Abstract
The polyphenol resveratrol (3,5,4′-trihydroxystilbene) is a well-known plant secondary metabolite, commonly used as a medical ingredient and a nutritional supplement. Due to its health-promoting properties, the demand for resveratrol is expected to continue growing. This stilbene can be found in different plants, including grapes, berries (blackberries, blueberries and raspberries), peanuts and their derived food products, such as wine and juice. The commercially available resveratrol is usually extracted from plants, however this procedure has several drawbacks such as low concentration of the product of interest, seasonal variation, risk of plant diseases and product stability. Alternative production processes are being developed to enable the biotechnological production of resveratrol by genetically engineering several microbial hosts, such as Escherichia coli, Corynebacterium glutamicum, Lactococcus lactis, among others. However, these bacterial species are not able to naturally synthetize resveratrol and therefore genetic modifications have been performed. The application of emerging metabolic engineering offers new possibilities for strain and process optimization. This mini-review will discuss the recent progress on resveratrol biosynthesis in engineered bacteria, with a special focus on the metabolic engineering modifications, as well as the optimization of the production process. These strategies offer new tools to overcome the limitations and challenges for microbial production of resveratrol in industry.
Similar content being viewed by others
References
Abe I, Watanabe T, Noguchi H (2004) Enzymatic formation of long-chain polyketide pyrones by plant type III polyketide synthases. Phytochemistry 65:2447–2453. https://doi.org/10.1016/j.phytochem.2004.08.005
Afonso MS, Ferreira S, Domingues FC, Silva F (2015) Resveratrol production in bioreactor: assessment of cell physiological states and plasmid segregational stability. Biotechnol Rep 5:7–13. https://doi.org/10.1016/j.btre.2014.10.008
Aggarwal BB, Bhardwaj A, Aggarwal RS et al (2004) Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res 24.5A:2783–2840
An JH, Kim YS (1998) A gene cluster encoding malonyl-CoA decarboxylase (MatA), malonyl-CoA synthetase (MatB) and a putative dicarboxylate carrier protein (MatC) in Rhizobium trifolii. Cloning, sequencing, and expression of the enzymes in Escherichia coli. Eur J Biochem 257:395–402. https://doi.org/10.1046/j.1432-1327.1998.2570395.x
Anekonda TS (2006) Resveratrol-A boon for treating Alzheimer’s disease? Brain Res Rev 52:316–326. https://doi.org/10.1016/j.brainresrev.2006.04.004
Bauer JH, Goupil S, Garber GB, Helfand SL (2004) An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster. Proc Natl Acad Sci 101:12980–12985. https://doi.org/10.1073/pnas.0403493101
Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506. https://doi.org/10.1038/nrd2060
Bavaresco L, Petegolli D, Cantù E et al (1997) Elicitation and accumulation of stilbene phytoalexins in grapevine berries infected by Botrytis cinerea. Vitis 36:77–83
Beekwilder J, Wolswinkel R, Jonker H et al (2006) Production of resveratrol in recombinant microorganisms. Appl Environ Microbiol 72:5670–5672. https://doi.org/10.1128/AEM.00609-06
Berg J, Tymoczko J, Stryer L (2002) Biochemistry. New York, New York, p 10010
Blond J, Denis M, Bezard J (1995) Antioxidant action of resveratrol in lipid peroxidation. Sci Aliments 15:347–358
Braga A, Oliveira J, Silva R et al (2018a) Impact of the cultivation strategy on resveratrol production from glucose in engineered Corynebacterium glutamicum. J Biotechnol 265:70–75. https://doi.org/10.1016/j.jbiotec.2017.11.006
