活性を示す上記化合物の量を増加させることができ、味噌中のＡＣＥ阻害活性が高くなる。発酵・熟成期間は短期間でも熟成可能であり、５日であってもよい。なお、大豆に対する米麹の仕込割合は特に限定されるものではなく、大豆の重量に対する米の重量は適宜変えられる。 The range of the fermentation / ripening temperature in the ripening process in which the koji and soybeans are mixed and fermented / ripened is 40 ° C. or higher and 50 ° C. or lower. By setting the fermentation / ripening temperature in the range of 40 ° C. or higher and 50 ° C. or lower, which is higher than that in the production of general miso, the amount of the above compound showing ACE inhibitory activity can be increased, and ACE inhibitory activity in miso Becomes higher. The fermentation / ripening period can be aged for a short period of time, and may be 5 days. The ratio of rice bran to soybean is not particularly limited, and the weight of rice relative to the weight of soybean can be changed as appropriate.
また、本実施形態の製造方法により得られる組成物、味噌は、上記のＡＣＥ阻害活性を有する化合物の他に、ＡＣＥ阻害活性を有するペプチドが含有されていてもよい。 Moreover, the composition and miso obtained by the manufacturing method of this embodiment may contain the peptide which has ACE inhibitory activity other than the compound which has said ACE inhibitory activity.
以下、実施例を挙げて説明するが、本実施形態はこれらに限定されるものではない。麹菌、製麹条件、大豆と米麹との仕込割合、発酵・熟成条件を変えて味噌を製造した。主な製造条件を表１に示す。塩の添加量などのその他の条件は同じである。なお、味噌については、食味評価の結果、製法が通常法と異なるものもあるが、食するのに適当である結果であった。 Hereinafter, although an example is given and explained, this embodiment is not limited to these. Miso was produced by changing the koji mold, koji-making conditions, the ratio of soybean and rice koji, and the fermentation and aging conditions. Table 1 shows the main manufacturing conditions. Other conditions such as the amount of salt added are the same. In addition, as for the miso, as a result of the taste evaluation, the production method was different from the normal method, but the result was suitable for eating.
［実施例１］（焼酎用の麹菌）
焼酎用の麹菌（株式会社樋口松之助商店製、アスペルギルス・カワチ）を米に接種し、製麹温度は４０℃以上、４５℃以下の範囲に収まるように保持し、製麹時間は４２時間で製麹して米麹を得た。得られた米麹と大豆とを所定の割合で混合した。発酵・熟成は５０℃、５日で行い、実施例１の味噌を得た。
[Example 1] (Koji mold for shochu)
Inoculate rice with a koji mold for shochu (manufactured by Higuchi Matsunosuke Shoten Co., Ltd., Aspergillus kawachi) and keep the koji making temperature within the range of 40 ° C or higher and 45 ° C or lower. I got a rice bran. The obtained rice bran and soybean were mixed at a predetermined ratio. Fermentation and aging were performed at 50 ° C. for 5 days to obtain a miso of Example 1.
［実施例２］（味噌用の麹菌）
味噌用の麹菌（株式会社樋口松之助商店製、アスペルギルス・オリゼ）を米に接種し、製麹条件、仕込割合、発酵・熟成条件は実施例１と同じ条件で実施例２の味噌を得た。
[Example 2] (Koji mold for miso)
Miso for miso (manufactured by Matsunosuke Shojiguchi Co., Ltd., Aspergillus oryzae) was inoculated into rice, and the miso of Example 2 was obtained under the same conditions as in Example 1 for the koji-making conditions, the charging ratio, and the fermentation / ripening conditions.
［実施例３］（味噌用の麹菌、製麹温度２８℃以上、４０℃未満、５年熟成）
実施例２で使用した味噌用の麹菌を米に接種し、製麹温度は２８℃以上、４０℃未満の範囲に収まるように保持し、製麹時間は４２時間で製麹して米麹を得た。得られた米麹と大豆とを混合した。発酵・熟成は２０℃〜３０℃の範囲で５年行い、実施例３の味噌を得た。
[Example 3] (Bacilli for miso, aging temperature of 28 ° C or higher, less than 40 ° C, aging for 5 years)
Inoculate the rice with the koji mold for miso used in Example 2, hold the koji temperature so that it falls within the range of 28 ° C. or more and less than 40 ° C. Obtained. The obtained rice bran and soybeans were mixed. Fermentation and aging were performed in the range of 20 ° C. to 30 ° C. for 5 years to obtain a miso of Example 3.
［実施例４］（味噌用の麹菌、発酵・熟成期間）
使用した麹菌の種類、製麹条件は実施例３と同じである。その他の条件について、発酵・熟成は２０℃〜３０℃の範囲で１か月行い、実施例４の味噌を得た。
[Example 4] (Bacilli for miso, fermentation / ripening period)
The type of koji mold used and the koji making conditions are the same as in Example 3. About other conditions, fermentation and aging were performed in the range of 20 to 30 ° C. for one month to obtain a miso of Example 4.
［ＡＣＥ阻害活性を示す物質の精製］
実施例１〜実施例４で得られた各味噌１０ｇを三角フラスコにとり、１００ｍＬの蒸留水を添加し、室温１時間で振とうした。振とう後に遠心分離（１２０００ｒｐｍ、１０分）を実施し、上清を味噌水抽出液とした。味噌水抽出液について、限外濾過フィルター（セントリコンプラス３０、１０、３、ミリポア社）を用いて高分子側から順番に限外濾過を実施し、各画分（３０ｋＤａ以上、１０〜３０ｋＤａ、３〜１０ｋＤａ、３ｋＤａ以下）を得た。各画分についてＡＣＥ阻害活性、タンパク定量を実施し、最もＡＣＥ阻害活性が高い画分について、凍結乾燥を実施し、逆相クロマトグラフィーによる分離、精製を実施した。逆相クロマトグラフィーの条件を表２に示す。各フラクションを減圧濃縮（Ｓａｖａｎｔ社、減圧濃縮装置）後０．１ｍＬの蒸留水に溶解した。
[Purification of substance showing ACE inhibitory activity]
10 g of each miso obtained in Examples 1 to 4 was placed in an Erlenmeyer flask, 100 mL of distilled water was added, and the mixture was shaken at room temperature for 1 hour. Centrifugation (12000 rpm, 10 minutes) was performed after shaking, and the supernatant was used as a miso water extract. For the miso water extract, ultrafiltration was performed in order from the polymer side using an ultrafiltration filter (Centricon Plus 30, 10, 3, Millipore), and each fraction (30 kDa or more, 10-30 kDa, 3 To 10 kDa, 3 kDa or less). Each fraction was subjected to ACE inhibitory activity and protein quantification, and the fraction with the highest ACE inhibitory activity was lyophilized, followed by separation and purification by reverse phase chromatography. The conditions for reverse phase chromatography are shown in Table 2. Each fraction was concentrated under reduced pressure (Savant, vacuum concentration apparatus) and then dissolved in 0.1 mL of distilled water.
［ＡＣＥ阻害活性を示す物質の分析］
実験方法は、日本食品工学会に記載の「ＡＣＥ（アンジオテンシン変換酵素）阻害活性（マイクロプレート法）」に準拠して実施した。実験方法は下記の通りである。
[Analysis of substances exhibiting ACE inhibitory activity]
The experimental method was carried out in accordance with “ACE (Angiotensin Converting Enzyme) Inhibitory Activity (Microplate Method)” described in Japan Food Engineering Association. The experimental method is as follows.
