Abstract: A nucleoside that is more practical for RNA pharmaceuticals and other applications and use thereof is represented by formula (1) or (2) below, or a salt thereof: (In formula (1), R1 represents a hydrogen atom, a hydroxyl group, a hydroxyl group in which a hydrogen atom is substituted by an alkyl group or alkenyl group, or a protected group, and in formula (2), X represents a halogen atom. In formula (1) and formula (2), R2 and R3 may be the same or different, and each represents a hydrogen atom etc., R4 represents NHR7 (in which R7 represents a hydrogen atom etc., and B represent represents any of a purine-9-yl group, 2-oxo-pyrimidin-1-yl group, substituted purine-9-yl group or substituted 2-oxo-pyrimidin-1-yl group).

Abstract: A lyophilized product of cyclic-di-AMP requires special production equipment and is thus not suitable for large-scale production. Crystals of cyclic-di-AMP free acid are unstable under severe conditions at 105° C. Then, the present invention addresses the problem of providing a cyclic-di-AMP crystal that can be easily acquired in a large amount and is very stable under the severe conditions at 105° C. Crystals of c-di-AMP sodium salt according to the present invention are extremely stable even under the severe conditions at 105° C. Further, the crystals of c-di-AMP sodium salt according to the present invention can be prepared in a large amount by a simple process including adjusting a c-di-AMP aqueous solution at pH 5.2-12.0 and then adding an organic solvent thereto.

Abstract: Among commonly known 3?,3?-cGAMP is a lyophilized product. The lyophilized product needs a lyophilizer during the manufacture. This, itself, causes a limitation in scale-up for mass production. Thus, it has been desired to develop and obtain a large amount of their crystals in a simple manner without using a special apparatus such as a lyophilizer. In addition, conventionally known lyophilized products or ethanol precipitates are highly hygroscopic. Hence, the present invention addresses the problem of providing an easy-to-handle crystal with excellent shelf life. A hydrate crystal of 3?,3?-cGAMP according to the invention may be either a crystal of alkali metal salt or a crystal of free acid. Either is less hygroscopic than existing powder. Thus, each is easy to handle in various purposes and is thus useful as a pharmaceutical raw material or the like.

Abstract: A method for producing P1,P4-di(uridine 5?-)tetraphosphate (UP4U) that can avoid reduction of the synthetic efficiency without using UTP free is developed. A method for producing UP4U comprising reacting a phosphoric acid-activating compound represented by formula [II] or [III] with a phosphoric acid compound selected from the group consisting of UMP, UDP, UTP and a pyrophosphoric acid or a salt thereof (excluding UTP free) in water or a hydrophilic organic solvent, in the presence of a metal ion selected from the group consisting of an iron (II) ion, an iron (III) ion, a trivalent aluminum ion, a trivalent lanthanum ion, and a trivalent cerium ion. where, in the formula [II], R1 represents a uridyl group binding to the 5?-position, X represents a heterocyclic group, and n represents an integer of 1 or 2, where, in the formula [III], X represents a heterocyclic group selected from the group consisting of an imidazolyl group, a benzimidazolyl group, and a 1,2,4-triazolyl group.

Abstract: There is provided a dried L-glutamate oxidase composition containing an L-glutamate oxidase, which is stable even if it is stored for such a long term as one year or longer. The composition is a dried composition, preferably lyophilized product, containing an L-glutamate oxidase and a disaccharide. A preferred example of the disaccharide is lactose. Content of the disaccharide per 100 U of the L-glutamate oxidase is preferably 0.5 to 50 mg.

Abstract: A nucleoside that is more practical for RNA pharmaceuticals and other applications and use thereof is represented by formula (1) or (2) below, or a salt thereof: (In formula (1), R1 represents a hydrogen atom, a hydroxyl group, a hydroxyl group in which a hydrogen atom is substituted by an alkyl group or alkenyl group, or a protected group, and in formula (2), X represents a halogen atom. In formula (1) and formula (2), R2 and R3 may be the same or different, and each represents a hydrogen atom etc., R4 represents NHR7 (in which R7 represents a hydrogen atom etc., and B represent represents any of a purine-9-yl group, 2-oxo-pyrimidin-1-yl group, substituted purine-9-yl group or substituted 2-oxo-pyrimidin-1-yl group).

Abstract: Though 3?,5?-cyclic diadenylic acid was conventionally provided only as a freeze-dried product, a solid material other than a freeze-dried product and a manufacturing method thereof is provided. By a step of adding acid to an aqueous solution of 3?,5?-cyclic diadenylic acid so as to lower pH to 1 to 3, an inclusion compound of 3?,5?-cyclic diadenylic acid can be obtained. Said manufacturing method is an extremely simple and easy method and does not need a special machine or the like.