Braga A, Silva M, Oliveira J et al (2018b) An adsorptive bioprocess for production and recovery of resveratrol with Corynebacterium glutamicum. J Chem Technol Biotechnol. https://doi.org/10.1002/jctb.5538
Bulter T, Bernstein JR, Liao JC (2003) A perspective of metabolic engineering strategies: moving up the systems hierarchy. Biotechnol Bioeng 84:815–821. https://doi.org/10.1002/bit.10845
Camacho-Zaragoza JM, Hernández-Chávez G, Moreno-Avitia F et al (2016) Engineering of a microbial coculture of Escherichia coli strains for the biosynthesis of resveratrol. Microb Cell Fact 15:163. https://doi.org/10.1186/s12934-016-0562-z
Choi O, Wu C-Z, Kang SY et al (2011) Biosynthesis of plant-specific phenylpropanoids by construction of an artificial biosynthetic pathway in Escherichia coli. J Ind Microbiol Biotechnol 38:1657–1665. https://doi.org/10.1007/s10295-011-0954-3
de Fouchécour F, Sánchez-Castañeda A-K, Saulou-Bérion C, Spinnler H (2018) Process engineering for microbial production of 3-hydroxypropionic acid. Biotechnol Adv. https://doi.org/10.1016/j.biotechadv.2018.03.020
Du J, Shao Z, Zhao H (2013) Engineering microbial factories for synthesis of value-added products. J Ind Microbiol Biotechnol 38:873–890. https://doi.org/10.1109/TMI.2012.2196707
Finzel K, Lee DJ, Burkart MD (2015) Using modern tools to probe the structure-function relationship of fatty acid synthases. ChemBioChem 16:528–547. https://doi.org/10.1002/cbic.201402578
Fowler ZL, Gikandi WW, Koffas MAG (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. https://doi.org/10.1128/AEM.00270-09
Frankel EN, Waterhouse AL, Kinsella JE (1993) Inhibition of human LDL oxidation by resveratrol. Lancet 341:1103–1104. https://doi.org/10.1016/0140-6736(93)92472-6
Gaspar P, Dudnik A, Neves AR, Föster J (2016) Engineering Lactococcus lactis for stilbene production. In: Abstract from 28th International Conference on Polyphenols 2016. Vienna, Austria
Halls C, Yu O (2008) Potential for metabolic engineering of resveratrol biosynthesis. Trends Biotechnol 26:77–81. https://doi.org/10.1016/j.tibtech.2007.11.002
Hamberger B, Hahlbrock K (2004) The 4-coumarate:CoA ligase gene family in Arabidopsis thaliana comprises one rare, sinapate-activating and three commonly occurring isoenzymes. Proc Natl Acad Sci 101:2209–2214. https://doi.org/10.1073/pnas.0307307101
Hua D, Ma C, Song L et al (2007) Enhanced vanillin production from ferulic acid using adsorbent resin. Appl Microbiol Biotechnol 74:783–790. https://doi.org/10.1007/s00253-006-0735-5
Huang Q, Lin Y, Yan Y (2013) Caffeic acid production enhancement by engineering a phenylalanine over-producing Escherichia coli strain. Biotechnol Bioeng 110:3188–3196. https://doi.org/10.1002/bit.24988
Hubbard BP, Sinclair DA (2014) Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci 35:146–154. https://doi.org/10.1016/j.tips.2013.12.004
Jiang H, Wood KV, Morgan J (2005) Metabolic engineering of the phenylpropanoid pathway in Saccharomyces cerevisiae. Appl Environ Microbiol 71:2962–2969. https://doi.org/10.1128/AEM.71.6.2962
Kallscheuer N, Vogt M, Stenzel A et al (2016) Construction of a Corynebacterium glutamicum platform strain for the production of stilbenes and (2S)-flavanones. Metab Eng 38:47–55. https://doi.org/10.1016/j.ymben.2016.06.003
Katsuyama Y, Funa N, Horinouchi S (2007) Precursor-directed biosynthesis of stilbene methyl ethers in Escherichia coli. Biotechnol J 2:1286–1293. https://doi.org/10.1002/biot.200700098
Kiselev KV (2011) Perspectives for production and application of resveratrol. Appl Microbiol Biotechnol 90:417–425. https://doi.org/10.1007/s00253-011-3184-8
Kloosterman H, Hessels GI, Vrijbloed JW et al (2003) (De)regulation of key enzyme steps in the shikimate pathway and phenylalanine-specific pathway of the actinomycete Amycolatopsis methanolica. Microbiology 149:3321–3330. https://doi.org/10.1099/mic.0.26494-0
Kundu JK, Surh YJ (2008) Cancer chemopreventive and therapeutic potential of resveratrol: mechanistic perspectives. Cancer Lett 269:243–261. https://doi.org/10.1016/j.canlet.2008.03.057
Li M, Kildegaard KR, Chen Y et al (2015) De novo production of resveratrol from glucose or ethanol by engineered Saccharomyces cerevisiae. Metab Eng 32:1–11. https://doi.org/10.1016/j.ymben.2015.08.007
Li M, Schneider K, Kristensen M et al (2016) Engineering yeast for high-level production of stilbenoid antioxidants. Sci Rep 6:1–8. https://doi.org/10.1038/srep36827
Light SH, Halavaty AS, Minasov G et al (2012) Structural analysis of a 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase with an N-terminal chorismate mutase-like regulatory domain. Protein Sci 21:887–895. https://doi.org/10.1002/pro.2075
Lim CG, Fowler ZL, Hueller T et al (2011) High-yield resveratrol production in engineered Escherichia coli. Appl Environ Microbiol 77:3451–3460. https://doi.org/10.1128/AEM.02186-10
Liu X, Lin J, Hu H et al (2016) De novo biosynthesis of resveratrol by site-specific integration of heterologous genes in Escherichia coli. FEMS Microbiol Lett 363:1–5. https://doi.org/10.1093/femsle/fnw061
Lozoya E, Hoffmann H, Douglas C et al (1988) Primary structures and catalytic properties of isoenzymes encoded by the two 4-coumarate:CoA ligase genes in parsley. Eur J Biochem 176:661–667. https://doi.org/10.1111/j.1432-1033.1988.tb14328.x
Lu Y, Shao D, Shi J et al (2016) Strategies for enhancing resveratrol production and the expression of pathway enzymes. Appl Microbiol Biotechnol 100:7407–7421. https://doi.org/10.1007/s00253-016-7723-1
Lucas-Abellán C, Fortea I, López-Nicolás JM, Núñez-Delicado E (2007) Cyclodextrins as resveratrol carrier system. Food Chem 104:39–44. https://doi.org/10.1016/j.foodchem.2006.10.068
Lütke-Eversloh T, Stephanopoulos G (2007) L-Tyrosine production by deregulated strains of Escherichia coli. Appl Microbiol Biotechnol 75:103–110. https://doi.org/10.1007/s00253-006-0792-9
Maeda H, Dudareva N (2012) The Shikimate pathway and aromatic amino acid biosynthesis in plants. Annu Rev Plant Biol 63:73–105. https://doi.org/10.1146/annurev-arplant-042811-105439
Makrides SC (1996) Strategies for achieving high-level expression of genes in Escherichia coli. Microbiol Rev 60:512–538
Mei YZ, Liu RX, Wang DP et al (2015) Biocatalysis and biotransformation of resveratrol in microorganisms. Biotechnol Lett 37:9–18. https://doi.org/10.1007/s10529-014-1651-x
Milke L, Aschenbrenner J, Marienhagen J, Kallscheuer N (2018) Production of plant-derived polyphenols in microorganisms: current state and perspectives. Appl Microbiol Biotechnol. https://doi.org/10.1007/s00253-018-8747-5
Morita H, Noguchi H, Schröder J, Abe I (2001) Novel polyketides synthesized with a higher plant stilbene synthase. Eur J Biochem 268:3759–3766. https://doi.org/10.1046/j.1432-1327.2001.02289.x
Na D, Yoo SM, Chung H et al (2013) Metabolic engineering of Escherichia coli using synthetic small regulatory RNAs. Nat Biotechnol 31:170–174. https://doi.org/10.1038/nbt.2461
Nonomura S, Kanagawa H, Makimoto A (1963) Chemical constituents of polygonaceous plants. I. Studies on the components of Ko-J O-Kon. (Polygonum cuspidatum Sieb. Et Zucc.). Yakugaku Zasshi 83:988–990
Park SR, Yoon JA, Paik JH et al (2009) Engineering of plant-specific phenylpropanoids biosynthesis in Streptomyces venezuelae. J Biotechnol 141:181–188. https://doi.org/10.1016/j.jbiotec.2009.03.013
Quideau S, Deffieux D, Douat-Casassus C, Pouységu L (2011) Plant polyphenols: chemical properties, biological activities, and synthesis. Angew Chemie-Int Ed 50:586–621. https://doi.org/10.1002/anie.201000044
