Natural flavonoids, especially in their glycosylated forms, are the most abundant phenolic compounds found in plants, fruit, and vegetables. They exhibit a large variety of beneficial physiological effects, which makes them generally interesting in a broad spectrum of scientific areas. In this review, we focus on recent advances in the modifications of the glycosidic parts of various flavonoids employing glycosidases, covering both selective trimming of the sugar moieties and glycosylation of flavonoid aglycones by natural and mutant glycosidases. Glycosylation of flavonoids strongly enhances their water solubility and thus increases their bioavailability. Antioxidant and most biological activities are usually less pronounced in glycosides, but some specific bioactivities are enhanced. The presence of l-rhamnose (6-deoxy-α-l-mannopyranose) in rhamnosides, rutinosides (rutin, hesperidin) and neohesperidosides (naringin) plays an important role in properties of flavonoid glycosides, which can be considered as "pro-drugs". The natural hydrolytic activity of glycosidases is widely employed in biotechnological deglycosylation processes producing respective aglycones or partially deglycosylated flavonoids. Moreover, deglycosylation is quite commonly used in the food industry aiming at the improvement of sensoric properties of beverages such as debittering of citrus juices or enhancement of wine aromas. Therefore, natural and mutant glycosidases are excellent tools for modifications of flavonoid glycosides.

Laboratory of Biotransformation Institute of Microbiology Czech Academy of Sciences Vídeňská 1083 CZ 14220 Prague 4 Czech Republic

Zobrazit více v PubMed

Xiao J. Dietary flavonoid aglycones and their glycosides: Which show better biological significance? Crit. Rev. Food Sci. Nutr. 2017;57:1874–1905. doi: 10.1080/10408398.2015.1032400. PubMed DOI

Quideau S., Deffieux D., Douat-Casassus C., Pouységu L. Plant polyphenols: Chemical properties, biological activities, and synthesis. Angew. Chem. Int. Edit. 2011;50:586–621. doi: 10.1002/anie.201000044. PubMed DOI

Rothwell J.A., Knaze V., Zamora-Ros R. Polyphenols: Dietary assessment and role in the prevention of cancers. Curr. Opin. Clin. Nutr. Metab. Care. 2017;20:512–521. doi: 10.1097/MCO.0000000000000424. PubMed DOI

Kim D.H., Jung H.A., Sohn H.S., Kim J.W., Choi J.S. Potential of icariin metabolites from Epimedium koreanum Nakai as antidiabetic therapeutic agents. Molecules. 2017;22 doi: 10.3390/molecules22060986. PubMed DOI PMC

Biler M., Biedermann D., Valentová K., Křen V., Kubala M. Quercetin and its analogues: Optical and acido-basic properties. Phys. Chem. Chem. Phys. 2017;19:26870–26879. doi: 10.1039/C7CP03845C. PubMed DOI

Xiao J., Muzashvili T.S., Georgiev M.I. Advances in the biotechnological glycosylation of valuable flavonoids. Biotechnol. Adv. 2014;32:1145–1156. doi: 10.1016/j.biotechadv.2014.04.006. PubMed DOI

Plaza M., Pozzo T., Liu J., Gulshan Ara K.Z., Turner C., Nordberg Karlsson E. Substituent effects on in vitro antioxidizing properties, stability, and solubility in flavonoids. J. Agric. Food Chem. 2014;62:3321–3333. doi: 10.1021/jf405570u. PubMed DOI

Xu L., Qi T., Xu L., Lu L., Xiao M. Recent progress in the enzymatic glycosylation of phenolic compounds. J. Carbohyd. Chem. 2016;35:1–23. doi: 10.1080/07328303.2015.1137580. DOI

Lairson L.L., Henrissat B., Davies G.J., Withers S.G. Glycosyltransferases: Structures, functions, and mechanisms. Annu. Rev. Biochem. 2008;77:521–555. doi: 10.1146/annurev.biochem.76.061005.092322. PubMed DOI

Dai L., Li J., Yao P., Zhu Y., Men Y., Zeng Y., Yang J., Sun Y. Exploiting the aglycon promiscuity of glycosyltransferase Bs-YjiC from Bacillus subtilis and its application in synthesis of glycosides. J. Biotechnol. 2017;248:69–76. doi: 10.1016/j.jbiotec.2017.03.009. PubMed DOI

Gantt R.W., Goff R.D., Williams G.J., Thorson J.S. Probing the aglycon promiscuity of an engineered glycosyltransferase. Angew. Chem. Int. Ed. 2008;47:8889–8892. doi: 10.1002/anie.200803508. PubMed DOI PMC

Bojarová P., Rosencrantz R.R., Elling L., Křen V. Enzymatic glycosylation of multivalent scaffolds. Chem. Soc. Rev. 2013;42:4774–4797. doi: 10.1039/c2cs35395d. PubMed DOI

