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Synthesis of umbelliferone derivatives in Escherichia coli and their biological activities

View Article: PubMed Central - PubMed

ABSTRACT

Background: Umbelliferone, also known as 7-hydroxycoumarin, is a phenolic metabolite found in many familiar plants. Its derivatives have been shown to have various pharmacological and chemo-preventive effects on human health. A uridine diphosphate glycosyltransferase YjiC from Bacillus licheniformis DSM 13, a cytochrome P450BM3 (CYP450 BM3) variant namely mutant 13 (M13) from Bacillus megaterium, and an O-methyltransferase from Streptomyces avermitilis (SaOMT2) were used for modifications of umbelliferone.

Results: Three umbelliferone derivatives (esculetin, skimmin, and herniarin) were generated through enzymatic and whole cell catalysis. To improve the efficiencies of biotransformation, different media, incubation time and concentration of substrate were optimized and the production was scaled up using a 3-L fermentor. The maximum yields of esculetin, skimmin, and herniarin were 337.10 μM (67.62%), 995.43 μM (99.54%), and 37.13 μM (37.13%), respectively. The water solubility of esculetin and skimmin were 1.28-folds and 3.98-folds as high as umbelliferone, respectively, whereas herniarin was 1.89-folds less soluble than umbelliferone. Moreover, the antibacterial and anticancer activities of herniarin showed higher than umbelliferone, esculetin and skimmin.

Conclusions: This study proves that both native and engineered enzymes could be employed for the production of precious compounds via whole cell biocatalysis. We successfully produced three molecules herniarin, esculetin and skimmin in practical amounts and their antibacterial and anticancer properties were accessed. One of the newly synthesized molecules the present research suggests that the combinatorial biosynthesis of different biosynthetic enzymes could rapidly promote to a novel secondary metabolite.

Electronic supplementary material: The online version of this article (doi:10.1186/s13036-017-0056-5) contains supplementary material, which is available to authorized users.

No MeSH data available.


The chemical structure of the simple coumarins
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Fig1: The chemical structure of the simple coumarins

Mentions: Umbelliferone and its derivatives are compounds derived from coumarin (Fig. 1) with pharmacological and chemopreventive benefits for human health. Umbelliferone is known to have antinociceptive and anti-inflammatory activities in animal models [1]. Moreover, esculetin exhibits various biological activities including antioxidant [2], anti-tumor, anti-metastatic [3], anti-proliferative, pro-apoptotic [4], and neuroprotective activities [5]. Umbelliferone glycosides have been found to possess neuroprotective effects against serum deprivation-induced PC12 cell damage [6] with antidiabetic, antihyperlipidemic, and antioxidative activities [7]. Furthermore, 7-methoxycoumarin showed antifugal and antibacterial activities [8]. Likewise, other umbelliferone derivatives such as scopoletin, scoparone, fraxetin, esculin, and daphnetin have been reported to have antioxidant and intestinal anti-inflammatory activities [9].Fig. 1


Synthesis of umbelliferone derivatives in Escherichia coli and their biological activities
The chemical structure of the simple coumarins
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5382406&req=5

Fig1: The chemical structure of the simple coumarins
Mentions: Umbelliferone and its derivatives are compounds derived from coumarin (Fig. 1) with pharmacological and chemopreventive benefits for human health. Umbelliferone is known to have antinociceptive and anti-inflammatory activities in animal models [1]. Moreover, esculetin exhibits various biological activities including antioxidant [2], anti-tumor, anti-metastatic [3], anti-proliferative, pro-apoptotic [4], and neuroprotective activities [5]. Umbelliferone glycosides have been found to possess neuroprotective effects against serum deprivation-induced PC12 cell damage [6] with antidiabetic, antihyperlipidemic, and antioxidative activities [7]. Furthermore, 7-methoxycoumarin showed antifugal and antibacterial activities [8]. Likewise, other umbelliferone derivatives such as scopoletin, scoparone, fraxetin, esculin, and daphnetin have been reported to have antioxidant and intestinal anti-inflammatory activities [9].Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Background: Umbelliferone, also known as 7-hydroxycoumarin, is a phenolic metabolite found in many familiar plants. Its derivatives have been shown to have various pharmacological and chemo-preventive effects on human health. A uridine diphosphate glycosyltransferase YjiC from Bacillus licheniformis DSM 13, a cytochrome P450BM3 (CYP450 BM3) variant namely mutant 13 (M13) from Bacillus megaterium, and an O-methyltransferase from Streptomyces avermitilis (SaOMT2) were used for modifications of umbelliferone.

Results: Three umbelliferone derivatives (esculetin, skimmin, and herniarin) were generated through enzymatic and whole cell catalysis. To improve the efficiencies of biotransformation, different media, incubation time and concentration of substrate were optimized and the production was scaled up using a 3-L fermentor. The maximum yields of esculetin, skimmin, and herniarin were 337.10 μM (67.62%), 995.43 μM (99.54%), and 37.13 μM (37.13%), respectively. The water solubility of esculetin and skimmin were 1.28-folds and 3.98-folds as high as umbelliferone, respectively, whereas herniarin was 1.89-folds less soluble than umbelliferone. Moreover, the antibacterial and anticancer activities of herniarin showed higher than umbelliferone, esculetin and skimmin.

Conclusions: This study proves that both native and engineered enzymes could be employed for the production of precious compounds via whole cell biocatalysis. We successfully produced three molecules herniarin, esculetin and skimmin in practical amounts and their antibacterial and anticancer properties were accessed. One of the newly synthesized molecules the present research suggests that the combinatorial biosynthesis of different biosynthetic enzymes could rapidly promote to a novel secondary metabolite.

Electronic supplementary material: The online version of this article (doi:10.1186/s13036-017-0056-5) contains supplementary material, which is available to authorized users.

No MeSH data available.