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Metabolic engineering of flavonoids in plants and microorganisms

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Abstract

Over 9,000 flavonoid compounds have been found in various plants, comprising one of the largest families of natural products. Flavonoids are an essential factor in plant interactions with the environment, often serving as the first line of defense against UV irradiation and pathogen attacks. Flavonoids are also major nutritional compounds in foods and beverages, with demonstrated health benefits. Some flavonoids are potent antioxidants, and specific flavonoid compounds are beneficial in many physiological and pharmacological processes. Therefore, engineering of flavonoid biosynthesis in plants or in microorganisms has significant scientific and economical importance. Construction of biosynthetic pathways in heterologous systems offers promising results for large-scale flavonoid production by fermentation or bioconversion. Genomics and metabolomics now offer unprecedented tools for detailed understanding of the engineered transgenic organism and for developing novel technologies to further increase flavonoid production yields. We summarize some of the recent metabolic engineering strategies in plants and microorganisms, with a focus on applications of metabolic flux analysis. We are confident that these engineering approaches will lead to successful industrial flavonoid production in the near future.

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References

  • Becker JV, Armstrong GO, van der Merwe MJ, Lambrechts MG, Vivier MA, Pretorius IS (2003) Metabolic engineering of Saccharomyces cerevisiae for the synthesis of the wine-related antioxidant resveratrol. FEMS Yeast Res 4:79–85

    Article  CAS  PubMed  Google Scholar 

  • Besseau S, Hoffmann L, Geoffroy P, Lapierre C, Pollet B, Legrand M (2007) Flavonoid accumulation in Arabidopsis repressed in lignin synthesis affects auxin transport and plant growth. Plant Cell 19:148–162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chemler JA, Lock LT, Koffas MA, Tzanakakis ES (2007) Standardized biosynthesis of flavan-3-ols with effects on pancreatic beta-cell insulin secretion. Appl Microbiol Biotechnol 77:797–807

    Article  CAS  PubMed  Google Scholar 

  • Chemler JA, Fowler ZL, McHugh KP, Koffas MA (2010) Improving NADPH availability for natural product biosynthesis in Escherichia coli by metabolic engineering. Metab Eng 12:96–104

    Article  CAS  PubMed  Google Scholar 

  • Davies KM, Schwinn KE, Deroles SC, Manson DG, Lewis DH, Bloor SJ, Bradley JM (2003) Enhancing anthocyanin production by altering competition for substrate between flavonol synthase and dihydroflavonol 4-reductase. Euphytica 131:259–268

    Article  CAS  Google Scholar 

  • Deroles S (2009) Anthocyanin biosynthesis in plant cell cultures: A potential source of natural colourants. In: Gould K (ed) Anthocyanins: Biosynthesis, functions, and applications. Springer, New York, pp 107–167

    Google Scholar 

  • Dixon RA, Steele CL (1999) Flavonoids and isoflavonoids—a gold mine for metabolic engineering. Trends Plant Sci 4:394–400

    Article  CAS  PubMed  Google Scholar 

  • Feng L, Jin J, Zhang LF, Yan T, Tao WY (2006) Analysis of the resveratrol-binding protein using phage-displayed random peptide library. Acta Biochim Biophys Sin (Shanghai) 38:342–348

    Article  CAS  Google Scholar 

  • Ferrer JL, Austin MB, Stewart C Jr, Noel JP (2008) Structure and function of enzymes involved in the biosynthesis of phenylpropanoids. Plant Physiol Biochem 46:356–370

    Article  CAS  PubMed  Google Scholar 

  • Fischer R, Budde I, Hain R (1997) Stilbene synthase gene expression causes changes in flower colour and male sterility in tobacco. Plant J 11:489–498

    Article  CAS  Google Scholar 

  • Forkmann G, Martens S (2001) Metabolic engineering and applications of flavonoids. Curr Opin Biotechnol 12:155–160

    Article  CAS  PubMed  Google Scholar 

  • Fornale S, Shi X, Chai C, Encina A, Irar S, Capellades M, Fuguet E, Torres JL, Rovira P, Puigdomenech P, Rigau J, Grotewold E, Gray J, Caparros-Ruiz D (2010) ZmMYB31 directly represses maize lignin genes and redirects the phenylpropanoid metabolic flux. Plant J 64:633–644