Pei J., Chen A., Zhao L., Cao F., Ding G., Xiao W. One-pot synthesis of hyperoside by a three-enzyme cascade using a UDP-galactose regeneration system. J. Agric. Food Chem. 2017;65:6042–6048. doi: 10.1021/acs.jafc.7b02320. PubMed DOI

Kim H.J., Kim B.G., Ahn J.H. Regioselective synthesis of flavonoid bisglycosides using Escherichia coli harboring two glycosyltransferases. Appl. Microbiol. Biotechnol. 2013;97:5275–5282. doi: 10.1007/s00253-013-4844-7. PubMed DOI

Pandey R.P., Malla S., Simkhada D., Kim B.G., Sohng J.K. Production of 3-O-xylosyl quercetin in Escherichia coli. Appl. Microbiol. Biotechnol. 2013;97:1889–1901. doi: 10.1007/s00253-012-4438-9. PubMed DOI

Slámová K., Bojarová P. Engineered N-acetylhexosamine-active enzymes in glycoscience. Biochim. Biophys. Acta. 2017;1861:2070–2087. doi: 10.1016/j.bbagen.2017.03.019. PubMed DOI

De Winter K., Dewitte G., Dirks-Hofmeister M.E., De Laet S., Pelantova H., Kren V., Desmet T. Enzymatic glycosylation of phenolic antioxidants: Phosphorylase-mediated synthesis and characterization. J. Agric. Food Chem. 2015;63:10131–10139. doi: 10.1021/acs.jafc.5b04380. PubMed DOI

Mazzaferro L.S., Pinuel L., Erra-Balsells R., Giudicessi S.L., Breccia J.D. Transglycosylation specificity of Acremonium sp. α-rhamnosyl-β-glucosidase and its application to the synthesis of the new fluorogenic substrate 4-methylumbelliferyl-rutinoside. Carbohydr. Res. 2012;347:69–75. doi: 10.1016/j.carres.2011.11.008. PubMed DOI

Šimčíková D., Kotik M., Weignerová L., Halada P., Pelantová H., Adamcová K., Křen V. α-l-Rhamnosyl-β-d-glucosidase (rutinosidase) from Aspergillus niger: Characterization and synthetic potential of a novel diglycosidase. Adv. Synth. Catal. 2015;357:107–117. doi: 10.1002/adsc.201400566. DOI

Bojarová P., Křen V. Glycosidases in carbohydrate synthesis: When organic chemistry falls short. Chimia (Aarau) 2011;65:65–70. doi: 10.2533/chimia.2011.65. PubMed DOI

Yadav V., Yadav P.K., Yadav S., Yadav K.D.S. α-l-Rhamnosidase: A review. Process Biochem. 2010;45:1226–1235. doi: 10.1016/j.procbio.2010.05.025. DOI

Weignerová L., Marhol P., Gerstorferová D., Křen V. Preparatory production of quercetin-3-β-d-glucopyranoside using alkali-tolerant thermostable α-l-rhamnosidase from Aspergillus terreus. Bioresour. Technol. 2012;115:222–227. doi: 10.1016/j.biortech.2011.08.029. PubMed DOI

Vila-Real H., Alfaia A.J., Bronze M.R., Calado A.R., Ribeiro M.H. Enzymatic synthesis of the flavone glucosides, prunin and isoquercetin, and the aglycones, naringenin and quercetin, with selective α-l-rhamnosidase and β-d-glucosidase activities of naringinase. Enzyme Res. 2011;2011:692618. doi: 10.4061/2011/692618. PubMed DOI PMC

Ribeiro M.H. Naringinases: Occurrence, characteristics, and applications. Appl. Microbiol. Biotechnol. 2011;90:1883–1895. doi: 10.1007/s00253-011-3176-8. PubMed DOI

Křen V., Valentová K. Isoquercetin enzymatic production: A true story: Response to the paper “Zhua et al. [1]”. Mol. Catal. 2018 doi: 10.1016/j.mcat.2018.04.033. DOI

Lombard V., Golaconda Ramulu H., Drula E., Coutinho P.M., Henrissat B. The carbohydrate-active enzymes database (CAZy) in 2013. Nucleic Acids Res. 2014;42:D490–D495. doi: 10.1093/nar/gkt1178. PubMed DOI PMC

Koshland D.E. Stereochemistry and the mechanism of enzymatic reactions. Biol. Rev. 1953;28:416–436. doi: 10.1111/j.1469-185X.1953.tb01386.x. DOI

Vocadlo D.J., Davies G.J. Mechanistic insights into glycosidase chemistry. Curr. Opin. Chem. Biol. 2008;12:539–555. doi: 10.1016/j.cbpa.2008.05.010. PubMed DOI

Bojarová-Fialová P., Křen V. Comprehensive Glycoscience. Elsevier; Oxford, UK: 2007. Enzymatic approaches to O-glycoside introduction: Glycosidases A2-Kamerling, Hans; pp. 453–487.

