- Discovery of Novel Bacterial Chalcone Isomerases by a Sequence-Structure-Function-Evolution Strategy for Enzymatic Synthesis of (S)-Flavanones
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Chalcone isomerase (CHI) is a key enzyme in the biosynthesis of flavonoids in plants. The first bacterial CHI (CHIera) was identified from Eubacterium ramulus, but its distribution, evolutionary source, substrate scope, and stereoselectivity are still unclear. Here, we describe the identification of 66 novel bacterial CHIs from Genbank using a novel Sequence-Structure-Function-Evolution (SSFE) strategy. These novel bacterial CHIs show diversity in substrate specificity towards various hydroxylated and methoxylated chalcones. The mutagenesis of CHIera according to the substrate binding models of these novel bacterial CHIs resulted in several variants with greatly improved activity towards these chalcones. Furthermore, the preparative scale conversion catalyzed by bacterial CHIs has been performed for five chalcones and revealed (S)-selectivity with up to 96 % ee, which provides an alternative biocatalytic route for the synthesis of (S)-flavanones in high yields.
- Bornscheuer, Uwe T.,Brückner, Stephan I.,Gei?ler, Torsten,Gross, Egon,Hartmann, Beate,Ley, Jakob P.,Meinert, Hannes,R?ttger, Carsten,Schuiten, Eva,Yi, Dong,Zirpel, Bastian
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supporting information
p. 16874 - 16879
(2021/07/06)
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- Influence of Substrate Binding Residues on the Substrate Scope and Regioselectivity of a Plant O-Methyltransferase against Flavonoids
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Methylation of free hydroxyl groups is an important modification for flavonoids. It not only greatly increases absorption and oral bioavailability of flavonoids, but also brings new biological activities. Flavonoid methylation is usually achieved by a specific group of plant O-methyltransferases (OMTs) which typically exhibit high substrate specificity. Here we investigated the effect of several residues in the binding pocket of the Clarkia breweri isoeugenol OMT on the substrate scope and regioselectivity against flavonoids. The mutation T133M, identified as reported in our previous publication, increased the activity of the enzyme against several flavonoids, namely eriodictyol, naringenin, luteolin, quercetin and even the isoflavonoid genistein, while a reduced set of amino acids at positions 322 and 326 affected both, the activity and the regioselectivity of the methyltranferase. On the basis of this work, methylated flavonoids that are rare in nature were produced in high purity.
- Tang, Qingyun,Vianney, Yoanes M.,Weisz, Klaus,Grathwol, Christoph W.,Link, Andreas,Bornscheuer, Uwe T.,Pavlidis, Ioannis V.
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p. 3721 - 3727
(2020/06/02)
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- Process for preparing flavonoid derivatives and the intermediate thereof
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The present invention provides: a method for manufacturing a flavonoid derivative using a reaction for synthesizing a chalcone derivative by a protection/deprotection reaction of a hydroxyl group and an aldol condensation reaction; and an intermediate thereof. By the method for manufacturing the flavonoid derivative of the present invention can manufacture the flavonoid derivative such as velutin and homoeriodictyol, the present invention can be usefully used in industrial fields such as cosmetics requiring mass production of flavonoid derivatives.
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- Biological Properties and Absolute Configuration of Flavanones From Calceolaria thyrsiflora Graham
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Flavanones (–)-(2S)-5,4’-dihydroxy-7-methoxyflavanone (1) and (–)-(2S)-5,3’,4’-trihydroxy-7-methoxyflavanone (2) were isolated from the extracts of Calceolaria thyrsiflora Graham, an endemic perennial small shrub growing in the central zone of Chile. The absolute configuration of these compounds was resolved by optical rotation experiments and in silico calculations. Three analogs (3, 4, and 5) were synthesized to do structure-activity relationships with the biological assays studied. Biological tests revealed that only flavanone 2 exhibited a moderate inhibitory activity against the methicillin-resistant strain S. aureus MRSA 97-77 (MIC value of 50 μg/ml). In addition, flavanone 2 showed a potent, selective, and competitive inhibition of 5-hLOX, which supports the traditional use of this plant as an anti-inflammatory in diseases of the respiratory tract. Also, 2 exhibited cytotoxic and selective effects against B16-F10 (8.07 ± 1.61 μM) but 4.6- and 17-fold lesser activity than etoposide and taxol.