Rodrigues JL, Prather KLJ, Kluskens LD, Rodrigues LR (2015) Heterologous production of curcuminoids. Microbiol Mol Biol Rev 79:39–60. https://doi.org/10.1128/MMBR.00031-14
Rosano GL, Ceccarelli EA (2014) Recombinant protein expression in Escherichia coli: advances and challenges. Front Microbiol 5:1–17. https://doi.org/10.3389/fmicb.2014.00172
Santos CNS, Koffas M, Stephanopoulos G (2011) Optimization of a heterologous pathway for the production of flavonoids from glucose. Metab Eng 13:392–400. https://doi.org/10.1016/j.ymben.2011.02.002
Schroeder AC, Kumaran S, Hicks LM et al (2008) Contributions of conserved serine and tyrosine residues to catalysis, ligand binding, and cofactor processing in the active site of tyrosine ammonia lyase. Phytochemistry 69:1496–1506. https://doi.org/10.1016/j.phytochem.2008.02.007
Sharma S, Kulkarni SK, Chopra K (2007) Effect of resveratrol, a polyphenolic phytoalexin, on thermal hyperalgesia in a mouse model of diabetic neuropathic pain. Fundam Clin Pharmacol 21:89–94. https://doi.org/10.1111/j.1472-8206.2006.00455.x
Shin SY, Han NS, Park YC et al (2011) Production of resveratrol from p-coumaric acid in recombinant Saccharomyces cerevisiae expressing 4-coumarate:coenzyme A ligase and stilbene synthase genes. Enzyme Microb Technol 48:48–53. https://doi.org/10.1016/j.enzmictec.2010.09.004
So-Yeon S, Nam SH, Yong-Cheol P et al (2011) Production of resveratrol from p-coumaric acid in recombinant Saccharomyces cerevisiae expressing 4-coumarate:coenzyme A ligase and stilbene synthase genes. Enzyme Microb Technol 48:48–53. https://doi.org/10.1016/j.enzmictec.2010.09.004
Subrahmanyam S Jr, Cronan JE (1998) Overproduction of a functional fatty acid biosynthetic enzyme blocks fatty acid synthesis in Escherichia coli. J Bacteriol 180:4596–4602
Sydor T, Schaffer S, Boles E (2010) Considerable increase in resveratrol production by recombinant industrial yeast strains with use of rich medium. Appl Environ Microbiol 76:3361–3363. https://doi.org/10.1128/AEM.02796-09
Takamura Y, Nomura G (1988) Changes in the intracellular concentration of Acetyl-CoA and Malonyl-CoA in relation to the carbon and energy metabolism of Escherichia coli K12. J Gen Microbiol 134:2249–2253
Takaoka M (1939) Resveratrol, a new phenolic compound, from Veratrumgrandiflorum. J Chem Soc Japan 60:1090–1100
Tee KL, Wong TS (2013) Polishing the craft of genetic diversity creation in directed evolution. Biotechnol Adv 31:1707–1721. https://doi.org/10.1016/j.biotechadv.2013.08.021
Theisen M, Liao JC (2016) Industrial biotechnology: Escherichia coli as a host. In: Industrial biotechnology. Wiley, New York, pp 149–181
Trošt K, Golc-Wondra A, Prošek M (2009) Degradation of polyphenolic antioxidants in blueberry nectar aseptically filled in PET. Acta Chim Slov 56:494–502
van Summeren-Wesenhagen PV, Marienhagen J (2013) Putting bugs to the blush: metabolic engineering for phenylpropanoid-derived products in microorganisms. Bioengineered 4:355–362. https://doi.org/10.4161/bioe.23885
van Summeren-Wesenhagen PV, Marienhagen J (2015) Metabolic engineering of Escherichia coli for the synthesis of the plant polyphenol pinosylvin. Appl Environ Microbiol 81:840–849. https://doi.org/10.1128/AEM.02966-14
Vannelli T, Wei Qi W, Sweigard J et al (2007) Production of p-hydroxycinnamic acid from glucose in Saccharomyces cerevisiae and Escherichia coli by expression of heterologous genes from plants and fungi. Metab Eng 9:142–151. https://doi.org/10.1016/j.ymben.2006.11.001
Vingtdeux V, Dreses-Werringloer U, Zhao H et al (2008) Therapeutic potential of resveratrol in Alzheimer’s disease. BMC Neurosci 9:1–5. https://doi.org/10.1186/1471-2202-9-S2-S6