Fialová P., Weignerová L., Rauvolfová J., Přikrylová V., Pišvejcová A., Ettrich R., Kuzma M., Sedmera P., Křen V.R. Hydrolytic and transglycosylation reactions of N-acyl modified substrates catalysed by β-N-acetylhexosaminidases. Tetrahedron. 2004;60:693–701. doi: 10.1016/j.tet.2003.10.111. DOI

Armstrong Z., Withers S.G. Synthesis of glycans and glycopolymers through engineered enzymes. Biopolymers. 2013;99:666–674. doi: 10.1002/bip.22335. PubMed DOI

Mackenzie L.F., Wang Q., Warren R.A.J., Withers S.G. Glycosynthases:  Mutant glycosidases for oligosaccharide synthesis. J. Am. Chem. Soc. 1998;120:5583–5584. doi: 10.1021/ja980833d. DOI

Malet C., Planas A. From β-glucanase to β-glucansynthase: Glycosyl transfer to α-glycosyl fluorides catalyzed by a mutant endoglucanase lacking its catalytic nucleophile. FEBS Lett. 1998;440:208–212. doi: 10.1016/S0014-5793(98)01448-3. PubMed DOI

Williams S.J., Withers S.G. Glycosyl fluorides in enzymatic reactions. Carbohyd. Res. 2000;327:27–46. doi: 10.1016/S0008-6215(00)00041-0. PubMed DOI

Slámová K., Krejzová J., Marhol P., Kalachova L., Kulik N., Pelantová H., Cvačka J., Křen V. Synthesis of derivatized chitooligomers using transglycosidases engineered from the fungal GH20 β-N-acetylhexosaminidase. Adv. Synth. Catal. 2015;357:1941–1950. doi: 10.1002/adsc.201500075. DOI

Bojarová P., Křenek K., Kuzma M., Petrásková L., Bezouška K., Namdjou D.-J., Elling L., Křen V. N-Acetylhexosamine triad in one molecule: Chemoenzymatic introduction of 2-acetamido-2-deoxy-β-d-galactopyranosyluronic acid residue into a complex oligosaccharide. J. Mol. Catal. B-Enzym. 2008;50:69–73. doi: 10.1016/j.molcatb.2007.09.002. DOI

Bojarová P., Slámová K., Křenek K., Gažák R., Kulik N., Ettrich R., Pelantová H., Kuzma M., Riva S., Adámek D., et al. Charged hexosaminides as new substrates for β-N-acetylhexosaminidase-catalyzed synthesis of immunomodulatory disaccharides. Adv. Synth. Catal. 2011;353:2409–2420. doi: 10.1002/adsc.201100371. DOI

Slámová K., Gažák R., Bojarová P., Kulik N., Ettrich R., Pelantová H., Sedmera P., Křen V. 4-Deoxy-substrates for β-N-acetylhexosaminidases: How to make use of their loose specificity. Glycobiology. 2010;20:1002–1009. doi: 10.1093/glycob/cwq058. PubMed DOI

Nakai H., Kitaoka M., Svensson B., Ohtsubo K. Recent development of phosphorylases possessing large potential for oligosaccharide synthesis. Curr. Opin. Chem. Biol. 2013;17:301–309. doi: 10.1016/j.cbpa.2013.01.006. PubMed DOI

Valentová K., Vrba J., Bancířová M., Ulrichová J., Křen V. Isoquercitrin: Pharmacology, toxicology, and metabolism. Food Chem. Toxicol. 2014;68:267–282. doi: 10.1016/j.fct.2014.03.018. PubMed DOI

Shimizu R., Shimabayashi H., Moriwaki M. Enzymatic production of highly soluble myricitrin glycosides using β-galactosidase. Biosci. Biotechnol. Biochem. 2006;70:940–948. doi: 10.1271/bbb.70.940. PubMed DOI

Li D., Park S.-H., Shim J.-H., Lee H.-S., Tang S.-Y., Park C.-S., Park K.-H. In vitro enzymatic modification of puerarin to puerarin glycosides by maltogenic amylase. Carbohyd. Res. 2004;339:2789–2797. doi: 10.1016/j.carres.2004.09.017. PubMed DOI

Makino T., Shimizu R., Kanemaru M., Suzuki Y., Moriwaki M., Mizukami H. Enzymatically modified isoquercitrin, α-oligoglucosyl quercetin 3-O-glucoside, is absorbed more easily than other quercetin glycosides or aglycone after oral administration in rats. Biol. Pharm. Bull. 2009;32:2034–2040. doi: 10.1248/bpb.32.2034. PubMed DOI

