Methylation and subsequent glycosylation of 7,8-dihydroxyflavone

Koirala, Niranjan; Pandey, Ramesh Prasad; Parajuli, Prakash; Jung, Hye Jin; Sohng, Jae Kyung

doi:10.1016/j.jbiotec.2014.05.005

Cited by 56 publications

(40 citation statements)

References 31 publications

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“…reported that POMT7 is a flavonoid SAM‐dependent methyltransferase toward flavonol and flavone such as kaempferol, apigenin, luteolin, and quercetin but had very low relative conversion rates (<5%) for genistein and daidzein calculated in reference with apigenin as 100%. Furthermore, as described by our group in earlier 2014 , SpOMT2884 has recruited daidzein as substrate with conversion rate of 37.0%, which is much lower than the bioconversion rate of SaOMT2 (95.63%, results obtained from this study). As all these data suggest that SaOMT2 is the best candidate for the bioconversion of isoflavonoids with higher bioconversion rates compared to other O ‐methyltransferases, we selected SaOMT2 for the production of isoflavonoid‐4′‐ O ‐methoxides.…”

Section: Resultsmentioning

confidence: 39%

“…It was found that methylation of the free hydroxyl groups in the flavonoids dramatically increases their metabolic stability and enhances the membrane transport, leading to facilitated absorption and greatly increased oral bioavailability . In our recent preliminary study, we found out that 7‐hydroxy‐8‐methoxyflavone, unlike its unmethylated form 7,8‐dihydroxyflavone, did not affect the endothelial cell viability at the concentration point with antioxidant activity even at long‐term treatment . In support of this, the methylated form of quercetin and rhamnetin has been proved to have an enhanced bioavailability compared with quercetin and induces apoptosis in MDA‐MB‐231 human breast cancer cells more than quercetin , suggesting that methylated forms have higher metabolic stability, oral bioavailability, and biological activity than those of the unmethylated forms.…”

Section: Introductionmentioning

confidence: 65%

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Metabolic engineering of Escherichia coli for the production of isoflavonoid‐4′‐O‐methoxides and their biological activities

Koirala

Pandey

Thuần

et al. 2017

Biotech and App Biochem

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Isoflavonoid representatives such as genistein, daidzein are high potent anti-cancer, anti-bacterial, anti-oxidant agents. It have been demonstrated that methylation of flavonoids enhanced the transporting ability, which lead to facilitated absorption and greatly increased bioavailability. In this paper, genetically engineered Escherichia coli was reconstructed by harboring E. coli K12-derived metK encoding S-adenosylmethionine (SAM) synthase (accession number: K02129) for enhancement of SAM as precursor and a Streptomyces avermitilis-originated SaOMT2 (O-methyltransferase, accession number: NP_823558) for methylation of daidzein and genistein as preferred substrates. The formation of desired products via biotransformation including 7-O-methyl-genistein and 7-O-methyl-daidzein were confirmed individually by chromatographical data such as HPLC, LC-TOF-MS and NMR ( H and C) as well. Furthermore, substrates concentration, incubation time and media parameters were optimized using flask culture. Finally, the most fit conditions were applied for fed-batch fermentation with scale up to 3 L (working volume) to obtain the maximum yield of the products including 164.25 μM (46.81 mg/L) and 382.50 μM (102.88 mg/L) for 7-O-methyl genistein and 7-O-methyl daidzein, respectively. In particular, potent inhibitory activities of those isoflavonoid methoxides against the growth of cancer line (B16F10, AGS and HepG2) and endothelical (HUVEC) cells were investigated and demonstrated. Taken together this research work described the production of isoflavonoid-7-O-methoxides by E. coli engineering, improvement of production, characterization of produced compounds and preliminary in vitro biological activities of the these flavonoids being manufactured. This article is protected by copyright. All rights reserved.

