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Identification of isoliquiritigenin as an activator that stimulates the enzymatic production of glycyrrhetinic acid monoglucuronide.

ABSTRACT: Glycyrrhetinic acid monoglucuronide (GAMG) is a great value-added and has considerable commercial interest due to its strong pharmacological activities and functional low-calorie sweetener. However GAMG is quite rare in natural plants, and it must be prepared from glycyrrhizin (GL) by hydrolysing one terminal glucuronic acid. β-Glucuronidase is the key enzyme in the biotransformation of GL to GAMG, but its activities need to be enhanced to facilitate the industrial large-scale production of GAMG. In this study, we identified that isoliquiritigenin (ISL), as one of chemical compositions from the total flavonoids glycyrrhiza (TFG), can significantly enhance β-glucuronidase activity in vitro. Measurements using high-performance liquid chromatography (HPLC) showed that the activity of β-glucuronidase could be increased by 2.66-fold via the addition of ISL to a β-glucuronidase solution that contained GL at a 3:10 molar ratio of ISL to GL. ISL was concluded to be an activator because ISL could reduce the K_m and E_a of β-glucuronidase reacting with GL. This study sheds new light on the mechanism of β-glucuronidase and helps to make industrial production of GAMG through fermentation feasible.

SUBMITTER: Wang X

PROVIDER: S-EPMC5624897 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Identification of isoliquiritigenin as an activator that stimulates the enzymatic production of glycyrrhetinic acid monoglucuronide.

Wang Xiaoxue X Wang Dong D Huo Yixin Y Dai Dazhang D Li Chihua C Li Chun C Liu Guiyan G

Scientific reports 20171002 1

Glycyrrhetinic acid monoglucuronide (GAMG) is a great value-added and has considerable commercial interest due to its strong pharmacological activities and functional low-calorie sweetener. However GAMG is quite rare in natural plants, and it must be prepared from glycyrrhizin (GL) by hydrolysing one terminal glucuronic acid. β-Glucuronidase is the key enzyme in the biotransformation of GL to GAMG, but its activities need to be enhanced to facilitate the industrial large-scale production of GAMG ...[more]

PMID: 28970510

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Project description:BackgroundGlycyrrhetinic acid (GA) is the most important ingredient in licorice due to its outstanding anti-inflammatory activity and wide application in the medicine and cosmetics industries. Contemporary industrial production of GA by acid hydrolysis of glycyrrhizin which was extracted from Glycyrrhiza plants, is not environment-friendly and devastates farmland since the Glycyrrhiza rhizomes grow up to 10 m underground.ResultsIn this study, GA was produced through metabolically engineering Saccharomyces cerevisiae by introducing the entire heterogeneous biosynthetic pathway of GA. Codon optimized CYP88D6 and CYP72A154, combined with β-AS (β-amyrin synthase encoding gene) and the NADPH-cytochrome P450 reductase gene of Arabidopsis thaliana were introduced into S. cerevisiae. The resulting strain (Y1) produced 2.5 mg/L of β-amyrin and 14 μg/L of GA. The cytochrome b5 from G. uralensis (GuCYB5) was identified and the introduction of this novel GuCYB5 increased the efficiency of GA production by eightfold. The joint utilization of the GuCYB5 gene along with 10 known MVA pathway genes from S. cerevisiae were overexpressed in a stable chromosome integration to achieve higher GA production. Using the combined strategy, GA concentration improved by 40-fold during batch fermentation. The production was further improved to 8.78 mg/L in fed-batch fermentation, which was increased by a factor of nearly 630.ConclusionsThis study first investigated the influence of carbon flux in the upstream module and the introduction of a newly identified GuCYB5 on GA production. The newly identified GuCYB5 was highly effective in improving GA production. An integrated strategy including enzyme discovery, pathway optimization, and fusion protein construction was provided in improving GA production, achieving a 630 fold increase in GA production. The metabolically engineered yeast cell factories provide an alternative approach to glycyrrhetinic acid production, replacing the traditional method of plant extraction.

Dataset Information

Identification of isoliquiritigenin as an activator that stimulates the enzymatic production of glycyrrhetinic acid monoglucuronide.

Publications

Identification of isoliquiritigenin as an activator that stimulates the enzymatic production of glycyrrhetinic acid monoglucuronide.

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