Lee Y.-S., Huh J.-Y., Nam S.-H., Moon S.-K., Lee S.-B. Enzymatic bioconversion of citrus hesperidin by Aspergillus sojae naringinase: Enhanced solubility of hesperetin-7-O-glucoside with in vitro inhibition of human intestinal maltase, HMG-CoA reductase, and growth of Helicobacter pylori. Food Chem. 2012;135:2253–2259. doi: 10.1016/j.foodchem.2012.07.007. PubMed DOI

Chebil L., Bouroukba M., Gaiani C., Charbonel C., Khaldi M., Engasser J.M., Ghoul M. Elucidation of the kinetic behavior of quercetin, isoquercitrin, and rutin solubility by physicochemical and thermodynamic investigations. Ind. Eng. Chem. Res. 2013;52:1464–1470. doi: 10.1021/ie3029202. DOI

Chebil L., Humeau C., Anthoni J., Dehez F., Engasser J.M., Ghoul M. Solubility of flavonoids in organic solvents. J. Chem. Eng. Data. 2007;52:1552–1556. doi: 10.1021/je7001094. DOI

Rothwell J.A., Day A.J., Morgan M.R.A. Experimental determination of octanol−water partition coefficients of quercetin and related flavonoids. J Agr. Food Chem. 2005;53:4355–4360. doi: 10.1021/jf0483669. PubMed DOI

Murota K., Matsuda N., Kashino Y., Fujikura Y., Nakamura T., Kato Y., Shimizu R., Okuyama S., Tanaka H., Koda T., et al. α-Oligoglucosylation of a sugar moiety enhances the bioavailability of quercetin glucosides in humans. Arch. Biochem. Biophys. 2010;501:91–97. doi: 10.1016/j.abb.2010.06.036. PubMed DOI

Murota K., Shimizu S., Chujo H., Moon J.-H., Terao J. Efficiency of absorption and metabolic conversion of quercetin and its glucosides in human intestinal cell line Caco-2. Arch. Biochem. Biophys. 2000;384:391–397. doi: 10.1006/abbi.2000.2123. PubMed DOI

Russo M., Spagnuolo C., Tedesco I., Bilotto S., Russo G.L. The flavonoid quercetin in disease prevention and therapy: Facts and fancies. Biochem. Pharmacol. 2012;83:6–15. doi: 10.1016/j.bcp.2011.08.010. PubMed DOI

Bang S.H., Hyun Y.J., Shim J., Hong S.W., Kim D.H. Metabolism of rutin and poncirin by human intestinal microbiota and cloning of their metabolizing α-l-rhamnosidase from Bifidobacterium dentium. J. Microbiol. Biotechnol. 2015;25:18–25. doi: 10.4014/jmb.1404.04060. PubMed DOI

Amaretti A., Raimondi S., Leonardi A., Quartieri A., Rossi M. Hydrolysis of the rutinose-conjugates flavonoids rutin and hesperidin by the gut microbiota and bifidobacteria. Nutrients. 2015;7:2788. doi: 10.3390/nu7042788. PubMed DOI PMC

Almeida A.F., Borge G.I.A., Piskula M., Tudose A., Tudoreanu L., Valentová K., Williamson G., Santos C.N. Bioavailability of quercetin in humans with a focus on interindividual variation. Comp. Rev. Food Sci. Food Saf. 2018;17:714–731. doi: 10.1111/1541-4337.12342. PubMed DOI

Morand C., Manach C., Crespy V., Remesy C. Quercetin 3-O-β-glucoside is better absorbed than other quercetin forms and is not present in rat plasma. Free Radic. Res. 2000;33:667–676. doi: 10.1080/10715760000301181. PubMed DOI

Cermak R., Landgraf S., Wolffram S. The bioavailability of quercetin in pigs depends on the glycoside moiety and on dietary factors. J. Nutr. 2003;133:2802–2807. doi: 10.1093/jn/133.9.2802. PubMed DOI

Olthof M.R., Hollman P.C.H., Vree T.B., Katan M.B. Bioavailabilities of quercetin-3-glucoside and quercetin-4'-glucoside do not differ in humans. J. Nutr. 2000;130:1200–1203. doi: 10.1093/jn/130.5.1200. PubMed DOI

He J., Feng Y., Ouyang H., Yu B., Chang Y., Pan G., Dong G., Wang T., Gao X. A sensitive LC-MS/MS method for simultaneous determination of six flavonoids in rat plasma: Application to a pharmacokinetic study of total flavonoids from mulberry leaves. J. Pharm. Biomed. Anal. 2013;84:189–195. doi: 10.1016/j.jpba.2013.06.019. PubMed DOI

Li J., Wang Z.W., Zhang L., Liu X., Chen X.H., Bi K.S. HPLC analysis and pharmacokinetic study of quercitrin and isoquercitrin in rat plasma after administration of Hypericum japonicum Thunb. extract. Biomed. Chromatogr. 2008;22:374–378. doi: 10.1002/bmc.942. PubMed DOI