Abstract: To provide an easy and practical iron ion removal method, as a method for purifying P1,P4-di(uridine 5?-)tetraphosphate from a solution containing iron ions. Purification is performed by a purification method including a method for purifying P1,P4-di(uridine 5?-)tetraphosphate by removing iron ions from an aqueous solution or hydrophilic solvent solution containing P1,P4-di(uridine 5?-)tetraphosphate and iron ions, including (1) a step of purification using a chelating resin packed column, and (2) a step of adjusting the pH of the solution after said purification step using the chelating resin packed column to 5.5 or less, and then crystallizing P1,P4-di(uridine 5?-)tetraphosphate, or a step of treating the solution after said purification step using the chelating resin packed column with zinc chloride-activated activated carbon.

Abstract: A crystal of free acid of 3?,5?-cyclic diguanylic acid containing no metal salt with cobalt, magnesium or the like is provided. A method is sought for obtaining said crystal in a large amount and with ease. By a manufacturing method comprising a step of adding acid to an aqueous solution of 3?,5?-cyclic diguanylic acid so as to lower pH to 1 to 3, crystals of 3?,5?-cyclic diguanylic acid can be obtained in a large amount with ease. Said crystals are free acid crystals which do not contain a metal salt with cobalt, magnesium or the like.

Abstract: A Koji production system including a culture area, an environment control device, a Koji container, a carrying-in lane, a Koji container moving device, and a control unit. The culture area is an area for culturing the Koji by storing a plurality of the Koji container in a predetermined position. The environment control device is configured to control a temperature and humidity in the culture area. The Koji container contains raw materials of Koji placed at a height of 1 cm to 10 cm, the raw materials comprising a mixture of soybeans and Koji mold. The carrying-in lane is configured to move the Koji container to the culture area.

Abstract: [Problem] Provided is a method for easily and stably storing crystals of P1,P4-bis(5?-uridyl)tetraphosphate for a long term. [Solution] A method for storing packed crystals of P1,P4-bis(5?-uridyl)tetraphosphate or a pharmaceutically acceptable salt thereof, wherein one of the following storage conditions (1) to (3): (1) a storage temperature of 0° C. or more and less than 25° C.; (2) a storage temperature of 25° C. or more and less than 40° C. and a crystal pH of 4.5 to 8.0; and (3) a storage temperature of 40° C. or more and less than 60° C. and a crystal pH of 5.0 to 6.4 is selected and the crystals of P1,P4-bis(5?-uridyl)tetraphosphate or the pharmaceutically acceptable salt thereof are stored under the selected condition.

Abstract: To provide an easy and practical iron ion removal method, as a method for purifying P1,P4-di(uridine 5?-)tetraphosphate from a solution containing iron ions. Purification is performed by a purification method including a method for purifying P1,P4-di(uridine 5?-)tetraphosphate by removing iron ions from an aqueous solution or hydrophilic solvent solution containing P1,P4-di(uridine 5?-)tetraphosphate and iron ions, including (1) a step of purification using a chelating resin packed column, and (2) a step of adjusting the pH of the solution after said purification step using the chelating resin packed column to 5.5 or less, and then crystallizing P1,P4-di(uridine 5?-)tetraphosphate, or a step of treating the solution after said purification step using the chelating resin packed column with zinc chloride-activated activated carbon.

Abstract: There is provided a dried L-glutamate oxidase composition containing an L-glutamate oxidase, which is stable even if it is stored for such a long term as one year or longer. The composition is a dried composition, preferably lyophilized product, containing an L-glutamate oxidase and a disaccharide. A preferred example of the disaccharide is lactose. Content of the disaccharide per 100 U of the L-glutamate oxidase is preferably 0.5 to 50 mg.

Abstract: A method for producing P1,P4-di(uridine 5?-)tetraphosphate (UP4U) that can avoid reduction of the synthetic efficiency without using UTP free is developed. A method for producing UP4U comprising reacting a phosphoric acid-activating compound represented by formula [II] or [III] with a phosphoric acid compound selected from the group consisting of UMP, UDP, UTP and a pyrophosphoric acid or a salt thereof (excluding UTP free) in water or a hydrophilic organic solvent, in the presence of a metal ion selected from the group consisting of an iron (II) ion, an iron (III) ion, a trivalent aluminum ion, a trivalent lanthanum ion, and a trivalent cerium ion. where, in the formula [II], R1 represents a uridyl group binding to the 5?-position, X represents a heterocyclic group, and n represents an integer of 1 or 2, where, in the formula [III], X represents a heterocyclic group selected from the group consisting of an imidazolyl group, a benzimidazolyl group, and a 1,2,4-triazolyl group.

