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Biosynthesis and production of glycosylated flavonoids in Escherichia coli: current state and perspectives

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Abstract

Flavonoids are plant secondary metabolites containing several hydroxyl groups that are targets for modification reactions such as methylation and glycosylation. In plants, flavonoids are present as glycones. Although glucose is the most common sugar attached to flavonoids, arabinose, galactose, glucuronic acid, rhamnose, and xylose are also linked to flavonoids. Depending on the kind and the position of the attached sugar, flavonoid glycones show different biological properties. Flavonoid-O-glycosides are synthesized by uridine diphosphate-dependent glycosyltransferases (UGTs), which use nucleotide sugar as a sugar donor and a diverse compound as a sugar acceptor. Recently, diverse flavonoid-O-glycosides have been synthesized in Escherichia coli by introducing UGTs from plants and bacteria and modifying endogenous pathways. The nucleotide sugar biosynthesis pathway in E. coli has been engineered to provide the proper nucleotide sugar for flavonoid-O-glycoside biosynthesis. In this review, we will discuss recent advances in flavonoid-O-glycoside biosynthesis using engineered E. coli.

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References

  • Ahn BC, Kim BG, Jeon YM, Lee EJ, Lim Y, Ahn J-H (2009) Formation of flavone di-O-glucosides using a glycosyltransferase from Bacillus cereus. J Microbiol Biotechnol 19:387–390

    Article  CAS  PubMed  Google Scholar 

  • Bhan N, Xu P, Koffas MA (2013) Pathway and protein engineering approaches to produce novel and commodity small molecules. Curr Opin Biotechnol 24:1137–1143

    Article  CAS  PubMed  Google Scholar 

  • Bowles D, Lim E-K, Poppenberger B, Vaistij FE (2006) Glycosyltransferases of lipophilic small molecules. Annu Rev Plant Biol 57:567–597

    Article  CAS  PubMed  Google Scholar 

  • Brazier-Hicks M, Evans KM, Gershater MC, Puschmann H, Steel PG, Edwards R (2009) The C-glycosylation of flavonoids in cereals. J Biol Chem 284:17926–17934

  • Breazeale SD, Riberio AA, McClerren AL, Raetz CRH (2005) Aformyltransferase required for polymyxin resistance in Escherichia coli and the modification of lipid A with 4-amino-4-deoxy-L-arabinose. J Biol Chem 280:14154–14167

    Article  CAS  PubMed  Google Scholar 

  • Burget EG, Verma R, Mølhøj M, Reiter W-D (2003) The biosynthesis of L-arabinose in plants: molecular cloning and characterization of a Golgi-localized UDP-D-xylose 4-epimerase encoded by the MUR4 gene of Arabidopsis. Plant Cell 15:523–553

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Caputi L, Lim E-K, Bowles DJ (2008) Discovery of new biocatalysts for the glycosylation of terpenoid scaffolds. Chem Eur J 14:6656–6662

    Article  CAS  PubMed  Google Scholar 

  • Dixon RA, Paiva NL (1995) Stress-induced phenylpropanoid metabolism. Plant Cell 7:1085–1097

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dong C, Beis K, Giraud MF, Blankenfeldt W, Allard S, Major LL, Kerr ID, Whitfield C, Naismith JH (2003) A structural perspective on the enzymes that convert dTDP-D-glucose into dTDP-L-rhamnose. Biochem Soc Trans 31:532–536

    Article  CAS  PubMed  Google Scholar 

  • Du J, Shao Z, Zhao H (2011) Engineering microbial factories for synthesis of value-added products. J Ind Microbiol Biotechnol 38:873–890

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gu X, Lee SG, Bar-Peled M (2011) Biosynthesis of UDP-xylose and UDP-arabinose in Sinorhizobium meliloti 1021: first characterization of a bacterial UDP-xylose synthase, and UDP-xylose 4-epimerase. Microbiology 157:260–269

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Han SH, Kim B-G, Yoon JA, Chong Y, Ahn J-H (2014) Synthesis of flavonoid O-pentosides by Escherichia coli through engineering nucleotide sugar synthesis pathway and glycosyltransferase. Appl Environ Microbiol 80:2754–2762

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hartmann T (2007) From waste products to ecochemicals: fifty years research of plant secondary metabolism. Phytochemistry 68:2831–2846

    Article  CAS  PubMed  Google Scholar 

  • He X-Z, Li W-S, Blount JW, Dixon RA (2008) Regioselective synthesis of plant (iso)flavone glycosides in Escherichia coli. Appl Microbiol Biotechnol 80:253–260

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jones P, Messner B, Nakajima J-I, Schäffner AR, Saito K (2003) UGT73C6 and UGT78D1, glycosyltransferases involved in flavonol glycoside biosynthesis in Arabidopsis thaliana. J Biol Chem 278:43910–43918