Zhou C., Liu Y., Su D., Gao G., Zhou X., Sun L., Ba X., Chen X., Bi K. A sensitive LC-MS-MS method for simultaneous quantification of two structural isomers, hyperoside and isoquercitrin: Application to pharmacokinetic studies. Chromatographia. 2011;73:353–359. doi: 10.1007/s10337-010-1879-0. DOI

Li Z., Meng F., Zhang Y., Sun L., Yu L., Zhang Z., Peng S., Guo J. Simultaneous quantification of hyperin, reynoutrin and guaijaverin in mice plasma by LC-MS/MS: Application to a pharmacokinetic study. Biomed. Chromatogr. 2016;30:1124–1130. doi: 10.1002/bmc.3660. PubMed DOI

Wolffram S., Blöck M., Ader P. Quercetin-3-glucoside is transported by the glucose carrier SGLT1 across the brush border membrane of rat small intestine. J. Nutr. 2002;132:630–635. doi: 10.1093/jn/132.4.630. PubMed DOI

Kottra G., Daniel H. Flavonoid glycosides are not transported by the human Na+/glucose transporter when expressed in Xenopus laevis oocytes, but effectively inhibit electrogenic glucose uptake. J. Pharm. Exp. Ther. 2007;322:829–835. doi: 10.1124/jpet.107.124040. PubMed DOI

Bellocco E., Barreca D., Lagana G., Leuzzi U., Tellone E., Ficarra S., Kotyk A., Galtieri A. Influence of L-rhamnosyl-d-glucosyl derivatives on properties and biological interaction of flavonoids. Mol. Cell. Biochem. 2009;321:165–171. doi: 10.1007/s11010-008-9930-2. PubMed DOI

Kumar S., Pandey A.K. Chemistry and biological activities of flavonoids: An overview. Sci. World J. 2013;2013:16. doi: 10.1155/2013/162750. PubMed DOI PMC

Heim K.E., Tagliaferro A.R., Bobilya D.J. Flavonoid antioxidants: Chemistry, metabolism and structure-activity relationships. J. Nutr. Biochem. 2002;13:572–584. doi: 10.1016/S0955-2863(02)00208-5. PubMed DOI

Trouillas P., Marsal P., Siri D., Lazzaroni R., Duroux J.L. A DFT study of the reactivity of OH groups in quercetin and taxifolin antioxidants: The specificity of the 3-OH site. Food Chem. 2006;97:679–688. doi: 10.1016/j.foodchem.2005.05.042. DOI

de Araujo M.E., Moreira Franco Y.E., Alberto T.G., Sobreiro M.A., Conrado M.A., Priolli D.G., Frankland Sawaya A.C., Ruiz A.L., de Carvalho J.E., de Oliveira Carvalho P. Enzymatic de-glycosylation of rutin improves its antioxidant and antiproliferative activities. Food Chem. 2013;141:266–273. doi: 10.1016/j.foodchem.2013.02.127. PubMed DOI

Bharti S., Rani N., Krishnamurthy B., Arya D.S. Preclinical evidence for the pharmacological actions of naringin: a review. Planta Med. 2014;80:437–451. doi: 10.1055/s-0034-1368351. PubMed DOI

Li C., Schluesener H. Health-promoting effects of the citrus flavanone hesperidin. Crit. Rev. Food Sci. Nutr. 2017;57:613–631. doi: 10.1080/10408398.2014.906382. PubMed DOI

Sharma S., Ali A., Ali J., Sahni J.K., Baboota S. Rutin: Therapeutic potential and recent advances in drug delivery. Expert. Opin. Investig. Drugs. 2013;22:1063–1079. doi: 10.1517/13543784.2013.805744. PubMed DOI

Houlmont J.P., Vercruysse K., Perez E., Rico-Lattes I., Bordat P., Treilhou M. Cosmetic use formulations containing pentyl rhamnoside and cetyl rhamnoside. Int. J. Cosmet. Sci. 2001;23:363–368. doi: 10.1046/j.0412-5463.2001.00111.x. PubMed DOI

Li L., Yu Y., Zhang X., Jiang Z., Zhu Y., Xiao A., Ni H., Chen F. Expression and biochemical characterization of recombinant α-l-rhamnosidase r-Rha1 from Aspergillus niger JMU-TS528. Int. J. Biol. Macromol. 2016;85:391–399. doi: 10.1016/j.ijbiomac.2015.12.093. PubMed DOI

Monti D., Pišvejcová A., Křen V., Lama M., Riva S. Generation of an α-l-rhamnosidase library and its application for the selective derhamnosylation of natural products. Biotechnol. Bioeng. 2004;87:763–771. doi: 10.1002/bit.20187. PubMed DOI

