Skip to main content
SpringerLink
Log in

The antioxidant hydroxytyrosol: biotechnological production challenges and opportunities

  • Mini-Review
  • Published:
Applied Microbiology and Biotechnology Aims and scope Submit manuscript

Abstract

Hydroxytyrosol (HT) is a highly potent antioxidant originating in nature as a second metabolite of plants, most abundantly in olives (Olea europaea). In the last decade, numerous research studies showed the health benefits of antioxidants in general and those of HT in particular. As olive oil is a prime constituent of the health-promoting Mediterranean diet, HT has obtained recognition for its attributes, supported by a recent health claim of the European Food Safety Authority. HT is already used as a food supplement and in cosmetic products, but it has the potential to be used as a food additive and drug, based on its anticarcinogenic, anti-inflammatory, antiapoptotic and neuroprotective activity. Nevertheless, there is a large gap between the potential of HT and its current availability in the market due to its high price tag. In this review, the challenges of producing HT using biotechnological methods are described with an emphasis on the substrate source, the biocatalyst and the process parameters, in order to narrow the gap towards an efficient bio-based industrial process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Achmon Y, Goldshtein J, Margel S, Fishman A (2011) Hydrophobic microspheres for in situ removal of 2-phenylethanol from yeast fermentation. J Microencapsul 28(7):628–638

    Article  CAS  PubMed  Google Scholar 

  • Achmon Y, Zelas ZB-B, Fishman A (2014) Cloning Rosa hybrid phenylacetaldehyde synthase for the production of 2-phenylethanol in a whole cell Escherichia coli system. Appl Microbiol Biotechnol 98(8):3603–3611

    Article  CAS  PubMed  Google Scholar 

  • Adhami H-R, Zehl M, Dangl C, Dorfmeister D, Stadler M, Urban E, Hewitson P, Ignatova S, Krenn L (2015) Preparative isolation of oleocanthal, tyrosol, and hydroxytyrosol from olive oil by HPCCC. Food Chem 170:154–159

    Article  CAS  PubMed  Google Scholar 

  • Allouche N, Damak M, Ellouz R, Sayadi S (2004) Use of whole cells of Pseudomonas aeruginosa for synthesis of the antioxidant hydroxytyrosol via conversion of tyrosol. Appl Environ Microbiol 70(4):2105–2109

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Anter J, Tasset I, Demyda-Peyras S, Ranchal I, Moreno-Millán M, Romero-Jimenez M, Muntané J, Castro MDL, Muñoz-Serrano A, Alonso-Moraga Á (2014) Evaluation of potential antigenotoxic, cytotoxic and proapoptotic effects of the olive oil by-product “alperujo”, hydroxytyrosol, tyrosol and verbascoside. Mut Res Genet Toxicol Environ Mutagen 772:25–33

    Article  CAS  Google Scholar 

  • Atsumi S, Hanai T, Liao JC (2008) Non-fermentative pathways for synthesis of branched-chain higher alcohols as biofuels. Nature 451(7174):86–89

    Article  CAS  PubMed  Google Scholar 

  • Auñon-Calles D, Canut L, Visioli F (2013) Toxicological evaluation of pure hydroxytyrosol. Food Chem Toxicol 55:498–504

    Article  PubMed  Google Scholar 

  • Azabou S, Najjar W, Ghorbel A, Sayadi S (2007) Mild photochemical synthesis of the antioxidant hydroxytyrosol via conversion of tyrosol. J Agric Food Chem 55(12):4877–4882

    Article  CAS  PubMed  Google Scholar 

  • Bali EB, Ergin V, Rackova L, Bayraktar O, Kucukboyaci N, Karasu C (2014) Olive leaf extracts protect cardiomyocytes against 4-hydroxynonenal-induced toxicity in vitro: comparison with oleuropein, hydroxytyrosol, and quercetin. Planta Med 80(12):984–992

    Article  CAS  PubMed  Google Scholar 

  • Bernath-Levin K, Shainsky J, Sigawi L, Fishman A (2014) Directed evolution of nitrobenzene dioxygenase for the synthesis of the antioxidant hydroxytyrosol. Appl Microbiol Biotechnol 98(11):4975–4985

    Article  CAS  PubMed  Google Scholar 

  • Bisignano C, Filocamo A, Ginestra G, Giofre SV, Navarra M, Romeo R, Mandalari G (2014) 3, 4-DHPEA-EA from Olea Europaea L. is effective against standard and clinical isolates of Staphylococcus sp. Ann Clin Microbiol Antimicrob 13(1):24–28

    Article  PubMed Central  PubMed  Google Scholar 

  • Bornscheuer U, Huisman G, Kazlauskas R, Lutz S, Moore J, Robins K (2012) Engineering the third wave of biocatalysis. Nature 485(7397):185–194

    Article  CAS  PubMed  Google Scholar 

  • Bouallagui Z, Sayadi S (2006) Production of high hydroxytyrosol yields via tyrosol conversion by Pseudomonas aeruginosa immobilized resting cells. J Agric Food Chem 54(26):9906–9911

    Article  CAS  PubMed  Google Scholar 

  • Bouaziz M, Sayadi S (2005) Isolation and evaluation of antioxidants from leaves of a Tunisian cultivar olive tree. Eur J Lipid Sci Technol 107(7–8):497–504