（１）９６ｗｅｌｌ ｂｌａｃｋ ｐｌａｔｅに１ｗｅｌｌあたり５０μＬの試料を添加する。ｂｌａｎｋとしてＨＥＰＥＳバッファーを使用する。
（２）ＡＣＥ溶液（１０ｍＵ／ｍＬ）を１００μＬ添加する。
（３）プレートミキサーで混和後、３７℃、１０分間温置する。
（４）ＡＣＥ基質溶液（２５ｍＭＨｉｐ−Ｈｉｓ−Ｌｅｕ）を添加する。
（５）プレートミキサーで混和後、３７℃で４０分間温置（反応）する。
（６）１Ｎ ＮａＯＨを５０μＬ添加し、反応を停止する。
（７）プレートミキサーで混和後、０．２％ｏ−フタルアルデヒド溶液を添加する。
（８）プレートミキサーで混和後、室温で１５分間静置（反応）する。
（９）３．６Ｍリン酸を添加し、反応を停止する。
（１０）プレートミキサーで混和後蛍光強度（励起波長３４０ｎｍ、蛍光波長４８５ｎｍ）を測定する。
(1) A sample of 50 μL per well is added to a 96-well black plate. A HEPES buffer is used as a blank.
(2) Add 100 μL of ACE solution (10 mU / mL).
(3) After mixing with a plate mixer, incubate at 37 ° C. for 10 minutes.
(4) Add ACE substrate solution (25 mM Hip-His-Leu).
(5) After mixing with a plate mixer, incubate (react) at 37 ° C. for 40 minutes.
(6) Add 50 μL of 1N NaOH to stop the reaction.
(7) After mixing with a plate mixer, add 0.2% o-phthalaldehyde solution.
(8) After mixing with a plate mixer, leave (react) at room temperature for 15 minutes.
(9) Add 3.6M phosphoric acid to stop the reaction.
(10) The fluorescence intensity (excitation wavelength: 340 nm, fluorescence wavelength: 485 nm) is measured after mixing with a plate mixer.
ＡＣＥの阻害活性（率）（％）は下記の計算式により算出される。
阻害活性（率）（％）＝［１−（Ｓ−Ｓｂ）／（Ｃ−Ｃｂ）］×１００
試料液の蛍光強度をＳ、試料液の代わりにＨＥＰＥＳバッファーを使用した場合の蛍光強度をＣとする。また、ＳおよびＣに対し、ＡＣＥ溶液の代わりにＨＥＰＥＳバッファーを添加した場合の蛍光強度をＳｂおよびＣｂとする。Ｓ：試料液＋ＡＣＥ溶液＋ＡＣＥ基質溶液。Ｓｂ：試料液＋ＡＣＥ基質溶液。Ｃ：ＨＥＰＥＳバッファー＋ＡＣＥ溶液＋ＡＣＥ基質溶液。Ｃｂ：ＨＥＰＥＳバッファー＋ＡＣＥ基質溶液。
The ACE inhibitory activity (rate) (%) is calculated by the following formula.
Inhibitory activity (rate) (%) = [1− (S−Sb) / (C−Cb)] × 100
Let S be the fluorescence intensity of the sample solution, and C be the fluorescence intensity when a HEPES buffer is used instead of the sample solution. Moreover, the fluorescence intensity when a HEPES buffer is added to S and C instead of the ACE solution is Sb and Cb. S: Sample solution + ACE solution + ACE substrate solution. Sb: sample solution + ACE substrate solution. C: HEPES buffer + ACE solution + ACE substrate solution. Cb: HEPES buffer + ACE substrate solution.
図１に各味噌の限外濾過画分のＡＣＥ阻害活性の測定結果を示す。各味噌における阻害活性は３ｋＤａ以下の画分が最も高い活性を示していた。一方、実施例３の味噌は３０ｋＤａ以上、１０〜３０ｋＤａの画分の高分子側にも活性が見られた。ＡＣＥ阻害活性の測定結果から、各味噌の３ｋＤａ以下の画分および実施例３の味噌の３０ｋＤａ以上、１０〜３０ｋＤａ画分について逆相クロマトグラフィーによる分離精製を実施した。 FIG. 1 shows the measurement results of the ACE inhibitory activity of the ultrafiltration fraction of each miso. The inhibitory activity in each miso showed the highest activity in the fraction of 3 kDa or less. On the other hand, the activity of the miso of Example 3 was also observed on the polymer side of the fraction of 30 kDa or more and 10-30 kDa. From the measurement results of the ACE inhibitory activity, the fractions of 3 kDa or less of each miso and the fractions of 30 kDa or more and 10 to 30 kDa of the miso of Example 3 were subjected to separation and purification by reverse phase chromatography.