Chang H.-Y., Lee Y.-B., Bae H.-A., Huh J.-Y., Nam S.-H., Sohn H.-S., Lee H.J., Lee S.-B. Purification and characterisation of Aspergillus sojae naringinase: The production of prunin exhibiting markedly enhanced solubility with in vitro inhibition of HMG-CoA reductase. Food Chem. 2011;124:234–241. doi: 10.1016/j.foodchem.2010.06.024. DOI

Yadav S., Yadava S., Yadav K.D. α-l-Rhamnosidase selective for rutin to isoquercitrin transformation from Penicillium griseoroseum MTCC-9224. Bioorg. Chem. 2017;70:222–228. doi: 10.1016/j.bioorg.2017.01.002. PubMed DOI

Alvarenga A.E., Romero C.M., Castro G.R. A novel α-l-rhamnosidase with potential applications in citrus juice industry and in winemaking. Eur. Food Res. Technol. 2013;237:977–985. doi: 10.1007/s00217-013-2074-y. DOI

De Lise F., Mensitieri F., Tarallo V., Ventimiglia N., Vinciguerra R., Tramice A., Marchetti R., Pizzo E., Notomista E., Cafaro V., et al. RHA-P: Isolation, expression and characterization of a bacterial α-l-rhamnosidase from Novosphingobium sp PP1Y. J. Mol. Catal. B-Enzym. 2016;134:136–147. doi: 10.1016/j.molcatb.2016.10.002. DOI

Izzo V., Tedesco P., Notomista E., Pagnotta E., di Donato A., Trincone A., Tramice A. α-Rhamnosidase activity in the marine isolate Novosphingobium sp PP1Y and its use in the bioconversion of flavonoids. J. Mol. Catal. B-Enzym. 2014;105:95–103. doi: 10.1016/j.molcatb.2014.04.002. DOI

Puri M., Kaur A., Singh R.S., Schwarz W.H., Kaur A. One-step purification and immobilization of His-tagged rhamnosidase for naringin hydrolysis. Process Biochem. 2010;45:451–456. doi: 10.1016/j.procbio.2009.11.001. DOI

Trincone A. Uncommon glycosidases for the enzymatic preparation of glycosides. Biomolecules. 2015;5:2160–2183. doi: 10.3390/biom5042160. PubMed DOI PMC

Zhu Y., Jia H., Xi M., Xu L., Wu S., Li X. Purification and characterization of a naringinase from a newly isolated strain of Bacillus amyloliquefaciens 11568 suitable for the transformation of flavonoids. Food Chem. 2017;214:39–46. doi: 10.1016/j.foodchem.2016.06.108. PubMed DOI

Ishikawa M., Shiono Y., Koseki T. Biochemical characterization of Aspergillus oryzae recombinant α-l-rhamnosidase expressed in Pichia pastoris. J. Biosci. Bioeng. 2017;124:630–634. doi: 10.1016/j.jbiosc.2017.07.007. PubMed DOI

Liu T., Yu H., Zhang C., Lu M., Piao Y., Ohba M., Tang M., Yuan X., Wei S., Wang K., et al. Aspergillus niger DLFCC-90 rhamnoside hydrolase, a new type of flavonoid glycoside hydrolase. Appl. Environ. Microbiol. 2012;78:4752–4754. doi: 10.1128/aem.00054-12. PubMed DOI PMC

Markošová K., Weignerová L., Rosenberg M., Křen V., Rebroš M. Upscale of recombinant α-l-rhamnosidase production by Pichia pastoris MutS strain. Front. Microbiol. 2015;6 doi: 10.3389/fmicb.2015.01140. PubMed DOI PMC

Céliz G., Rodriguez J., Soria F., Daz M. Synthesis of hesperetin 7-O-glucoside from flavonoids extracted from Citrus waste using both free and immobilized α-l-rhamnosidases. Biocatal. Agric. Biotechnol. 2015;4:335–341. doi: 10.1016/j.bcab.2015.06.005. DOI

Rebroš M., Pilniková A., Šimčíková D., Weignerová L., Stloukal R., Křen V., Rosenberg M. Recombinant α-l-rhamnosidase of Aspergillus terreus immobilization in polyvinylalcohol hydrogel and its application in rutin derhamnosylation. Biocatal. Biotransform. 2013;31:329–334. doi: 10.3109/10242422.2013.858711. DOI

Guan C.J., Ji Y.J., Hu J.L., Hu C.N., Yang F., Yang G.E. Biotransformation of rutin using crude enzyme from Rhodopseudomonas palustris. Curr. Microbiol. 2017;74:431–436. doi: 10.1007/s00284-017-1204-3. PubMed DOI

Liu Q., Lu L.L., Xiao M. Cell surface engineering of α-l-rhamnosidase for naringin hydrolysis. Bioresour. Technol. 2012;123:144–149. doi: 10.1016/j.biortech.2012.05.083. PubMed DOI