Abstract: A method for producing P1,P4-di(uridine 5?-)tetraphosphate (UP4U) that can avoid reduction of the synthetic efficiency without using UTP free is developed. A method for producing UP4U comprising reacting a phosphoric acid-activating compound represented by formula [II] or [III] with a phosphoric acid compound selected from the group consisting of UMP, UDP, UTP and a pyrophosphoric acid or a salt thereof (excluding UTP free) in water or a hydrophilic organic solvent, in the presence of a metal ion selected from the group consisting of an iron (II) ion, an iron (III) ion, a trivalent aluminum ion, a trivalent lanthanum ion, and a trivalent cerium ion. where, in the formula [II], R1 represents a uridyl group binding to the 5?-position, X represents a heterocyclic group, and n represents an integer of 1 or 2, where, in the formula [III], X represents a heterocyclic group selected from the group consisting of an imidazolyl group, a benzimidazolyl group, and a 1,2,4-triazolyl group.

Abstract: [Problem] Provided is a method for easily and stably storing crystals of P1, P4-bis(5?-uridyl)tetraphosphate for a long term. [Solution] A method for storing packed crystals of P1, P4-bis(5?-uridyl)tetraphosphate or a pharmaceutically acceptable salt thereof, wherein one of the following storage conditions (1) to (3): (1) a storage temperature of 0° C. or more and less than 25° C.; (2) a storage temperature of 25° C. or more and less than 40° C. and a crystal pH of 4.5 to 8.0; and (3) a storage temperature of 40° C. or more and less than 60° C. and a crystal pH of 5.0 to 6.4 is selected and the crystals of P1, P4-bis (5?-uridyl) tetraphosphate or the pharmaceutically acceptable salt thereof are stored under the selected condition.

Abstract: A practical method for enzymatically synthesizing c-di-GMP with excellent productivity is provided. A diguanylate cyclase having physical and chemical characteristics (A) to (F): (A) catalytic action on reaction “2 GTP?c-di-GMP”; (B) a molecular weight of 19800±2000; (C) an optimum pH of 7.3 to 9.4; (D) an optimum temperature of 35 to 60° C.; (E) thermal stability as the remaining activity of 90% or higher after heated for 60 minutes under conditions of 50° C. and pH7.8; and (F) the presence of GGDEF (SEQ ID NO:26) domain and the lack of amino acid sequence KXXD (SEQ ID NO:23) in the i-site.

Abstract: A practical method for enzymatically synthesizing c-di-GMP with excellent productivity is provided. A diguanylate cyclase having physical and chemical characteristics (A) to (F): (A) catalytic action on reaction “2 GTP?c-di-GMP”; (B) a molecular weight of 19800±2000; (C) an optimum pH of 7.3 to 9.4; (D) an optimum temperature of 35 to 60° C.; (E) thermal stability as the remaining activity of 90% or higher after heated for 60 minutes under conditions of 50° C. and pH7.8; and (F) the presence of GGDEF (SEQ ID NO:26) domain and the lack of amino acid sequence KXXD (SEQ ID NO:23) in the i-site.

Abstract: The present invention provides a brewed soy sauce that has light color and reduced smell with a robust taste. In the brewed soy sauce, HEMF is less than 15 ppm. Glutamic acid is 0.9% (w/v) or more. Lactic acid and acetic acid are respectively 0.1% (w/v) or more. Reducing sugar is 1.5% (w/v) or less. Levulinic acid is less than 0.01% (w/v). And, pH is 4.5-5.5. The brewed soy sauce is produced as follows: First, a raw material is prepared from a plant protein-source material and a low-starch carbohydrate-source material. Then, koji is made by inoculating koji mold to the prepared raw material. Next, salt water is added to the koji, and the mixture of the salt water and koji is fermented. At least 5 days after initiating the fermentation, yeast belonging to Candida genus is added to the mixture. Then, the fermentation is matured.

Abstract: A method for producing P1,P4-di(uridine 5?-) tetraphosphate (UP4U) that can avoid reduction of the synthetic efficiency without using UTP free is developed. A method for producing UP4U comprising reacting a phosphoric acid-activating compound represented by formula [II] or [III] with a phosphoric acid compound selected from the group consisting of UMP, UDP, UTP and a pyrophosphoric acid or a salt thereof (excluding UTP free) in water or a hydrophilic organic solvent, in the presence of a metal ion selected from the group consisting of an iron (II) ion, an iron (III) ion, a trivalent aluminum ion, a trivalent lanthanum ion, and a trivalent cerium ion. where, in the formula [II], R1 represents a uridyl group binding to the 5?-position, X represents a heterocyclic group, and n represents an integer of 1 or 2, where, in the formula [III], X represents a heterocyclic group selected from the group consisting of an imidazolyl group, a benzimidazolyl group, and a 1,2,4-triazolyl group.