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Bioproduction of Resveratrol

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Biotechnology of Natural Products

Abstract

Resveratrol is one of the most well-known and extensively-studied polyphenol compounds from plants. Its natural biosynthetic pathway and enzymes have been well characterized. Resveratrol possesses many health-promoting properties that promote an increasing demand for resveratrol as a food and nutrition supplement. In contrast to the traditional methods of direct extraction from plants, bioproduction of resveratrol by microorganisms serves as a cost-effective alternative strategy and has achieved remarkable progress. This review highlights the recent progress in metabolic engineering for production of resveratrol and its value-added derivatives in microbial hosts.

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References

  1. Sun P, Liang JL, Kang LZ, Huang XY, Huang JJ, Ye ZW, et al. Increased resveratrol production in wines using engineered wine strains Saccharomyces cerevisiae EC1118 and relaxed antibiotic or auxotrophic selection. Biotechnol Prog. 2015;31(3):650–5.

    Article  CAS  Google Scholar 

  2. Ferreira S, Domingues F. The antimicrobial action of resveratrol against Listeria monocytogenes in food-based models and its antibiofilm properties. J Sci Food Agric. 2016;96(13):4531–5.

    Article  CAS  Google Scholar 

  3. Kiselev KV, Shumakova OA, Maniakhin A. Effect of plant stilbene precursors on the biosynthesis of resveratrol in Vitis amurensis Rupr. Cell cultures. Prikl Biokhim Mikrobiol. 2013;49(1):61–6.

    CAS  Google Scholar 

  4. Jeandet P, Hebrard C, Deville MA, Cordelier S, Dorey S, Aziz A, et al. Deciphering the role of phytoalexins in plant-microorganism interactions and human health. Molecules. 2014;19(11):18033–56.

    Article  Google Scholar 

  5. Shin SY, Jung SM, Kim MD, Han NS, Seo JH. Production of resveratrol from tyrosine in metabolically engineered Saccharomyces cerevisiae. Enzyme Microb Technol. 2012;51(4):211–6.

    Article  CAS  Google Scholar 

  6. Latruffe N, Rifler JP. Bioactive polyphenols from grapes and wine emphasized with resveratrol. Curr Pharm Des. 2013;19(34):6053–63.

    Article  CAS  Google Scholar 

  7. Xia N, Daiber A, Forstermann U, Li H. Antioxidant effects of resveratrol in the cardiovascular system. Br J Pharmacol. 2016;174(12):1633–46.

    Google Scholar 

  8. Tellone E, Galtieri A, Russo A, Giardina B, Ficarra S. Resveratrol: a focus on several neurodegenerative diseases. Oxidative Med Cell Longev. 2015;doi:10.1155/2015/392169.

    Google Scholar 

  9. Rege SD, Geetha T, Griffin GD, Broderick TL, Babu JR. Neuroprotective effects of resveratrol in Alzheimer disease pathology. Front Aging Neurosci. 2014;6:218.

    Article  Google Scholar 

  10. Bhullar KS, Hubbard BP. Lifespan and healthspan extension by resveratrol. BBA-Mol Basis Dis. 2015;1852(6):1209–18.

    Article  CAS  Google Scholar 

  11. Mei Y-Z, Liu R-X, Wang D-P, Wang X, Dai C-C. Biocatalysis and biotransformation of resveratrol in microorganisms. Biotechnol Lett. 2015;37(1):9–18.

    Article  CAS  Google Scholar 

  12. Wang TT, Schoene NW, Kim YS, Mizuno CS, Rimando AM. Differential effects of resveratrol and its naturally occurring methylether analogs on cell cycle and apoptosis in human androgen-responsive LNCaP cancer cells. Mol Nutr Food Res. 2010;54(3):335–44.

    Article  CAS  Google Scholar 

  13. Su D, Cheng Y, Liu M, Liu D, Cui H, Zhang B, et al. Comparision of piceid and resveratrol in antioxidation and antiproliferation activities in vitro. PLoS One. 2013;8(1):e54505.