Yadav S., Kumar D., Yadava S., Yadav K. De-rhamnosylation of hesperidin to hesperitin-7-O-glucoside by alkali tolerant α-l-rhamnosidase from Fusarium poae MTCC-2086. Int. J. Curr. Microbiol. App. Sci. 2018;7:1952–1968. doi: 10.20546/ijcmas.2018.703.231. DOI

Xia Q., Xu D., Huang Z., Liu J., Wang X., Wang X., Liu S. Preparation of icariside II from icariin by enzymatic hydrolysis method. Fitoterapia. 2010;81:437–442. doi: 10.1016/j.fitote.2009.12.006. PubMed DOI

Wang J., Ma Y.-L., Wu X.-Y., Yu L., Xia R., Sun G.-X., Wu F.-A. Selective hydrolysis by commercially available hesperidinase for isoquercitrin production. J. Mol. Catal. B-Enzym. 2012;81:37–42. doi: 10.1016/j.molcatb.2012.05.005. DOI

Zhu D., Gong A., Xu Y., Kinfack Tsabing D.a., Wu F., Wang J. Isoquercitrin production from rutin catalyzed by naringinase under ultrasound irradiation. J. Mol. Catal. B-Enzym. 2016;134:186–195. doi: 10.1016/j.molcatb.2016.11.011. DOI

Kim D.Y., Yeom S.J., Park C.S., Kim Y.S. Effect of high hydrostatic pressure treatment on isoquercetin production from rutin by commercial α-l-rhamnosidase. Biotechnol. Lett. 2016;38:1775–1780. doi: 10.1007/s10529-016-2157-5. PubMed DOI

Vila-Real H., Alfaia A.J., Calado A.R., Ribeiro M.H.L. Improvement of activity and stability of soluble and sol–gel immobilized naringinase in co-solvent systems. J. Mol. Catal. B-Enzym. 2010;65:91–101. doi: 10.1016/j.molcatb.2010.01.024. DOI

Wang J., Gong A., Yang C.F., Bao Q., Shi X.Y., Han B.B., Wu X.Y., Wu F.A. An effective biphase system accelerates hesperidinase-catalyzed conversion of rutin to isoquercitrin. Sci. Rep. 2015;5:8682. doi: 10.1038/srep08682. PubMed DOI PMC

Gerstorferová D., Fliedrová B., Halada P., Marhol P., Křen V., Weignerová L. Recombinant α-l-rhamnosidase from Aspergillus terreus in selective trimming of rutin. Process. Biochem. 2012;47:828–835. doi: 10.1016/j.procbio.2012.02.014. DOI

De Winter K., Šimčíková D., Schalck B., Weignerová L., Pelantová H., Soetaert W., Desmet T., Křen V. Chemoenzymatic synthesis of α-l-rhamnosides using recombinant α-l-rhamnosidase from Aspergillus terreus. Bioresour. Technol. 2013;147:640–644. doi: 10.1016/j.biortech.2013.08.083. PubMed DOI

Mazzaferro L., Pinuel L., Minig M., Breccia J.D. Extracellular monoenzyme deglycosylation system of 7-O-linked flavonoid β-rutinosides and its disaccharide transglycosylation activity from Stilbella fimetaria. Arch. Microbiol. 2010;192:383–393. doi: 10.1007/s00203-010-0567-7. PubMed DOI

Ishikawa M., Kawasaki M., Shiono Y., Koseki T. A novel Aspergillus oryzae diglycosidase that hydrolyzes 6-O-α-l-rhamnosyl-β-d-glucoside from flavonoids. Appl. Microbiol. Biotechnol. 2018;102:3193–3201. doi: 10.1007/s00253-018-8840-9. PubMed DOI

Neher B.D., Mazzaferro L.S., Kotik M., Oyhenart J., Halada P., Kren V., Breccia J.D. Bacteria as source of diglycosidase activity: Actinoplanes missouriensis produces 6-O-α-l-rhamnosyl-β-d-glucosidase active on flavonoids. Appl. Microbiol. Biotechnol. 2016;100:3061–3070. doi: 10.1007/s00253-015-7088-x. PubMed DOI

Piñuel L., Breccia J.D., Guisan J.M., Lopez-Gallego F. Production of hesperetin using a covalently multipoint immobilized diglycosidase from Acremonium sp. DSM24697. J. Mol. Microbiol. Biotechnol. 2013;23:410–417. doi: 10.1159/000353208. PubMed DOI

Piñuel L., Mazzaferro L.S., Breccia J.D. Operational stabilization of fungal α-rhamnosyl-β-glucosidase by immobilization on chitosan composites. Process Biochem. 2011;46:2330–2335. doi: 10.1016/j.procbio.2011.09.014. DOI

Mazzaferro L.S., Breccia J.D. Quantification of hesperidin in citrus-based foods using a fungal diglycosidase. Food Chem. 2012;134:2338–2344. doi: 10.1016/j.foodchem.2012.03.107. PubMed DOI