図２、図３に各分画の逆相クロマトグラフィー画分のＡＣＥ阻害率（図２：画分を１０倍希釈してＡＣＥ阻害率を測定、図３：画分を１００倍希釈してＡＣＥ阻害率を測定）を示す。１０倍希釈では各画分とも高いＡＣＥ阻害率を示していた。しかし、１００希釈では各画分のＡＣＥ阻害率は低下し、実施例１の焼酎用の麹菌を用いた味噌の３ｋＤａ以下の画分Ｆ５のみ高いＡＣＥ阻害活性（ＡＣＥ阻害率８０％以上）を示した。実施例３の味噌は、１０倍希釈では高いＡＣＥ阻害活性を示したが、希釈により精製フラクションの活性低下が見られたことから、味噌中のＡＣＥ阻害物質が単一ではなく複合的に活性を示すことが考えられる。これらのことから、今回精製を試みた味噌の中で、実施例１の味噌が（１）ＡＣＥ阻害活性、（２）希釈による活性が低下しにくい点で他の味噌に比べて優位であると考えられる。 2 and 3 show the ACE inhibition rate of the reverse phase chromatography fractions of each fraction (FIG. 2: ACE inhibition rate was measured by diluting the fraction 10 times, FIG. 3: ACE inhibition rate was obtained by diluting the fraction 100 times. Inhibition rate is measured). At 10-fold dilution, each fraction showed a high ACE inhibition rate. However, at 100 dilution, the ACE inhibition rate of each fraction decreased, and only the fraction F5 of the miso 3% or less of miso using the koji mold for shochu of Example 1 showed high ACE inhibitory activity (ACE inhibition rate of 80% or more). It was. Although the miso of Example 3 showed a high ACE inhibitory activity at 10-fold dilution, since the activity of the purified fraction was reduced by the dilution, the ACE inhibitor in the miso was not single but was active in a complex manner. It is possible to show. Based on these facts, among the miso that were tried to be purified this time, the miso of Example 1 was superior to other miso in that (1) ACE inhibitory activity and (2) the activity due to dilution was less likely to decrease. Conceivable.
実施例１〜実施例４の味噌について、タンパク質濃度を測定したところ、実施例１、実施例４は全ての画分でタンパク質が検出されたが、実施例２、実施例３は１０ｋＤａ以下ではタンパク質が検出されなかった。実施例１は、製麹時間、熟成期間が短いにもかかわらず、実施例４とほぼ同じ分子量分布であった。一方、実施例１と同様の製麹時間、熟成期間であるにもかかわらず実施例２は１０ｋＤａ以下に分解されなかった。この結果は、実施例１と実施例２〜実施例４における麹菌の違いによるプロテアーゼ活性の差により、タンパク質の濃度に違いが現れたと推測される。 When the protein concentration was measured for the miso of Examples 1 to 4, protein was detected in all fractions in Examples 1 and 4, but in Examples 2 and 3, protein was below 10 kDa. Was not detected. In Example 1, the molecular weight distribution was almost the same as that in Example 4 although the time for slag making and the aging period were short. On the other hand, Example 2 was not decomposed to 10 kDa or less in spite of the same iron making time and aging period as Example 1. From this result, it is presumed that the difference in the protein concentration appeared due to the difference in protease activity due to the difference in Neisseria gonorrhoeae in Example 1 and Examples 2 to 4.
［ＬＣ−ＴＯＦ−ＭＳの分析］
実施例１のＦ５についてＡＣＥ阻害物質の同定を実施した。ＬＣ−ＴＯＦ−ＭＳの分析条件を表３に示す。イオン化はＥＳＩ＋で実施し、ＭＳ分析モードで実施した。
[Analysis of LC-TOF-MS]
An ACE inhibitor was identified for F5 of Example 1. The analysis conditions for LC-TOF-MS are shown in Table 3. Ionization was performed with ESI + and in MS analysis mode.
