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Regulation and control of microbial metabolism of streptomyces toxytricini

A technology of microbial metabolism and microbial fermentation, which is applied in the field of preparation of high-unit orlistat intermediate riprestatin, can solve the problems of shortened product synthesis stage, high nutrient concentration, and reduced output of metabolites, and achieve easy Effect of industrialized production, high fermentation level and low production cost

Active Publication Date: 2015-04-15
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST +1
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  • Application Information

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Problems solved by technology

This feeding method has great disadvantages. Because it is a one-time supplement of carbon source, nitrogen source and other necessary substrates, the concentration of nutrients will be too high in a short period of time, which will cause the bacteria to multiply mycelia in large quantities. The direction of the body is developed, so that the nutrients are mainly consumed in the growth of the mycelia, the synthesis stage of the product is shortened, and the output of the final metabolite is reduced.
After improvement, the continuous constant-speed feeding method can also be used for feeding. Although this method can eliminate the suppression phenomenon caused by the excessive concentration of nutrients produced by periodic feeding due to the one-time feeding of a large amount of nutrients, it does not affect the mycelium growth. There are still certain defects in the feeding method, that is, the same amount of substrate is fed at a constant rate throughout the feeding cycle, while ignoring the actual consumption of the bacteria in each stage of the metabolic process. Compared with periodic feeding, continuous feeding is used. Although the fermentation unit of constant-rate fed riprestatin has increased, there is still room for improvement

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  • Regulation and control of microbial metabolism of streptomyces toxytricini

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Effect test

Embodiment 1

[0028] Embodiment 1: period feed

[0029] Connect the feeding tank and the fermenter through a liquid filtration sterilizing feeding pipeline. After the feeding pipeline is sterilized, start on the second day, and the next day, 0.5 tons of linoleic acid and 0.33 tons of linoleic acid and 0.33 tons of The leucine solution is pressed into the fermenter to complete feeding. The whole fermentation process then needs 4 times of this feeding process, and the total feeding amount is 3.32 tons. After cultivating for 156 hours, put it into the tank, and the fermentation unit is 2674 μg / ml.

Embodiment 2

[0030] Embodiment 2: continuous constant speed feeding

[0031] Connect the feeding tank and the fermenter through a liquid filtration and sterilization feeding pipeline. After the feeding pipeline is sterilized, feed at a constant speed from the beginning of fermentation culture. The feeding speed is: linoleic acid: 12L / h, leucine solution: 8L / h, the total feeding amount is 3.12 tons, cultured for 160 hours and placed in the tank, the measured fermentation unit is: 5636μg / ml.

Embodiment 3

[0032] Embodiment 3: variable speed feeding

[0033] The feed liquid weight in the fermentation tank is about 40 tons. The feeding tank and the fermenter are connected through a liquid filtration sterilizing feeding pipeline, and the feeding pipeline is sterilized for standby. Dissolved oxygen is monitored in real time, and feeding is performed according to changes in dissolved oxygen.

[0034] After 35 hours of fermentation and cultivation, the dissolved oxygen rose to 98% in a straight line, and the feeding rate was as follows: linoleic acid: 8L / h, leucine solution, 5.2L / h for feeding; after cultivating for 60 hours, dissolve The performance of oxygen is rising continuously, and it is higher than 35% for more than 1 hour. The amount of feeding is increased as follows: linoleic acid: 12L / h, leucine solution: 8 L / h; after culturing for 122 hours, the performance of dissolved oxygen is constant. Decrease, less than 20% for 1 hour, reduce the amount of feeding: linoleic acid: ...

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Abstract

The invention discloses preparation of Lipstatin namely an Orlistat intermediate through regulation and control of microbial metabolism of streptomyces toxytricini. After 24-36 hours of microbial fermentation, dissolved oxygen is controlled to be 20 - 30%, and then the high-unit Lipstatin is obtained. The invention also discloses concrete preparation technology. The method has the advantages of simple operation, high purity of products, low production cost, no need of change of the original equipment and easy industrialized production.

Description

technical field [0001] The invention relates to the field of biochemical industry, and more specifically relates to a method for preparing high-unit orlistat intermediate liplastatin by regulating microbial metabolism. Background technique [0002] Orlistat (Orlistat), chemical name: (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S,3S)-3-hexyl-4-oxo- 2-Oxetanyl]methyl]-dodecyl ester, orlistat is a derivative produced by catalytic hydrogenation of lipstatin, a secondary metabolite of Streptomyces toxytricini fermentation. A long-acting and potent specific gastrointestinal lipase inhibitor, it exerts a therapeutic effect by forming a covalent bond with the active serine site of gastric lipase and pancreatic lipase in the lumen of the stomach and small intestine to inactivate the enzyme. Live enzymes cannot hydrolyze dietary fat, mainly triglycerides, into absorbable free fatty acids and monoacylglycerols. Undigested triglycerides cannot be absorbed by the body, thereby ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P17/02C12R1/465
Inventor 沈康方军李立似李宏杰蒋彩霞刘金国
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST