Phenolic C-glycoside synthesis using microbial systems

Chong, Yoojin; Lee, Shinwon; Ahn, Joong‐Hoon

doi:10.1016/j.copbio.2022.102827

Cited by 6 publications

(10 citation statements)

References 51 publications

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“…Based on the aromatic aglycone structure, carbon glycosides are classified into flavonoid C- glycosides, xanthone C- glycosides, chromone C- glycosides, anthrone C- glycosides, and C- glycosylated gallic acids (GAs) ( Jihen et al., 2017 ; Wang et al., 2022 ). Carbon glycosides are formed through the combination of aglycones with sugars catalyzed by C- glycosyltransferases (CGTs), which can generate C-C bonds to endow acid and glycosidase hydrolysis tolerance ( Mori et al., 2021 ; Bililign et al., 2005 ; Oualid and Artur, 2012 ; Chong et al., 2022 ). Owing to these advantages, C- glycoside drugs show remarkably stable drug absorption, molecular recognition, and drug metabolism ( Vidal et al., 2013 ; Singh et al., 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Biosynthetic pathway of prescription bergenin from Bergenia purpurascens and Ardisia japonica

Liu,

Wang,

et al. 2024

Front. Plant Sci.

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Bergenin is a typical carbon glycoside and the primary active ingredient in antitussive drugs widely prescribed for central cough inhibition in China. The bergenin extraction industry relies on the medicinal plant species Bergenia purpurascens and Ardisia japonica as their resources. However, the bergenin biosynthetic pathway in plants remains elusive. In this study, we functionally characterized a shikimate dehydrogenase (SDH), two O-methyltransferases (OMTs), and a C-glycosyltransferase (CGT) involved in bergenin synthesis through bioinformatics analysis, heterologous expression, and enzymatic characterization. We found that BpSDH2 catalyzes the two-step dehydrogenation process of shikimic acid to form gallic acid (GA). BpOMT1 and AjOMT1 facilitate the methylation reaction at the 4-OH position of GA, resulting in the formation of 4-O-methyl gallic acid (4-O-Me-GA). AjCGT1 transfers a glucose moiety to C-2 to generate 2-Glucosyl-4-O-methyl gallic acid (2-Glucosyl-4-O-Me-GA). Bergenin production ultimately occurs in acidic conditions or via dehydration catalyzed by plant dehydratases following a ring-closure reaction. This study for the first time uncovered the biosynthetic pathway of bergenin, paving the way to rational production of bergenin in cell factories via synthetic biology strategies.

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Section: Introductionmentioning

confidence: 99%

Biosynthetic pathway of prescription bergenin from Bergenia purpurascens and Ardisia japonica

Liu,

Wang,

et al. 2024

Front. Plant Sci.

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“…The biosynthesis of di‐ C ‐β‐glucosides involves a special subclass of sugar nucleotide‐dependent (Leloir) glycosyltransferases (GTs) (He et al, 2022). The enzymes, here referred to as CGTs, use uridine‐5′‐diphosphate (UDP)‐glucose for site‐selective C ‐β‐glycosylation of the polyphenol acceptor substrate (Figure 1) (Chong et al, 2022; Dai et al, 2021; Gao et al, 2022; Putkaradze et al, 2021; Tegl & Nidetzky, 2020; Y. Q. Zhang et al, 2022). The iterative two‐fold glycosylation leading to the di‐ C ‐β‐glucosides may arise from the coordinated action of separate CGTs (Feng et al, 2021; Y.…”

Section: Introductionmentioning

confidence: 99%

Reaction intensification for biocatalytic production of polyphenolic natural product di‐C‐β‐glucosides

Borg

Krammer

et al. 2023

Biotech & Bioengineering

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Polyphenolic aglycones featuring two sugars individually attached via C-glycosidic linkage (di-C-glycosides) represent a rare class of plant natural products with unique physicochemical properties and biological activities. Natural scarcity of such di-C-glycosides limits their use-inspired exploration as pharmaceutical ingredients. Here, we show a biocatalytic process technology for reaction-intensified production of the di-C-β-glucosides of two representative phenol substrates, phloretin (a natural flavonoid) and phenyl-trihydroxyacetophenone (a phenolic synthon for synthesis), from sucrose. The synthesis proceeds via an iterative two-fold C-glycosylation of the respective aglycone, supplied as inclusion complex with 2-hydroxypropyl β-cyclodextrin for enhanced water solubility of up to 50 mmol/L, catalyzed by a kumquat di-C-glycosyltransferase (di-CGT), and it uses UDP-Glc provided in situ from sucrose by a soybean sucrose synthase, with catalytic amounts (≤3 mol%) of UDP added. Time course analysis reveals the second C-glycosylation as rate-limiting (0.4-0.5 mmol/L/min) for the di-C-glucoside production. With internal supply from sucrose keeping the UDP-Glc at a constant steady-state concentration (≥50% of the UDP added) during the reaction, the di-C-glycosylation is driven to completion (≥95% yield). Contrary to the mono-C-glucoside intermediate which is stable, the di-C-glucoside requires the addition of reducing agent (10 mmol/L 2-mercaptoethanol) to prevent its decomposition during the synthesis. Both di-C-glucosides are isolated from the reaction mixtures in excellent purity (≥95%), and their expected structures are confirmed by NMR. Collectively, this study demonstrates efficient glycosyltransferase cascade reaction for flexible use in natural product di-C-β-glucoside synthesis from expedient substrates.

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“…Instead of directly acting on the flavonoids, C -glycosylation predominantly occurs on 2-hydroxyflavone intermediates followed by dehydration reactions . Only a few C -glycosyltransferases (CGTs) that catalyze the direct C -glycosylation of flavonoids have been identified . These CGTs transfer UDP-sugars directly to the flavonoid skeleton.…”

Section: Introductionmentioning

confidence: 99%

“…3 Only a few C-glycosyltransferases (CGTs) that catalyze the direct C-glycosylation of flavonoids have been identified. 15 These CGTs transfer UDP-sugars directly to the flavonoid skeleton. For example, GtUF6CGT1 from Gentiana trif lora showed C6 glucosylation activity toward flavones such as luteolin and apigenin, 16 and WjGT1 from Wasabia japonica showed specificity toward apigenin and kaempferol, with regioselectivity at C6.…”

Section: ■ Introductionmentioning

confidence: 99%

Production of Four Flavonoid C-Glucosides in Escherichia coli

Chong

Kim

Park

et al. 2023

J. Agric. Food Chem.

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Flavonoid C-glucosides, which are found in several plant families, are characterized by several biological properties, including antioxidant, anticancer, anti-inflammatory, neuroprotective, hepatoprotective, cardioprotective, antibacterial, antihyperalgesic, antiviral, and antinociceptive activities. The biosynthetic pathway of flavonoid C-glucosides in plants has been elucidated. In the present study, a pathway was introduced to Escherichia coli to synthesize four flavonoid C-glucosides, namely, isovitexin, vitexin, kaempferol 6-C-glucoside, and kaempferol 8-C-glucoside. A five- or six-step metabolic pathway for synthesizing flavonoid aglycones from tyrosine was constructed and two regioselective flavonoid C-glycosyltransferases from Wasabia japonica (WjGT1) and Trollius chinensis (TcCGT) were used. Additionally, the best shikimate gene module construct was selected to maximize the titer of each C-glucoside flavonoid. Isovitexin (30.2 mg/L), vitexin (93.9 mg/L), kaempferol 6-C-glucoside (14.4 mg/L), and kaempferol 8-C-glucoside (38.6 mg/L) were synthesized using these approaches. The flavonoid C-glucosides synthesized in this study provide a basis for investigating and unraveling their novel biological properties.

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Phenolic C-glycoside synthesis using microbial systems

Cited by 6 publications

References 51 publications

Biosynthetic pathway of prescription bergenin from Bergenia purpurascens and Ardisia japonica

Biosynthetic pathway of prescription bergenin from Bergenia purpurascens and Ardisia japonica

Reaction intensification for biocatalytic production of polyphenolic natural product di‐C‐β‐glucosides

Production of Four Flavonoid C-Glucosides in Escherichia coli

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