図４に実施例１のＦ５のＬＣ−ＴＯＦ−ＭＳ分析結果を示す。Ａ２１０のデータからＦ５の化合物はほぼ単一ピークであると示された。図５にＦ５のマススペクトルデータを示す。Ｆ５の化合物には、ｍ／ｚ＝２０３．０５２５に、質量１６２、３２４が付加されたピークである３６５、５２７が存在する（単糖の分子量は１８０、二糖の分子量は３４２であるが、配糖体結合時にＨ２Ｏが脱離するため、付加される単糖、二糖のｍ／ｚはそれぞれ１６２、３２４となる）。この結果から本化合物が、ｍ／ｚ＝２０３．０５２５の化合物に糖が付加された配糖体であることが推測された。この二つの化合物は丁度、二糖に相当する分だけｍ／ｚ値が異なることからＦ５のターゲット化合物はｍ／ｚ＝２０３．０５２５に二糖が結合した配糖体であると考えられる。 The LC-TOF-MS analysis result of F5 of Example 1 is shown in FIG. The data of A 210 showed that the compound of F5 has almost a single peak. FIG. 5 shows mass spectrum data of F5. In the compound of F5, there are 365 and 527 which are peaks obtained by adding masses 162 and 324 to m / z = 203.0525 (monosaccharide has a molecular weight of 180 and disaccharide has a molecular weight of 342. Since H 2 O is eliminated at the time of glycoside binding, the m / z of the added monosaccharide and disaccharide is 162 and 324, respectively). From this result, it was speculated that the present compound was a glycoside obtained by adding a sugar to a compound having m / z = 203.0525. Since these two compounds have different m / z values corresponding to the disaccharide, it is considered that the target compound of F5 is a glycoside in which a disaccharide is bound at m / z = 203.0525.
ＬＣ−ＴＯＦ−ＭＳの分析結果から、ｍ／ｚ＝２０３．０５２５の化合物について、構造式の検索を実施した。検索結果にはフラン環を有する化合物があり、フラン化合物はＡＣＥ阻害活性を有するという報告があることから、フラン環を有する化合物がＡＣＥ阻害物質の候補になりうると推測される。式（１）、式（２）、式（３）に示す化合物を選定した。 From the analysis result of LC-TOF-MS, the structural formula was searched for the compound of m / z = 203.0525. The search results include a compound having a furan ring, and there is a report that the furan compound has an ACE inhibitory activity. Therefore, it is presumed that a compound having a furan ring can be a candidate for an ACE inhibitor. Compounds represented by formula (1), formula (2), and formula (3) were selected.
［ＮＭＲ分析］
実施例１のＦ５について乾固し、ＮＭＲ解析を実施した。解析はプロトンＮＭＲおよびカーボンＮＭＲを実施した。
[NMR analysis]
F5 of Example 1 was dried and subjected to NMR analysis. Analysis was performed by proton NMR and carbon NMR.
糖のＣ−ＮＭＲにおいて１００ｐｐｍ付近（アノマー末端１位の糖のシグナル）、７０−８０ｐｐｍ付近（糖の２位から５位のシグナル）、６０ｐｐｍ付近（６位のＣＨ２シグナル）のピークが検出された。Ｃ−ＮＭＲの分析結果から、実施例１のＦ５は糖であることが示唆された。また、Ｈ−ＮＭＲにおいてβ結合に寄与するシグナルが４．５ｐｐｍ付近にタブレットで確認されたことから、本化合物はβ結合を有する二糖類であると推測された。各水素、炭素の結合状況については、ＴＯＣＳＹ、ＣＯＳＹ、ＨＳＱＣ、ＨＭＢＣの解析により構造を推定した。これにより、二糖類はβ１、６グルコシド結合を有するゲンチオビオースであることが確認された。 In C-NMR of the sugar, peaks were detected around 100 ppm (sugar signal at the 1st position of the anomeric terminal), around 70-80 ppm (signal from the 2nd to 5th position of the sugar), and around 60 ppm (CH2 signal at the 6th position). . The results of C-NMR analysis suggested that F5 of Example 1 was a sugar. Moreover, since the signal which contributes to (beta) bond in H-NMR was confirmed by the tablet at 4.5 ppm vicinity, it was estimated that this compound is a disaccharide which has (beta) bond. About the bonding state of each hydrogen and carbon, the structure was estimated by analysis of TOCSY, COSY, HSQC, and HMBC. This confirmed that the disaccharide was gentiobiose having a β1,6 glucoside bond.