Nam H.K., Hong S.H., Shin K.C., Oh D.K. Quercetin production from rutin by a thermostable β-rutinosidase from Pyrococcus furiosus. Biotechnol. Lett. 2012;34:483–489. doi: 10.1007/s10529-011-0786-2. PubMed DOI

Desmet T., Soetaert W., Bojarová P., Křen V., Dijkhuizen L., Eastwick-Field V., Schiller A. Enzymatic glycosylation of small molecules: Challenging substrates require tailored catalysts. Chemistry. 2012;18:10786–10801. doi: 10.1002/chem.201103069. PubMed DOI

Bassanini I., Krejzová J., Panzeri W., Monti D., Křen V., Riva S. A sustainable one-pot, two-enzyme synthesis of naturally occurring arylalkyl glucosides. ChemSusChem. 2017;10:2040–2045. doi: 10.1002/cssc.201700136. PubMed DOI

Minig M., Mazzaferro L.S., Erra-Balsells R., Petroselli G., Breccia J.D. α-Rhamnosyl-β-glucosidase-catalyzed reactions for analysis and biotransformations of plant-based foods. J. Agric. Food Chem. 2011;59:11238–11243. doi: 10.1021/jf202412e. PubMed DOI

Cho H.K., Kim H.H., Seo D.H., Jung J.H., Park J.H., Baek N.I., Kim M.J., Yoo S.H., Cha J., Kim Y.R., et al. Biosynthesis of (+)-catechin glycosides using recombinant amylosucrase from Deinococcus geothermalis DSM 11300. Enzyme. Microb. Technol. 2011;49:246–253. doi: 10.1016/j.enzmictec.2011.05.007. PubMed DOI

Kitao S., Ariga T., Matsudo T., Sekine H. The syntheses of catechin-glucosides by transglycosylation with leuconostoc mesenteroides sucrose phosphorylase. Biosci. Biotechnol. Biochem. 1993;57:2010–2015. doi: 10.1271/bbb.57.2010. DOI

Gao C., Mayon P., MacManus D.A., Vulfson E.N. Novel enzymatic approach to the synthesis of flavonoid glycosides and their esters. Biotechnol. Bioeng. 2000;71:235–243. doi: 10.1002/1097-0290(2000)71:3<235::AID-BIT1013>3.0.CO;2-M. PubMed DOI

Chen S., Xing X.-H., Huang J.-J., Xu M.-S. Enzyme-assisted extraction of flavonoids from Ginkgo biloba leaves: Improvement effect of flavonol transglycosylation catalyzed by Penicillium decumbens cellulase. Enzym. Microb. Technol. 2011;48:100–105. doi: 10.1016/j.enzmictec.2010.09.017. PubMed DOI

Yang M., Davies G.J., Davis B.G. A glycosynthase catalyst for the synthesis of flavonoid glycosides. Angew. Chem. Int. Ed. Engl. 2007;46:3885–3888. doi: 10.1002/anie.200604177. PubMed DOI

Pozzo T., Plaza M., Romero-García J., Faijes M., Karlsson E.N., Planas A. Glycosynthases from Thermotoga neapolitana β-glucosidase 1A: A comparison of α-glucosyl fluoride and in situ-generated α-glycosyl formate donors. J. Mol. Catal. B-Enzym. 2014;107:132–139. doi: 10.1016/j.molcatb.2014.05.021. DOI

FDA GRAS Notification-α-glycosyl isoquercitrin. [(accessed on 25 September 2013)]; Available online: http://wayback.archive-it.org/7993/20171031051756/https://www.fda.gov/downloads/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/UCM269110.pdf.

Sun T., Jiang B., Pan B. Microwave accelerated transglycosylation of rutin by cyclodextrin glucanotransferase from Bacillus sp. SK13.002. Int. J. Mol. Sci. 2011;12:3786–3796. doi: 10.3390/ijms12063786. PubMed DOI PMC

Li X., Li D., Park S.-H., Gao C., Park K.-H., Gu L. Identification and antioxidative properties of transglycosylated puerarins synthesised by an archaeal maltogenic amylase. Food Chem. 2011;124:603–608. doi: 10.1016/j.foodchem.2010.06.082. DOI

Wu X., Chu J., Wu B., Zhang S., He B. An efficient novel glycosylation of flavonoid by β-fructosidase resistant to hydrophilic organic solvents. Bioresour. Technol. 2013;129:659–662. doi: 10.1016/j.biortech.2012.12.041. PubMed DOI

Flavonoids as Aglycones in Retaining Glycosidase-Catalyzed Reactions: Prospects for Green Chemistry

Two fungal flavonoid-specific glucosidases/rutinosidases for rutin hydrolysis and rutinoside synthesis under homogeneous and heterogeneous reaction conditions

Dietary Polyphenols Targeting Arterial Stiffness: Interplay of Contributing Mechanisms and Gut Microbiome-Related Metabolism