    Article  CAS  Google Scholar 

  14. Martinez-Marquez A, Morante-Carriel JA, Ramirez-Estrada K, Cusido RM, Palazon J, Bru-Martinez R. Production of highly bioactive resveratrol analogues pterostilbene and piceatannol in metabolically engineered grapevine cell cultures. Plant Biotechnol J. 2016;14(9):1813–25.

    Article  CAS  Google Scholar 

  15. Muzzio M, Huang Z, SC H, Johnson WD, McCormick DL, Kapetanovic IM. Determination of resveratrol and its sulfate and glucuronide metabolites in plasma by LC-MS/MS and their pharmacokinetics in dogs. J Pharm Biomed Anal. 2012;59:201–8.

    Article  CAS  Google Scholar 

  16. Gambini J, Ingles M, Olaso G, Lopez-Grueso R, Bonet-Costa V, Gimeno-Mallench L, et al. Properties of resveratrol: in vitro and in vivo studies about metabolism, bioavailability, and biological effects in animal models and humans. Oxidative Med Cell Longev. 2015;doi:10.1155/2015/837042.

    Google Scholar 

  17. Schneider Y, Chabert P, Stutzmann J, Coelho D, Fougerousse A, Gossé F, et al. Resveratrol analog (Z)-3, 5, 4′-trimethoxystilbene is a potent anti-mitotic drug inhibiting tubulin polymerization. Int J Cancer. 2003;107(2):189–96.

    Article  CAS  Google Scholar 

  18. Antus C, Radnai B, Dombovari P, Fonai F, Avar P, Matyus P, et al. Anti-inflammatory effects of a triple-bond resveratrol analog: structure and function relationship. Eur J Pharmacol. 2015;748:61–7.

    Article  CAS  Google Scholar 

  19. Fulda S. Resveratrol and derivatives for the prevention and treatment of cancer. Drug Discov Today. 2010;15(17–18):757–65.

    Article  CAS  Google Scholar 

  20. Madadi NR, Zong HL, Ketkar A, Zheng C, Penthala NR, Janganati V, et al. Synthesis and evaluation of a series of resveratrol analogues as potent anti-cancer agents that target tubulin. Medchemcomm. 2015;6(5):788–94.

    Article  CAS  Google Scholar 

  21. Savio M, Ferraro D, Maccario C, Vaccarone R, Jensen LD, Corana F, et al. Resveratrol analogue 4,4 '-dihydroxy-trans-stilbene potently inhibits cancer invasion and metastasis. Sci Rep-Uk. 2016:6.

    Google Scholar 

  22. Wang Y, Bhuiya MW, Zhou R, Yu O. Pterostilbene production by microorganisms expressing resveratrol O-methyltransferase. Ann Microbiol. 2015;65(2):817–26.

    Article  CAS  Google Scholar 

  23. Wang S, Zhang S, Xiao A, Rasmussen M, Skidmore C, Zhan J. Metabolic engineering of Escherichia coli for the biosynthesis of various phenylpropanoid derivatives. Metab Eng. 2015;29:153–9.

    Article  CAS  Google Scholar 

  24. Lin Y, Jain R, Yan Y. Microbial production of antioxidant food ingredients via metabolic engineering. Curr Opin Biotechnol. 2014;26:71–8.

    Article  CAS  Google Scholar 

  25. Mora-Pale M, Sanchez-Rodriguez SP, Linhardt RJ, Dordick JS, Koffas MA. Metabolic engineering and in vitro biosynthesis of phytochemicals and non-natural analogues. Plant Sci. 2013;210:10–24.

    Article  CAS  Google Scholar 

  26. Delaunois B, Cordelier S, Conreux A, Clément C, Jeandet P. Molecular engineering of resveratrol in plants. Plant Biotechnol J. 2009;7(1):2–12.

    Article  CAS  Google Scholar 

  27. Donnez D, Jeandet P, Clément C, Courot E. Bioproduction of resveratrol and stilbene derivatives by plant cells and microorganisms. Trends Biotechnol. 2009;27(12):706–13.