Viswanathan M, Kim SK, Berdichevsky A, Guarente L (2005) A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Dev Cell 9:605–615. https://doi.org/10.1016/j.devcel.2005.09.017
Wang J, Ho L, Zhao Z et al (2006) Moderate consumption of Cabernet Sauvignon attenuates A neuropathology in a mouse model of Alzheimer’s disease. FASEB J 20:2313–2320. https://doi.org/10.1096/fj.06-6281com
Wang T, Ma X, Du G, Chen J (2012) Overview of regulatory strategies and molecular elements in metabolic engineering of bacteria. Mol Biotechnol 52:300–308. https://doi.org/10.1007/s12033-012-9514-y
Wang J, Yang Y, Yan Y (2018) Bioproduction of resveratrol. In: Biotechnology of natural products. Springer, Cham, pp 61–79
Watts KT, Lee PC, Schmidt-Dannert C (2006) Biosynthesis of plant-specific stilbene polyketides in metabolically engineered Escherichia coli. BMC Biotechnol 6:1–12. https://doi.org/10.1186/1472-6750-6-22
Wu J, Liu P, Fan Y et al (2013) Multivariate modular metabolic engineering of Escherichia coli to produce resveratrol from l-tyrosine. J Biotechnol 167:404–411. https://doi.org/10.1016/j.jbiotec.2013.07.030
Wu J, Zhou P, Zhang X, Dong M (2017) Efficient de novo synthesis of resveratrol by metabolically engineered Escherichia coli. J Ind Microbiol Biotechnol 44:1083–1095. https://doi.org/10.1007/s10295-017-1937-9
Xu P, Ranganathan S, Fowler ZL et al (2011) Genome-scale metabolic network modeling results in minimal interventions that cooperatively force carbon flux towards malonyl-CoA. Metab Eng 13:578–587. https://doi.org/10.1016/j.ymben.2011.06.008
Yang X, Li X, Ren J (2014) From French Paradox to cancer treatment: anti-cancer activities and mechanisms of resveratrol. Anti-Cancer Agents Med Chem (formerly Curr Med Chem Agents) 14:806–825
Yang Y, Lin Y, Li L et al (2015) Regulating malonyl-CoA metabolism via synthetic antisense RNAs for enhanced biosynthesis of natural products. Metab Eng 29:217–226. https://doi.org/10.1016/j.ymben.2015.03.018
Yesilirmak F, Sayers Z (2009) Heterelogous expression of plant genes. Int J Plant Genom. https://doi.org/10.1155/2009/296482
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. https://doi.org/10.1016/j.ymben.2009.01.005
Zhang H, Stephanopoulos G (2013) Engineering E. coli for caffeic acid biosynthesis from renewable sugars. Appl Microbiol Biotechnol 97:3333–3341. https://doi.org/10.1007/s00253-012-4544-8
Zhang Y, Li SZ, Li J et al (2006) Using unnatural protein fusions to engineer resveratrol biosynthesis in yeast and mammalian cells. J Am Chem Soc 128:13030–13031. https://doi.org/10.1021/ja0622094
Zhang E, Guo X, Meng Z et al (2015) Construction, expression, and characterization of Arabidopsis thaliana 4CL and Arachis hypogaea RS fusion gene 4CL::RS in Escherichia coli. World J Microbiol Biotechnol 31:1379–1385. https://doi.org/10.1007/s11274-015-1889-z1
Zhou K, Qiao K, Edgar S, Stephanopoulo G (2015) Distributing a metabolic pathway among a microbial consortium enhances production of natural products. Nat Biotechnol 33:377–383
Acknowledgements
We would like to thank the European Union Framework Program 7 “BacHBerry” (http://www.bachberry.eu), Project No. FP7-613793 for financial support, the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469 unit, COMPETE 2020 (POCI-01-0145-FEDER-006684) and BiotecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declared that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Braga, A., Ferreira, P., Oliveira, J. et al. Heterologous production of resveratrol in bacterial hosts: current status and perspectives. World J Microbiol Biotechnol 34, 122 (2018). https://doi.org/10.1007/s11274-018-2506-8
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11274-018-2506-8