    Article  CAS  PubMed  Google Scholar 

  • Fowler ZL, Gikandi WW, Koffas MA (2009) Increased malonyl coenzyme A biosynthesis by tuning the Escherichia coli metabolic network and its application to flavanone production. Appl Environ Microbiol 75:5831–5839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ge H, Zhang JF, Guo BS, He Q, Wang BY, He B, Wang CQ (2007) Resveratrol inhibits macrophage expression of EMMPRIN by activating PPARgamma. Vascul Pharmacol 46:114–121

    Article  CAS  PubMed  Google Scholar 

  • Huang L, Xiao P, Guo L, Gao W (2010) Molecular pharmacognosy. Sci China Life Sci 53:643–652

    Article  PubMed  Google Scholar 

  • Hwang EI, Kaneko M, Ohnishi Y, Horinouchi S (2003) Production of plant-specific flavanones by Escherichia coli containing an artificial gene cluster. Appl Environ Microbiol 69:2699–2706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang H, Wood KV, Morgan JA (2005) Metabolic engineering of the phenylpropanoid pathway in Saccharomyces cerevisiae. Appl Environ Microbiol 71:2962–2969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lanot A, Hodge D, Jackson RG, George GL, Elias L, Lim EK, Vaistij FE, Bowles DJ (2006) The glucosyltransferase UGT72E2 is responsible for monolignol 4-O-glucoside production in Arabidopsis thaliana. Plant J 48:286–295

    Article  CAS  PubMed  Google Scholar 

  • Lanot A, Hodge D, Lim EK, Vaistij FE, Bowles DJ (2008) Redirection of flux through the phenylpropanoid pathway by increased glucosylation of soluble intermediates. Planta 228:609–616

    Article  CAS  PubMed  Google Scholar 

  • Leonard E, Chemler J, Lim KH, Koffas MA (2006a) Expression of a soluble flavone synthase allows the biosynthesis of phytoestrogen derivatives in Escherichia coli. Appl Microbiol Biotechnol 70:85–91

    Article  CAS  PubMed  Google Scholar 

  • Leonard E, Yan Y, Koffas MA (2006b) Functional expression of a P450 flavonoid hydroxylase for the biosynthesis of plant-specific hydroxylated flavonols in Escherichia coli. Metab Eng 8:172–181

    Article  CAS  PubMed  Google Scholar 

  • Leonard E, Lim KH, Saw PN, Koffas MA (2007) Engineering central metabolic pathways for high-level flavonoid production in Escherichia coli. Appl Environ Microbiol 73:3877–3886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leonard E, Yan Y, Fowler ZL, Li Z, Lim CG, Lim KH, Koffas MA (2008) Strain improvement of recombinant Escherichia coli for efficient production of plant flavonoids. Mol Pharm 5:257–265

    Article  CAS  PubMed  Google Scholar 

  • Li X, Bonawitz ND, Weng JK, Chapple C (2010) The growth reduction associated with repressed lignin biosynthesis in Arabidopsis thaliana is independent of flavonoids. Plant Cell 22:1620–1632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lim SS, Jung SH, Ji J, Shin KH, Keum SR (2001) Synthesis of flavonoids and their effects on aldose reductase and sorbitol accumulation in streptozotocin-induced diabetic rat tissues. J Pharm Pharmacol 53:653–668

    Article  CAS  PubMed  Google Scholar 

  • Mavel S, Dikic B, Palakas S, Emond P, Greguric I, de Gracia AG, Mattner F, Garrigos M, Guilloteau D, Katsifis A (2006) Synthesis and biological evaluation of a series of flavone derivatives as potential radioligands for imaging the multidrug resistance-associated protein 1 (ABCC1/MRP1). Bioorg Med Chem 14:1599–1607

    Article  CAS  PubMed  Google Scholar 

  • Meyer P, Heidmann I, Forkmann G, Saedler H (1987) A new petunia flower colour generated by transformation of a mutant with a maize gene. Nature 330:677–678

    Article  CAS  PubMed  Google Scholar 

  • Miyahisa I, Kaneko M, Funa N, Kawasaki H, Kojima H, Ohnishi Y, Horinouchi S (2005) Efficient production of (2S)-flavanones by Escherichia coli containing an artificial biosynthetic gene cluster. Appl Microbiol Biotechnol 68:498–504

    Article  CAS  PubMed  Google Scholar 

  • Nijveldt RJ, van Nood E, van Hoorn DE, Boelens PG, van Norren K, van Leeuwen PA (2001) Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr 74:418–425