以上の結果から、ＬＣ−ＴＯＦ−ＭＳ、ＮＭＲの分析結果から、実施例１のＦ５の候補化合物の一例として、式（１）にゲンチオビオースが配位した配糖体があり、図６のような構造をＡＣＥ阻害物質として想定した。 From the above results, from the LC-TOF-MS and NMR analysis results, as an example of the F5 candidate compound of Example 1, there is a glycoside in which gentiobiose is coordinated with formula (1), as shown in FIG. The structure was assumed as an ACE inhibitor.
［実施例１および実施例４の味噌中のターゲット化合物およびジペプチドの含有量］
ターゲット化合物とジペプチドについてＬＣ−Ｑ−ＭＳ／ＭＳを用いて分析を実施した。サンプル１ｍＬに３０％トリクロロ酢酸（ＴＣＡ）を８０μＬ添加、除タンパク後に得られた遠心分離上清を測定試料とし、ＬＣＭＳ分析を実施した。分析条件を表４に示す。
[Contents of target compound and dipeptide in miso of Example 1 and Example 4]
The target compound and dipeptide were analyzed using LC-Q-MS / MS. LCMS analysis was performed by adding 80 μL of 30% trichloroacetic acid (TCA) to 1 mL of the sample and using the centrifuged supernatant obtained after deproteinization as a measurement sample. The analysis conditions are shown in Table 4.
分析結果を表５に示す。ターゲット化合物の標準品は無いが、Ｆ５の乾燥重量を基に味噌中の量を推定した。Ｆ４、Ｆ５におけるターゲット化合物の推定含有量はペプチド量と
比較して１００倍程度多いことが確認でき、ターゲット化合物のＡＣＥ阻害活性を確認できた。
The analysis results are shown in Table 5. Although there is no standard target compound, the amount in miso was estimated based on the dry weight of F5. It was confirmed that the estimated content of the target compound in F4 and F5 was about 100 times greater than the peptide amount, and the ACE inhibitory activity of the target compound was confirmed.
［動物試験］
図７に、実施例１の味噌、実施例４の味噌、食塩水の投与による血圧の変化を示すグラフを示す。９週齢の雄ＳＨＲｓｐラット３０匹を、実施例１の味噌、実施例４の味噌、比較例の食塩水をそれぞれ投与する３群に分け、３週間成育した。この間毎週ｔａｉｌ−ｃｕｆｆ法で血圧を測定した。実施例１および実施例４の味噌投与群ではそれぞれの５％味噌水を自由摂取とし、比較例の食塩水投与群には味噌水と同濃度の食塩水（０．６％ＮａＣｌ、ｗ／ｖ）を与えた。餌は通常食（０．７５％ＮａＣｌ、ｗ／ｗ）を自由摂取とした。
実験期間中、対照群（食塩水投与群）では年齢依存性に血圧が上昇した。実施例１および実施例４の味噌投与群は１週目から全期間比較例の食塩水投与群より有意に血圧が低下した。実施例１の味噌投与群では２週目及び３週目には実施例４の味噌投与群より有意に血圧が低かった（２００±８ ｖｓ ２０８±９ｍｍＨｇ、ｐ＜０．０５； ２０７±７ ｖｓ ２１６±８ｍｍＨｇ、ｐ＜０．０１）。
[Animal test]
In FIG. 7, the graph which shows the change of the blood pressure by administration of the miso of Example 1, the miso of Example 4, and a saline solution is shown. Thirty 9-week-old male SHRsp rats were divided into 3 groups to which the taste buds of Example 1, the taste buds of Example 4 and the saline solution of Comparative Example were respectively administered, and were grown for 3 weeks. During this period, blood pressure was measured weekly by the tail-cuff method. In the miso administration groups of Example 1 and Example 4, each 5% miso water was freely consumed, and in the saline administration group of the comparative example, a saline solution (0.6% NaCl, w / v) having the same concentration as miso water was used. ) Was given. A normal diet (0.75% NaCl, w / w) was freely consumed.