- Cabezas, Francisco,Cortez-San Martín, Marcelo,Díaz, Katy,González, César,Joseph-Nathan, Pedro,Mascayano, Carolina,Mejias, Sophia,Montoya, Margarita,Mu?oz, Marcelo A.,Osorio, Mauricio,Taborga, Lautaro,Torrent, Claudia,Vásquez-Martínez, Yesseny,Valdés, Ernesto
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- Characterization of a Flavonoid 3’/5’/7-O-Methyltransferase from Citrus reticulata and Evaluation of the in Vitro Cytotoxicity of Its Methylated Products
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O-methylation of flavonoids is an important modification reaction that occurs in plants. O-methylation contributes to the structural diversity of flavonoids, which have several biological and pharmacological functions. In this study, an O-methyltransferase gene (CrOMT2) was isolated from the fruit peel of Citrus reticulata, which encoding a multifunctional O-methyltransferase and could effectively catalyze the methylation of 3’-, 5’-, and 7-OH of flavonoids with vicinal hydroxyl substitutions. Substrate preference assays indicated that this recombinant enzyme favored polymethoxylated flavones (PMF)-type substrates in vitro, thereby providing biochemical evidence for the potential role of the enzyme in plants. Additionally, the cytotoxicity of the methylated products from the enzymatic catalytic reaction was evaluated in vitro using human gastric cell lines SGC-7901 and BGC-823. The results showed that the in vitro cytotoxicity of the flavonoids with the unsaturated C2-C3 bond was increased after being methylated at position 3’. These combined results provide biochemical insight regarding CrOMT2 in vitro and indicate the in vitro cytotoxicity of the products methylated by its catalytic reaction.
- Liu, Xiaojuan,Wang, Yue,Chen, Yezhi,Xu, Shuting,Gong, Qin,Zhao, Chenning,Cao, Jinping,Sun, Chongde
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- Discovery of lesser known flavones as inhibitors of NF-κB signaling in MDA-MB-231 breast cancer cells - A SAR study
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Seventeen flavonoids with different substitutions were evaluated for inhibition of nuclear factor-κB (NF-κB) signaling in the invasive breast cancer cell line MDA-MB-231. They were screened using an engineered MDA-MB-231 cell line reporting NF-κB activation. The modulation of expression of two NF-κB regulated genes involved in tumorigenesis, matrix metalloproteinase-9 (MMP-9), and cyclooxygenase-2 (COX-2) were also analyzed in these cells. Among the compounds tested, all except gossypetin and quercetagetin inhibited the activation of NF-κB, and the expression of MMP-9 and COX-2 to different degree. Methylated flavone, chrysoeriol (luteolin-3′-methylether), was found to be the most potent inhibitor of MMP-9 and COX-2 expressions. The effect of chrysoeriol on cell proliferation, cell cycle, apoptosis and metastasis was analyzed by established methods. Chrysoeriol caused cell cycle arrest at G2/M and inhibited migration and invasion of MDA-MB-231 cells. The structure-activity relations amongst the flavonoids as NF-κB signaling inhibitors was studied. The study indicates differences between the actions of various flavonoids on NF-κB activation and on the biological activities of breast cancer cells. Flavones in general, were more active than the corresponding flavonols.