    Article  CAS  Google Scholar 

  28. Almagro L, Belchí-Navarro S, Sabater-Jara AB, Vera-Urbina JC, Sellés-Marchart S, Bru R, et al. Bioproduction of trans-resveratrol from grapevine cell cultures. In: Natural Products. Berlin Heidelberg: Springer; 2013. p. 1683–713.

    Chapter  Google Scholar 

  29. Giovinazzo G, Ingrosso I, Paradiso A, De Gara L, Santino A. Resveratrol biosynthesis: plant metabolic engineering for nutritional improvement of food. Plant Foods Hum Nutr. 2012;67(3):191–9.

    Article  CAS  Google Scholar 

  30. Jeandet P, Clément C, Courot E. Resveratrol production at large scale using plant cell suspensions. Eng Life Sci. 2014;14(6):622–32.

    Article  CAS  Google Scholar 

  31. Halls C, Yu O. Potential for metabolic engineering of resveratrol biosynthesis. Trends Biotechnol. 2008;26(2):77–81.

    Article  CAS  Google Scholar 

  32. Li M, Kildegaard KR, Chen Y, Rodriguez A, Borodina I, Nielsen J. De novo production of resveratrol from glucose or ethanol by engineered Saccharomyces cerevisiae. Metab Eng. 2015;32:1–11.

    Article  Google Scholar 

  33. Kang S-Y, Lee JK, Choi O, Kim CY, Jang J-H, Hwang BY, et al. Biosynthesis of methylated resveratrol analogs through the construction of an artificial biosynthetic pathway in E. coli. BMC Biotechnol. 2014;14(1):1.

    Article  Google Scholar 

  34. Kallscheuer N, Vogt M, Stenzel A, Gätgens J, Bott M, Marienhagen J. Construction of a Corynebacterium glutamicum platform strain for the production of stilbenes and (2S)-flavanones. Metab Eng. 2016;38:47–55.

    Google Scholar 

  35. Liu X, Lin J, Hu H, Zhou B, Zhu B. De novo biosynthesis of resveratrol by site-specific integration of heterologous genes in Escherichia coli. FEMS Microbiol Lett. 2016;363(8):fnw061.

    Article  Google Scholar 

  36. Krivoruchko A, Nielsen J. Production of natural products through metabolic engineering of Saccharomyces cerevisiae. Curr Opin Biotechnol. 2015;35:7–15.

    Article  CAS  Google Scholar 

  37. Wang J, Guleria S, Koffas MA, Yan Y. Microbial production of value-added nutraceuticals. Curr Opin Biotechnol. 2016;37:97–104.

    Article  Google Scholar 

  38. Beekwilder J, Wolswinkel R, Jonker H, Hall R, de Vos CR, Bovy A. Production of resveratrol in recombinant microorganisms. Appl Environ Microbiol. 2006;72(8):5670–2.

    Article  CAS  Google Scholar 

  39. Sydor T, Schaffer S, Boles E. Considerable increase in resveratrol production by recombinant industrial yeast strains with use of rich medium. Appl Environ Microbiol. 2010;76(10):3361–3.

    Article  CAS  Google Scholar 

  40. Shin S-Y, Han NS, Park Y-C, Kim M-D, Seo J-H. Production of resveratrol from p-coumaric acid in recombinant Saccharomyces cerevisiae expressing 4-coumarate: coenzyme a ligase and stilbene synthase genes. Enzym Microb Technol. 2011;48(1):48–53.

    Article  CAS  Google Scholar 

  41. Wang Y, Halls C, Zhang J, Matsuno M, Zhang Y, Yu O. Stepwise increase of resveratrol biosynthesis in yeast Saccharomyces cerevisiae by metabolic engineering. Metab Eng. 2011;13(5):455–63.

    Article  CAS  Google Scholar 

  42. Wang Y, Yu O. Synthetic scaffolds increased resveratrol biosynthesis in engineered yeast cells. J Biotechnol. 2012;157(1):258–60.