During the experiment, blood pressure increased in an age-dependent manner in the control group (saline-administered group). In the miso-administered groups of Examples 1 and 4, blood pressure significantly decreased from the week 1 compared to the saline-administered group of Comparative Examples for the entire period. In the miso administration group of Example 1, blood pressure was significantly lower in the second and third weeks than in the miso administration group of Example 4 (200 ± 8 vs 208 ± 9 mmHg, p <0.05; 207 ± 7 vs. 216 ± 8 mmHg, p <0.01).
Claims (16)
（１）分子量：２０２
（２）分子式：Ｃ８Ｈ１０Ｏ６ An angiotensin converting enzyme inhibitor characterized by containing, as an active ingredient, a compound having the following physicochemical properties (1) to (2) and having a substance having a structure having a furan ring and a hydroxy group as a basic skeleton.
(1) Molecular weight: 202
(2) Molecular formula: C 8 H 10 O 6
米に麹菌を接種して製麹する製麹工程と、
前記製麹工程により得られた麹と、大豆とを混合して発酵・熟成する熟成工程とを含むことを特徴とする組成物の製造方法。 A method for producing a composition comprising the angiotensin converting enzyme inhibitor according to claim 9 or 10,
A koji making process in which rice is inoculated with koji mold and koji,
The manufacturing method of the composition characterized by including the aging process which mixes the koji obtained by the said koji-making process, and soybean, and ferments and matures.
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| JP2020130139A (en) * | 2019-02-25 | 2020-08-31 | マルコメ株式会社 | Food and drink, night blood pressure lowering agent, pharmaceutical composition, food additive, and supplement |
| WO2021065307A1 (en) * | 2019-09-30 | 2021-04-08 | 丸善製薬株式会社 | Angiotensin-converting enzyme inhibitor, blood pressure-lowering agent, and beverages and food products |
| JP2021124845A (en) * | 2020-02-03 | 2021-08-30 | トヨタ自動車株式会社 | Authentication system |
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| JPH07289281A (en) * | 1994-04-28 | 1995-11-07 | Nichimo Co Ltd | Product containing inhibitor of angiotensin-converting enzyme and its production |
| JP2008125380A (en) * | 2006-11-17 | 2008-06-05 | Marukome Kk | Method for producing functional fermented soybean paste |
| JP2008247888A (en) * | 2007-03-08 | 2008-10-16 | Gekkeikan Sake Co Ltd | Hypotensive composition using koji |
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| JP2020130139A (en) * | 2019-02-25 | 2020-08-31 | マルコメ株式会社 | Food and drink, night blood pressure lowering agent, pharmaceutical composition, food additive, and supplement |
| JP7289441B2 (en) | 2019-02-25 | 2023-06-12 | マルコメ株式会社 | Foods and drinks, nocturnal blood pressure lowering agents, pharmaceutical compositions, food additives and supplements |
| WO2021065307A1 (en) * | 2019-09-30 | 2021-04-08 | 丸善製薬株式会社 | Angiotensin-converting enzyme inhibitor, blood pressure-lowering agent, and beverages and food products |
| CN114449906A (en) * | 2019-09-30 | 2022-05-06 | 丸善制药株式会社 | Angiotensin converting enzyme inhibitor, antihypertensive agent, and food or drink |
| JP2021124845A (en) * | 2020-02-03 | 2021-08-30 | トヨタ自動車株式会社 | Authentication system |
| JP7322732B2 (en) | 2020-02-03 | 2023-08-08 | トヨタ自動車株式会社 | Authentication system |
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