    Article  CAS  PubMed  Google Scholar 

  • Jüergenliemk G, Boje K, Huewel S, Lohmann C, Galla HJ, Nahrstedt A (2003) In vitro studies indicate that miquelianin (quercetin 3-O-beta-D-glucuronopyranoside) is able to reach the CNS from the small intestine. Planta Med 69:1013–1017

    Article  PubMed  Google Scholar 

  • Kim JH, Kim BG, Kim JA, Park Y, Lee YJ, Lim Y, Ahn J-H (2007) Glucosylation of flavonoids with E. coli expressing glycosyltransferase from Xanthomonas campestris. J Microbiol Biotechnol 17:539–542

    CAS  PubMed  Google Scholar 

  • Kim JH, Shin KH, Ko JH, AHn J-H (2006) GLucosylation of flavonols by Escherichia coli expressiong glucosyltransferase from rice (Oryza sativa). J Biosci Bioeng 102:135–137

  • Kim B-G, Jung NR, Joe EJ, Hur H-G, Lim Y, Chong Y, Ahn J-H (2010a) Bacterial synthesis of a flavonoid deoxyaminosugar conjugate in Escherichia coli expressing a glycosyltransferase of Arabidopsis thaliana. Chem Biol Chem 11:2389–2392

    Article  CAS  Google Scholar 

  • Kim B-G, Sung SH, Jung NR, Chong Y, Ahn J-H (2010b) Biological synthesis of isorhamnetin 3-O-glucoside using engineered glucosyltransferase. J Mol Catal B-Enzym 63:194–199

    Article  CAS  Google Scholar 

  • Kim BG, Kim HJ, Ahn J-H (2012a) Production of bioactive flavonol rhamnosides by expression of plant genes in Escherichia coli. J Agric Food Chem 60:11143–11148

    Article  CAS  PubMed  Google Scholar 

  • Kim B-G, Sung SH, Ahn J-H (2012b) Biological synthesis of quercetin 3-O-N-acetylglucosamine conjugate using engineered Escherichia coli expressing UGT78D2. Appl Microbiol Biotechnol 93:2447–2453

    Article  CAS  PubMed  Google Scholar 

  • Kim HJ, Kim BG, Ahn J-H (2013a) Regioselective synthesis of flavonoid bisglycosides using Escherichia coli harboring two glycosyltransferases. Appl Microbiol Biotechnol 97:5275–5282

    Article  CAS  PubMed  Google Scholar 

  • Kim MJ, Kim B-G, Ahn J-H (2013b) Biosynthesis of bioactive O-methylated flavonoids in Escherichia coli. Appl Microbiol Biotechnol 97:7195–7720

    Article  CAS  PubMed  Google Scholar 

  • Kim SY, Lee HR, Park K-s, Kim BG, Ahn J-H (2015) Metabolic engineering of Escherichia coli for the biosynthesis of flavonoid O-glucuronides and flavonoid O-galactoside. Appl Microbiol Biotechnol 99:2233–2242

  • Ko JH, Kim BG, Ahn J-H (2006) Glycosylation of flavonoids with a glycosyltransferase from Bacillus cereus. FEMS Microbiol Lett 258:263–268

    Article  CAS  Google Scholar 

  • Koirala N, Pandey RP, Thang DV, Jung HJ, Sohng JK (2014) Glycosylation and subsequent malonylation of isoflavonoids in E. coli: strain development, production and insights into future metabolic perspectives. J Ind Microbiol Biotechnol 41:1647–1658

  • Kumar S, Pandey AK (2013) Chemistry and biological activities of flavonoids: an overview. Sci World J 2013:162750

    Google Scholar 

  • Levander F, Svensson M, Rädström P (2002) Enhanced exopolysaccharide production by metabolic engineering of Streptococcus thermophiles. Appl Environ Microbiol 68:784–790

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lim E-K, Ashford DA, Hou B, Jackson RG, Bowles DJ (2004) Arabidopsis glycosyltransferases as biocatalysts in fermentation for regioselective synthesis of diverse quercetinglucosides. Biotechnol Bioeng 87:623–631

    Article  CAS  PubMed  Google Scholar 

  • Malla S, Koffas MAG, Kazlauskas R, Kim B-G (2012) Production of 7-O-methyl aromadendrin, a medicinally valuable flavonoid, in Escherichia coli. Appl Environ Microbiol 78:684–694

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Malla S, Pandey RP, Kim B-G, Sohng JK (2013) Regiospecific modifications of naringenin for astragalin production in Escherichia coli. Biotechnol Bioeng 110:2525–2535

    Article  CAS  PubMed  Google Scholar 

  • Mao Z, Shin H-D, Chen RR (2006) Engineering the E. coli UDP-glucose synthesis pathway for oligosaccharide synthesis. Biotechnol Prog 22:369–374