    Article  CAS  Google Scholar 

  43. Watts KT, Lee PC, Schmidt-Dannert C. Biosynthesis of plant-specific stilbene polyketides in metabolically engineered Escherichia coli. BMC Biotechnol. 2006;6(1):22.

    Article  Google Scholar 

  44. Katsuyama Y, Funa N, Miyahisa I, Horinouchi S. Synthesis of unnatural flavonoids and stilbenes by exploiting the plant biosynthetic pathway in Escherichia coli. Chem Biol. 2007;14(6):613–21.

    Article  CAS  Google Scholar 

  45. Zhang E, Guo X, Meng Z, Wang J, Sun J, Yao X, et al. Construction, expression, and characterization of Arabidopsis thaliana 4CL and Arachis hypogaea RS fusion gene 4CL:: RS in Escherichia coli. World J Microbiol Biotechnol. 2015;31(9):1379–85.

    Article  CAS  Google Scholar 

  46. Yang Y, Lin Y, Li L, Linhardt RJ, Yan Y. Regulating malonyl-CoA metabolism via synthetic antisense RNAs for enhanced biosynthesis of natural products. Metab Eng. 2015;29:217–26.

    Article  CAS  Google Scholar 

  47. Lim CG, Fowler ZL, Hueller T, Schaffer S, Koffas MA. High-yield resveratrol production in engineered Escherichia coli. Appl Environ Microbiol. 2011;77(10):3451–60.

    Article  CAS  Google Scholar 

  48. Bhan N, Xu P, Khalidi O, Koffas MA. Redirecting carbon flux into malonyl-CoA to improve resveratrol titers: proof of concept for genetic interventions predicted by OptForce computational framework. Chem Eng Sci. 2013;103:109–14.

    Article  CAS  Google Scholar 

  49. Katsuyama Y, Funa N, Horinouchi S. Precursor-directed biosynthesis of stilbene methyl ethers in Escherichia coli. Biotechnol J. 2007;2(10):1286–93.

    Article  CAS  Google Scholar 

  50. Wu J, Liu P, Fan Y, Bao H, Du G, Zhou J, et al. Multivariate modular metabolic engineering of Escherichia coli to produce resveratrol from L-tyrosine. J Biotechnol. 2013;167(4):404–11.

    Article  CAS  Google Scholar 

  51. Choi O, C-Z W, Kang SY, Ahn JS, Uhm T-B, Hong Y-S. Biosynthesis of plant-specific phenylpropanoids by construction of an artificial biosynthetic pathway in Escherichia coli. J Ind Microbiol Biotechnol. 2011;38(10):1657–65.

    Article  CAS  Google Scholar 

  52. Zhang Y, Li S-Z, Li J, Pan X, Cahoon RE, Jaworski JG, et al. Using unnatural protein fusions to engineer resveratrol biosynthesis in yeast and mammalian cells. J Am Chem Soc. 2006;128(40):13030–1.

    Article  CAS  Google Scholar 

  53. Marienhagen J, Bott M. Metabolic engineering of microorganisms for the synthesis of plant natural products. J Biotechnol. 2013;163(2):166–78.

    Article  CAS  Google Scholar 

  54. Huang Q, Lin Y, Yan Y. Caffeic acid production enhancement by engineering a phenylalanine over-producing Escherichia coli strain. Biotechnol Bioeng. 2013;110(12):3188–96.

    Article  CAS  Google Scholar 

  55. van Summeren-Wesenhagen PV, Marienhagen J. Metabolic engineering of Escherichia coli for the synthesis of the plant polyphenol pinosylvin. Appl Environ Microbiol. 2015;81(3):840–9.

    Article  Google Scholar 

  56. Liang JL, Guo LQ, Lin J-F, He Z-Q, Cai F-J, Chen J-F. A novel process for obtaining pinosylvin using combinatorial bioengineering in Escherichia coli. World J Microbiol Biotechnol. 2016;32(6):1–10.