- Amrutha,Nanjan, Pandurangan,Shaji, Sanu K.,Sunilkumar, Damu,Subhalakshmi,Rajakrishna, Lakshmi,Banerji, Asoke
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supporting information
p. 4735 - 4742
(2015/01/08)
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- Synthesis and antidiabetic activity of 5,7-dihydroxyflavonoids and analogs
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In a study to evaluate the structural elements essential for the antidiabetic activity of flavonoids, we synthesized two series of flavonoids, 5,7-dihydroxyflavanones and 5,7-dihydroxyflavones. In a screening for potential antidiabetic activity, most of the flavonoids showed a remarkable in vitro activity, and compounds 1f, 2d, and 3c were significantly more effective than the positive control, metformin. The biological activity was mainly affected by structural modification at the ring B moiety of the flavonoid skeleton. The results suggest that 5,7-dihydroxyflavonoids can be considered as promising candidates in the development of new antidiabetic lead compounds. Copyright
- Chang, Liu-Shuan,Li, Chun-Bao,Qin, Nan,Jin, Mei-Na,Duan, Hong-Quan
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scheme or table
p. 162 - 169
(2012/04/04)
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- Synthesis and studies on antidepressant effect of 5,7-Dihydroxyflavanone derivatives
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A series of 5,7-dihydroxyflavanone derivatives were synthesized and evaluated their antidepressant activities. The results showed that of nine compounds significantly reduced times during the forced swimming test at a dose of 10 mg/kg, indicative of antidepressant activity. Among the compounds, 4o (4'-methoxy-5,7,3'-trihydroxyflavanone) was found to be the most potent and it was observed that the compound 4o at dose of 10, 20 and 40 mg/kg significantly reduced the duration of immobility times in the Forced swimming test in mice 0.5 h after treatment.
- Zhao, Dong-Hai,Sui, Xin,Qu, You-Le,Yang, Li-Ye,Wang, Xian,Guan, Li-Ping
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p. 1129 - 1132
(2011/12/16)
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- Flavonoid 3′-O-methyltransferase from rice: cDNA cloning, characterization and functional expression
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Plant O-methyltransferases (OMTs) are known to be involved in methylation of plant secondary metabolites, especially phenylpropanoid and flavonoid compounds. An OMT, ROMT-9, was cloned and characterized from rice using a reverse transcriptase polymerase chain reaction (RT-PCR). The blast results for ROMT-9 showed a 73% identity with caffeic acid OMTs from maize and Triticum aestivum. ROMT-9 was expressed in Escherichia coli and its recombinant protein was purified using affinity chromatography. It was then tested for its ability to transfer the methyl group of S-adenosyl-l-methionine to the flavonoid substrates, eriodictyol, luteolin, quercetin, and taxifolin, all of which have a 3′-hydroxyl functional group. The reaction products were analyzed using TLC, HPLC, HPLC/MS, and NMR spectroscopy. The NMR analysis showed that ROMT-9 transferred the methyl group specifically to the 3′-hydroxyl group of quercetin, resulting in the formation of its methoxy derivative. Furthermore, ROMT-9 converted flavonoids containing the 3′-hydroxy functional group such as eriodictyol, luteolin, quercetin and taxifolin into the corresponding methoxy derivatives, suggesting that ROMT-9 is an OMT with strict specificity for the 3′-hydroxy group of flavonoids.
- Kim, Bong-Gyu,Lee, Youngshim,Hur, Hor-Gil,Lim, Yoongho,Ahn, Joong-Hoon
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p. 387 - 394
(2008/02/04)
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- O-demethylation and sulfation of 7-methoxylated flavanones by Cunninghamella elegans
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Metabolism of 7-O-methylnaringenin (sakuranetin) by Cunninghamella elegans NRRL 1392 yielded naringenin and naringenin-4′-sulfate. C. elegans also converted 5,3′,4′-trihydroxy-7-methoxyflavanone into eriodictyol-4′-sulfate. Furthermore, incubation of 5,4′
- Ibrahim, Abdel-Rahim Sayed,Galal, Ahmed Mohamed,Ahmed, Mohammed Shamim,Mossa, Gabir Salem
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p. 203 - 206
(2007/10/03)
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- Novel synthesis of 4′,5,7-trihydroxy-3′-methoxyflavanone (homoeriodictyol)
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4′,5,7-Trihydroxy-3′-methoxyflavanone (homoeriodictyol) has been isolated from methanol extract of roots of Zanthoxylum budrunga DC. Wall for the first time and same compound has been synthesized by novel route in good yields. The structure has been established on the basis of spectroscopic technique and chemical means. Synthetic compound is found to be exactly identical with the natural sample of homoeriodictyol.
- Shetgiri,Rege
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p. 648 - 650
(2007/10/03)
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