    Article  CAS  PubMed  Google Scholar 

  • Miller KD, Guyon V, Evans JN, Shuttleworth WA, Taylor LP (1999) Purification cloning and heterologous expression of a catalytically efficient flavonol 3-O-galactosyltransferase expressed in the male gametophyte of Petunia hybrid. J Biol Chem 274:34011–34019

    Article  CAS  PubMed  Google Scholar 

  • Miyahisa I, Funa N, Ohnishi Y, Martens S, Moriguchi T, Horinouchi S (2006) Combinatorial biosynthesis of flavones and flavonols in Escherichia coli. Appl Microbiol Biotechnol 71:53–58

    Article  CAS  PubMed  Google Scholar 

  • Noguchi A, Horikawa M, Fukui Y, Fukuchi-Mizutani M, Luchi-Okada A, Ishiguro M, Kiso Y, Nakayama T, Ono E (2009) Local differentiation of sugar donor specificity of flavonoid glycosyltransferase in Lamiales. Plant Cell 21:1556–1572

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Oh T-J, Mo SJ, Yoon YJ, Sohng JK (2007) Discovery and molecular engineering of sugar-containing natural product biosynthetic pathways in actinomycetes. J Microbiol Biotechnol 17:1909–1921

    CAS  PubMed  Google Scholar 

  • Oka T, Nemoto T, Jigami Y (2007) Functional analysis of Arabidopsis thaliana RHM2/MUM4, a multidomain protein involved in UDP-D-glucose to UDP-L-rhamnose conversion. J Biol Chem 282:5389–5403

    Article  CAS  PubMed  Google Scholar 

  • Ono E, Homma Y, Horikawa M, Kunikane-Doi S, Imai H, Takahashi S, Kawai Y, Ishiguro M, Fukui Y, Nakayama T (2010) Functional differentiation of the glycosyltransferases that contribute to the chemical diversity of bioactive flavonol glycosides in grapevines (Vitis vinifera). Plant Cell 22:2856–2871

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Osmani SA, Bak S, Møller BL (2009) Substrate specificity of plant UDP-dependent glycosyltransferases predicted from crystal structures and homology modeling. Phytochemistry 70:325–347

    Article  CAS  PubMed  Google Scholar 

  • Pandey RP, Malla S, Simkhada B, Kim B-G, Sohng JG (2013) Production of 3-O-xylosyl quercetin in Escherichia coli. Appl Microbiol Biotechnol 97:1889–1901

    Article  CAS  PubMed  Google Scholar 

  • Pandey RP, Gurung RB, Parajuli P, Koirala N, Tuoi LT, Sohng JK (2014) Assessing acceptor substrate promiscuity of YjiC-mediated glycosylation toward flavonoids. Carbohydr Res 393:26–31

    Article  CAS  PubMed  Google Scholar 

  • Reiter W-D (2008) Biochemical genetics of nucleotide sugar interconversion reactions. Curr Opin Plant Biol 11:236–243

    Article  CAS  PubMed  Google Scholar 

  • Roepke J, Bozzo GG (2013) Biocatalytic synthesis of quercetin 3-O-glucoside-7-O-rhamnoside by metabolic engineering of Escherichia coli. Chem Biol Chem 14:2418–2422

    Article  CAS  Google Scholar 

  • Santos CNS, Koffas M, Stephanopoulos (2011) Optimization of a heterologous pathway for the production of flavonoids from glucose. Metab Eng 13:392–400

    Article  CAS  PubMed  Google Scholar 

  • Scheffers D-J, Pinho MG (2005) Bacterial cell wall synthesis: new insights from localization studies. Microbiol Mol Biol Rev 69:585–607

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schwab W, Fischer TC, Giri A, Wüst M (2015) Potential applications of glucosyltransferases in terpene glucosideproduction: impacts on the use of aroma and fragrance. Appl Microbiol Biotechnol 99:165–174

    Article  CAS  PubMed  Google Scholar 

  • Seifert GJ (2004) Nucleotide sugar interconversion and cell wall biosynthesis: how to bring the inside to the outside. Curr Opin Plant Biol 7:277–284

    Article  CAS  PubMed  Google Scholar 

  • Simkhada D, Lee HC, Sohng JK (2010) Genetic engineering approach for the production of rhamnosyl and allosylflavonoids from Escherichia coli. Biotechnol Bioeng 107:154–162

    Article  CAS  PubMed  Google Scholar 

  • Soundararajan R, Wishart AD, Rupasinghe HP, Arcellana-Panlilio M, Nelson CM, Mayne M, Robertson GS (2008) Quercetin 3-glucoside protects neuroblastoma (SH-SY5Y) cells in vitro against oxidative damage by inducing sterol regulatory element-binding protein-2-mediated cholesterol biosynthesis. J Biol Chem 283:2231–2245