    Article  CAS  Google Scholar 

  57. Kim D-H, Ahn T, Jung H-C, Pan J-G, Yun C-H. Generation of the human metabolite piceatannol from the anticancer-preventive agent resveratrol by bacterial cytochrome P450 BM3. Drug Metab Dispos. 2009;37(5):932–6.

    Article  CAS  Google Scholar 

  58. Lee N, Kim EJ, Kim B-G. Regioselective hydroxylation of trans-resveratrol via inhibition of tyrosinase from Streptomyces avermitilis MA4680. ACS Chem Biol. 2012;7(10):1687–92.

    Article  CAS  Google Scholar 

  59. Furuya T, Kino K. Regioselective synthesis of piceatannol from resveratrol: catalysis by two-component flavin-dependent monooxygenase HpaBC in whole cells. Tetrahedron Lett. 2014;55(17):2853–5.

    Article  CAS  Google Scholar 

  60. Jeong YJ, An CH, Woo SG, Jeong HJ, Kim Y-M, Park S-J, et al. Production of pinostilbene compounds by the expression of resveratrol O-methyltransferase genes in Escherichia coli. Enzym Microb Technol. 2014;54:8–14.

    Article  CAS  Google Scholar 

  61. Baerson SR, Dayan FE, Rimando AM, Nanayakkara ND, Liu C-J, Schröder J, et al. A functional genomics investigation of allelochemical biosynthesis in Sorghum Bicolor root hairs. J Biol Chem. 2008;283(6):3231–47.

    Article  CAS  Google Scholar 

  62. Rimando AM, Pan Z, Polashock JJ, Dayan FE, Mizuno CS, Snook ME, et al. In planta production of the highly potent resveratrol analogue pterostilbene via stilbene synthase and O-methyltransferase co-expression. Plant Biotechnol J. 2012;10(3):269–83.

    Article  CAS  Google Scholar 

  63. Schmidlin L, Poutaraud A, Claudel P, Mestre P, Prado E, Santos-Rosa M, et al. A stress-inducible resveratrol O-methyltransferase involved in the biosynthesis of pterostilbene in grapevine. Plant Physiol. 2008;148(3):1630–9.

    Article  CAS  Google Scholar 

  64. Ozaki S-i, Imai H, Iwakiri T, Sato T, Shimoda K, Nakayama T, et al. Regioselective glucosidation of trans-resveratrol in Escherichia coli expressing glucosyltransferase from Phytolacca americana. Biotechnol Lett. 2012;34(3):475–81.

    Article  CAS  Google Scholar 

  65. Choi O, Lee JK, Kang S-Y, Pandey RP, Sohng J-K, Ahn JS, et al. Construction of artificial biosynthetic pathways for resveratrol glucoside derivatives. J Microbiol Biotechnol. 2014;24(5):614–8.

    Article  CAS  Google Scholar 

  66. Rodriguez A, Kildegaard KR, Li M, Borodina I, Nielsen J. Establishment of a yeast platform strain for production of p-coumaric acid through metabolic engineering of aromatic amino acid biosynthesis. Metab Eng. 2015;31:181–8.

    Article  CAS  Google Scholar 

  67. Juminaga D, Baidoo EE, Redding-Johanson AM, Batth TS, Burd H, Mukhopadhyay A, et al. Modular engineering of L-tyrosine production in Escherichia coli. Appl Environ Microbiol. 2012;78(1):89–98.

    Article  CAS  Google Scholar 

  68. Zhang H, Stephanopoulos G. Engineering E. coli for caffeic acid biosynthesis from renewable sugars. Appl Microbiol Biotechnol. 2013;97(8):3333–41.

    Article  CAS  Google Scholar 

  69. Lütke-Eversloh T, Stephanopoulos G. L-tyrosine production by deregulated strains of Escherichia coli. Appl Microbiol Biotechnol. 2007;75(1):103–10.