    Article  CAS  PubMed  Google Scholar 

  • Nishiyama Y, Yun CS, Matsuda F, Sasaki T, Saito K, Tozawa Y (2010) Expression of bacterial tyrosine ammonia-lyase creates a novel p-coumaric acid pathway in the biosynthesis of phenylpropanoids in Arabidopsis. Planta 232:209–218

    Article  CAS  PubMed  Google Scholar 

  • Ralston L, Subramanian S, Matsuno M, Yu O (2005) Partial reconstruction of flavonoid and isoflavonoid biosynthesis in yeast using soybean type I and type II chalcone isomerases. Plant Physiol 137:1375–1388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ro DK, Douglas CJ (2004) Reconstitution of the entry point of plant phenylpropanoid metabolism in yeast (Saccharomyces cerevisiae): implications for control of metabolic flux into the phenylpropanoid pathway. J Biol Chem 279:2600–2607

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Subramanian S, Stacey G, Yu O (2007) Distinct, crucial roles of flavonoids during legume nodulation. Trends Plant Sci 12:282–285

    Article  CAS  PubMed  Google Scholar 

  • Trantas E, Panopoulos N, Ververidis F (2009) Metabolic engineering of the complete pathway leading to heterologous biosynthesis of various flavonoids and stilbenoids in Saccharomyces cerevisiae. Metab Eng 11:355–366

    Article  CAS  PubMed  Google Scholar 

  • van der Meer IM, Stam ME, van Tunen AJ, Mol JN, Stuitje AR (1992) Antisense inhibition of flavonoid biosynthesis in petunia anthers results in male sterility. Plant Cell 4:253–262

    PubMed  PubMed Central  Google Scholar 

  • Wang Y, Chen H, Yu O (2010) Metabolic engineering of resveratrol and other longevity boosting compounds. Biofactors 36:394–400

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Halls C, Zhang J, Matsuno M, Zhang Y, Yu O (2011) Stepwise increase of resveratrol biosynthesis in yeast Saccharomyces cerevisiae by metabolic engineering. Metab Eng. doi:https://doi.org/10.1016/j.ymben.2011.04.005

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yan Y, Kohli A, Koffas MA (2005) Biosynthesis of natural flavanones in Saccharomyces cerevisiae. Appl Environ Microbiol 71:5610–5613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yazaki K (2005) Transporters of secondary metabolites. Curr Opin Plant Biol 8:301–307

    Article  CAS  PubMed  Google Scholar 

  • Ylstra B, Touraev A, Moreno RM, Stoger E, van Tunen AJ, Vicente O, Mol JN, Heberle-Bors E (1992) Flavonols stimulate development, germination, and tube growth of tobacco pollen. Plant Physiol 100:902–907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu O, Jez JM (2008) Nature’s assembly line: biosynthesis of simple phenylpropanoids and polyketides. Plant J 54:750–762

    Article  CAS  PubMed  Google Scholar 

  • Zha W, Rubin-Pitel SB, Shao Z, Zhao H (2009) Improving cellular malonyl-CoA level in Escherichia coli via metabolic engineering. Metab Eng 11:192–198

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Li SZ, Li J, Pan X, Cahoon RE, Jaworski JG, Wang X, Jez JM, Chen F, Yu O (2006) Using unnatural protein fusions to engineer resveratrol biosynthesis in yeast and mammalian cells. J Am Chem Soc 128:13030–13031

    Article  CAS  PubMed  Google Scholar 

  • Zhao J, Huhman D, Shadle G, He XZ, Sumner LW, Tang Y, Dixon RA (2011) MATE2 mediates vacuolar sequestration of flavonoid glycosides and glycoside malonates in Medicago truncatula. Plant Cell 23:1536–1555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgment

This work is support in part by three federal grants to Oliver Yu, one is from US Department of Energy (DE-SC0001295), one from National Science Foundation (MCB-0923779), and one from US Department of Agriculture (2010-65116-20514).

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Authors and Affiliations

  1. Donald Danforth Plant Science Center, 975 N Warson Road, St. Louis, MO, 63132, USA

    Yechun Wang & Oliver Yu

  2. Blue California, 30111 Tomas, Rancho Santa Margarita, CA, 92688, USA

    Steven Chen

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  1. Yechun Wang
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  2. Steven Chen
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  3. Oliver Yu
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Correspondence to Yechun Wang.

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Wang, Y., Chen, S. & Yu, O. Metabolic engineering of flavonoids in plants and microorganisms. Appl Microbiol Biotechnol 91, 949–956 (2011). https://doi.org/10.1007/s00253-011-3449-2

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  • DOI: https://doi.org/10.1007/s00253-011-3449-2

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