    Article  CAS  PubMed  Google Scholar 

  • Thibodeaux CJ, Melanҫon C, H-w L (2007) Unusual sugar biosynthesis and natural product glycodiversification. Nature 446:1008–1016

    Article  CAS  PubMed  Google Scholar 

  • Thuan NH, Pandey RP, Thuy TT, Park JW, Sohng JK (2013) Improvement of regio-specific production of myricetin-3-O-α-L-rhamnoside in engineered Escherichia coli. Appl Biochem Biotechnol 171:1956–1967

    Article  CAS  PubMed  Google Scholar 

  • Veitch NC, Grayer RJ (2011) Flavonoids and their glycosides, including anthocyanins. Nat Prod Rep 28:1626–1695

    Article  CAS  PubMed  Google Scholar 

  • Vogt T (2010) Phenylpropanoid biosynthesis. Mol Plant 3:2–20

    Article  CAS  PubMed  Google Scholar 

  • Vogt T, Jones P (2000) Glycosyltransferases in plant natural product synthesis: characterization of a supergene family. Trend Plant Sci 5:380–386

    Article  CAS  Google Scholar 

  • Wang X (2009) Structure, mechanism and engineering of plant natural product glycosyltransferases. FEBS Lett 583:3303–3309

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Han W, Xie C, Hou J, Fang Q, Gu J, Wang PG, Cheng J (2013) Comparing the acceptor promiscuity of a Rosa hybrid glucosyltransferase RhGT1 and an engineered microbial glucosyltransferase OleDPSA toward a small flavonoid library. Carbohydr Res 368:73–77

    Article  CAS  PubMed  Google Scholar 

  • Watts KT, Lee PC, Schmidt-Dannert C (2004) Exploring recombinant flavonoid biosynthesis in metabolically engineered Escherichia coli. Chem Biol Chem 5:500–507

    Article  CAS  Google Scholar 

  • Willits MG, Giovanni M, Prata RT, Kramer CM, De Luca V, Steffens JC, Graser G (2004) Bio-fermentation of modified flavonoids: an example of in vivo diversification of secondary metabolites. Phytochemistry 5:31–41

    Article  Google Scholar 

  • Winkel-Shirely B (2001) Flavonoid biosynthesis. A colorful model for genetics, biochemistry, cell biology, and biotechnology. Plant Physiol 126:485–493

    Article  Google Scholar 

  • Yan Y, Li Z, Koffas MAG (2007) High-yield anthocyanin biosynthesis in engineered Escherichia coli. Biotechnol Bioeng 100:126–140

    Article  Google Scholar 

  • Yang S-M, Han SH, Kim B-G, Ahn J-H (2014) Production of kaempferol 3-O-rhamnoside from glucose using engineered Escherichia coli. J Ind Microbiol Biotechnol 41:1311–1318

    Article  CAS  PubMed  Google Scholar 

  • Yonekura-Sakakibara K, Hanada K (2011) An evolutionary view of functional diversity in family 1 glycosyltransferases. Plant J 66:182–193

    Article  CAS  PubMed  Google Scholar 

  • Yonekura-Sakakibara K, Tohge T, Matsuda F, Nakabayashi R, Takayama H, Niida R, Watanabe-Takahashi A, Inoue E, Saito K (2008) Comprehensive flavonol profiling and transcriptome coexpression analysis leading to decoding gene-metabolite correlation in Arabidopsis. Plant Cell 20:2160–2176

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yonekura-Sakakibara K, Fukushima A, Nakabayashi R, Hanada K, Matsuda F, Sugawara S, Inoue E, Kuromori T, Ito T, Shinozaki K, Wangwattana B, Yamazaki M, Saito K (2012) Two glycosyltransferases involved in anthocyanin modification delineated by transcriptome independent component analysis in Arabidopsis thaliana. Plant J 69:154–167

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yoon J-A, Kim B-G, Lee WJ, Lim Y, Chong Y, Ahn J-H (2012) Production of a novel quercetin glycoside through metabolic engineering of Escherichia coli. Appl Environ Microbiol 78:4256–4262

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by a grant from the Next-Generation BioGreen 21 Program (PJ01114801), Rural Development Administration, and Priority Research Centers Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology 2009-0093824).

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Correspondence to Joong-Hoon Ahn.

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Kim, B.G., Yang, S.M., Kim, S.Y. et al. Biosynthesis and production of glycosylated flavonoids in Escherichia coli: current state and perspectives. Appl Microbiol Biotechnol 99, 2979–2988 (2015). https://doi.org/10.1007/s00253-015-6504-6

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  • DOI: https://doi.org/10.1007/s00253-015-6504-6

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