    Article  Google Scholar 

  70. Chávez-Béjar MI, Lara AR, López H, Hernández-Chávez G, Martinez A, Ramírez OT, et al. Metabolic engineering of Escherichia coli for L-tyrosine production by expression of genes coding for the chorismate mutase domain of the native chorismate mutase-prephenate dehydratase and a cyclohexadienyl dehydrogenase from Zymomonas mobilis. Appl Environ Microbiol. 2008;74(10):3284–90.

    Article  Google Scholar 

  71. Lütke-Eversloh T, Stephanopoulos G. Combinatorial pathway analysis for improved L-tyrosine production in Escherichia coli: identification of enzymatic bottlenecks by systematic gene overexpression. Metab Eng. 2008;10(2):69–77.

    Article  Google Scholar 

  72. Jiang H, Wood KV, Morgan JA. Metabolic engineering of the phenylpropanoid pathway in Saccharomyces cerevisiae. Appl Environ Microbiol. 2005;71(6):2962–9.

    Article  CAS  Google Scholar 

  73. Bulter T, Bernstein JR, Liao JC. A perspective of metabolic engineering strategies: moving up the systems hierarchy. Biotechnol Bioeng. 2003;84(7):815–21.

    Article  CAS  Google Scholar 

  74. Na D, Yoo SM, Chung H, Park H, Park JH, Lee SY. Metabolic engineering of Escherichia coli using synthetic small regulatory RNAs. Nat Biotechnol. 2013;31(2):170–4.

    Article  CAS  Google Scholar 

  75. Takamura Y, Nomura G. Changes in the intracellular concentration of acetyl-CoA and malonyl-CoA in relation to the carbon and energy metabolism of Escherichia coli K12. Microbiology. 1988;134(8):2249–53.

    Article  CAS  Google Scholar 

  76. Zha W, Rubin-Pitel SB, Shao Z, Zhao H. Improving cellular malonyl-CoA level in Escherichia coli via metabolic engineering. Metab Eng. 2009;11(3):192–8.

    Article  CAS  Google Scholar 

  77. Finzel K, Lee DJ, Burkart MD. Using modern tools to probe the structure–function relationship of fatty acid synthases. Chembiochem. 2015;16(4):528–47.

    Article  CAS  Google Scholar 

  78. Lu Y, Shao D, Shi J, Huang Q, Yang H, Jin M. Strategies for enhancing resveratrol production and the expression of pathway enzymes. Appl Microbiol Biotechnol. 2016;100(17):7407–21.

    Google Scholar 

  79. Wu J, Yu O, Du G, Zhou J, Chen J. Fine-tuning of the fatty acid pathway by synthetic antisense RNA for enhanced (2S)-naringenin production from L-tyrosine in Escherichia coli. Appl Environ Microbiol. 2014;80(23):7283–92.

    Article  Google Scholar 

  80. Wu J, Du G, Chen J, Zhou J. Enhancing flavonoid production by systematically tuning the central metabolic pathways based on a CRISPR interference system in Escherichia coli. Sci Rep. 2015;5

    Google Scholar 

  81. Wang Y, Yi H, Wang M, Yu O, Jez JM. Structural and kinetic analysis of the unnatural fusion protein 4-coumaroyl-CoA ligase:: stilbene synthase. J Am Chem Soc. 2011;133(51):20684–7.

    Article  CAS  Google Scholar 

  82. Dueber JE, GC W, Malmirchegini GR, Moon TS, Petzold CJ, Ullal AV, et al. Synthetic protein scaffolds provide modular control over metabolic flux. Nat Biotechnol. 2009;27(8):753–9.

    Article  CAS  Google Scholar 

  83. Bhan N, Cress BF, Linhardt RJ, Koffas M. Expanding the chemical space of polyketides through structure-guided mutagenesis of Vitis vinifera stilbene synthase. Biochimie. 2015;115:136–43.

    Article  CAS  Google Scholar 

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Wang, J., Yang, Y., Yan, Y. (2018). Bioproduction of Resveratrol. In: Schwab, W., Lange, B., Wüst, M. (eds) Biotechnology of Natural Products. Springer, Cham. https://doi.org/10.1007/978-3-319-67903-7_3

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