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Section: Resultsmentioning

confidence: 39%

Section: Introductionmentioning

confidence: 65%

Metabolic engineering of Escherichia coli for the production of isoflavonoid‐4′‐O‐methoxides and their biological activities

Koirala

Pandey

Thuần

et al. 2017

Biotech and App Biochem

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“…Two recent in vivo biotransformations coupling O-glycosylation to ortho O-methylation present notable exceptions. 26,27 However, there is a lack of comparable studies involving C-methylations, which are perceived as chemically more challenging. 9,28,29 The applied model substrate 4,5,7-trihydroxy-3-phenyl-coumarin (1) possesses a representative hydroxy-coumarin scaffold which resembles structurally the backbones of aminocoumarin antibiotics and matteuorienates (Chart 1).…”

Section: Introductionmentioning

confidence: 99%

An ortho C-methylation/O-glycosylation motif on a hydroxy-coumarin scaffold, selectively installed by biocatalysis

et al. 2017

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Various bioactive natural products, like the aminocoumarin antibiotics novobiocin and coumermycin, exhibit an aromatic C-methyl group adjacent to a glycosylated phenolic hydroxyl group. Therefore, tailoring of basic phenolic scaffolds to contain the intricate C-methyl/O-glycosyl motif is of high interest for structural and functional diversification of natural products. We demonstrate site-selective 8-C-methylation and 7-O-β-D-glucosylation of 4,5,7-trihydroxy-3-phenyl-coumarin (1) by S-adenosyl-L-methionine dependent C-methyltransferase (from Streptomyces niveus) and uridine 5'-diphosphate glucose dependent glycosyltransferase from apple (Malus × domestica). Both enzymes were characterized and shown to react readily with underivatized 1. However, glucosylation of the ortho-hydroxyl group prevented C-methylation, probably by precluding an essential substrate activation through deprotonation of 7-OH. Therefore, dual modification was only feasible when C-methylation occurred strictly before O-glucosylation. The target product was synthesized in near quantitative yield (98% conversion) from 500 µM 1 and its structure was confirmed by NMR. Combination of C-methyltransferase and O-glycosyltransferase reactions for synthetic tailoring of a natural product through biocatalysis was demonstrated for the first time.

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“…However, only few of the chemically synthesized molecules have shown potent biological activities . We also produced four different derivatives of 7,8‐DHF by in vivo biotransformation using engineered Escherichia coli harboring methyltransferase and enzymatic modifications using glycosyltransferase …”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of novel 7,8‐dihydroxyflavone glycoside derivatives and in silico study of their effects on BACE1 inhibition

Pandey

Parajuli

Pokhrel

et al. 2017

Biotech and App Biochem

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7,8-Dihydroxyflavone (7,8-DHF) has been conjugated with glucose moiety to produce glucoside derivatives. Three analogues of 7,8-DHF (7-O-β-d-glucosyl-8-hydroxyflavone, 7-hydroxy-8-O-β-d-glucosyl flavone, and 7,8-di-O-β-d-glucosylflavone) have been successfully produced from in vitro reaction using glycosyltransferase of Bacillus licheniformis. Production of these 7,8-DHF derivatives were shifted to cheaper and easier approach in this study by using engineered Escherichia coli BL21 (DE3) ΔpgiΔzwfΔushA cells in which the flow of glucose-6-phospahte toward glycolysis and pentose phosphate pathway and hydrolysis of UDP-α-d-glucose were blocked while directing the carbon flux toward UDP-α-d-glucose by overexpressing UDP-α-d-glucose pathway genes. Supplementation of 300 μM of 7,8-DHF to the culture resulted in production of 171 μM of 7-O-β-d-glucosyl-8-hydroxyflavone, 68 μM of 7-hydroxy-8-O-β-d-glucoxyflavone, and 55 μM of 7,8-di-O-β-d-glucoxyflavone in laboratory-scale 3-L fermentor, representing 98% bioconversion of initially fed substrate to respective glucoside derivatives within 48 H. These products were characterized by high-performance liquid chromatography-photodiode array (HPLC-PDA), HPLC-PDA-quadruple time of flight-electron spray ionization mass spectrometry, and nuclear magnetic resonance analyses. These newly synthesized derivatives were found to be able to interact with amino acids of active site of human β-site amyloid precursor protein cleaving β-site amyloid precursor protein cleaving enzyme 1 (BACE1) β-secretase enzyme in in silico studies, thus displaying possible application in cure of Alzheimer's disease.

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Methylation and subsequent glycosylation of 7,8-dihydroxyflavone

Cited by 56 publications

References 31 publications

Metabolic engineering of Escherichia coli for the production of isoflavonoid‐4′‐O‐methoxides and their biological activities

Metabolic engineering of Escherichia coli for the production of isoflavonoid‐4′‐O‐methoxides and their biological activities

An ortho C-methylation/O-glycosylation motif on a hydroxy-coumarin scaffold, selectively installed by biocatalysis

Biosynthesis of novel 7,8‐dihydroxyflavone glycoside derivatives and in silico study of their effects on BACE1 inhibition

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