    Article  CAS  Google Scholar 

  • Bovicelli P, Antonioletti R, Mancini S, Causio S, Borioni G, Ammendola S, Barontini M (2007) Expedient synthesis of hydroxytyrosol and its esters. Synth Commun 37(23):4245–4252

    Article  CAS  Google Scholar 

  • Brooks SJ, Doyle EM, O’Connor KE (2006) Tyrosol to hydroxytyrosol biotransformation by immobilised cell extracts of Pseudomonas putida F6. Enzyme Microb Technol 39(2):191–196

    Article  CAS  Google Scholar 

  • Brouk M, Fishman A (2009) Protein engineering of toluene monooxygenases for synthesis of hydroxytyrosol. Food Chem 116(1):114–121

    Article  CAS  Google Scholar 

  • Brouk M, Fishman A (2012) Improving process conditions of hydroxytyrosol synthesis by toluene-4-monooxygenase. J Mol Catal B Enzym 84:121–127

    Article  CAS  Google Scholar 

  • Brouk M, Nov Y, Fishman A (2010) Improving biocatalyst performance by integrating statistical methods into protein engineering. Appl Environ Microbiol 76(19):6397–6403

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bulotta S, Celano M, Lepore SM, Montalcini T, Pujia A, Russo D (2014) Beneficial effects of the olive oil phenolic components oleuropein and hydroxytyrosol: focus on protection against cardiovascular and metabolic diseases. J Transl Med 12(1):219

    Article  PubMed Central  PubMed  Google Scholar 

  • Burattini S, Salucci S, Baldassarri V, Accorsi A, Piatti E, Madrona A, Espartero JL, Candiracci M, Zappia G, Falcieri E (2013) Anti-apoptotic activity of hydroxytyrosol and hydroxytyrosyl laurate. Food Chem Toxicol 55:248–256

    Article  CAS  PubMed  Google Scholar 

  • Cabrerizo S, La Cruz D, Pedro J, López-Villodres JA, Muñoz-Marín J, Guerrero A, Reyes JJ, Labajos MT, González-Correa JA (2013) Role of the inhibition of oxidative stress and inflammatory mediators in the neuroprotective effects of hydroxytyrosol in rat brain slices subjected to hypoxia reoxygenation. J Nutr Biochem 24(12):2152–2157

    Article  CAS  PubMed  Google Scholar 

  • Cao K, Xu J, Zou X, Li Y, Chen C, Zheng A, Li H, Li H, Szeto IM-Y, Shi Y (2014) Hydroxytyrosol prevents diet-induced metabolic syndrome and attenuates mitochondrial abnormalities in obese mice. Free Radic Biol Med 67:396–407

    Article  CAS  PubMed  Google Scholar 

  • Carrera-González M, Ramírez-Expósito M, Mayas M, Martínez-Martos J (2013) Protective role of oleuropein and its metabolite hydroxytyrosol on cancer. Trends Food Sci Technol 31(2):92–99

    Article  Google Scholar 

  • Charoenprasert S, Mitchell A (2012) Factors influencing phenolic compounds in table olives (Olea europaea). J Agric Food Chem 60(29):7081–7095

    Article  CAS  PubMed  Google Scholar 

  • De Leonardis A, Aretini A, Alfano G, Macciola V, Ranalli G (2008) Isolation of a hydroxytyrosol-rich extract from olive leaves (Olea europaea L.) and evaluation of its antioxidant properties and bioactivity. Eur Food Res Technol 226(4):653–659

    Article  CAS  Google Scholar 

  • Dror A, Fishman A (2012) Engineering non-heme mono-and dioxygenases for biocatalysis. Comput Structur Biotechnol J 2(3):doi: http://dx.doi.org/10.5936/csbj.201209011

  • EFSA Panel on Dietetic Products Nutrition and Allergies (2011) Scientific opinion on the substantiation of health claims related to polyphenols in olive. EFSA J 9(4):2033–2058

    Google Scholar 

  • Engler C, Gruetzner R, Kandzia R, Marillonnet S (2009) Golden gate shuffling: a one-pot DNA shuffling method based on type IIs restriction enzymes. PLoS ONE 4(5):doi: 10.1371/journal.pone.0005553

  • Espín JC, Soler-Rivas C, Cantos E, Tomás-Barberán FA, Wichers HJ (2001) Synthesis of the antioxidant hydroxytyrosol using tyrosinase as biocatalyst. J Agric Food Chem 49(3):1187–1193

    Article  PubMed  Google Scholar 

  • Feki M, Allouche N, Bouaziz M, Gargoubi A, Sayadi S (2006) Effect of storage of olive mill wastewaters on hydroxytyrosol concentration. Eur J Lipid Sci Technol 108(12):1021–1027

    Article  CAS  Google Scholar 

  • Fernández-Mar M, Mateos R, García-Parrilla M, Puertas B, Cantos-Villar E (2012) Bioactive compounds in wine: resveratrol, hydroxytyrosol and melatonin: a review. Food Chem 130(4):797–813

    Article  Google Scholar 

  • Gao F, Daugulis AJ (2009) Bioproduction of the aroma compound 2‐phenylethanol in a solid–liquid two‐phase partitioning bioreactor system by Kluyveromyces marxianus. Biotechnol Bioeng 104(2):332–339

    Article  CAS  PubMed  Google Scholar 

  • García-García MI, Hernández-García S, Sanchez-Ferrer A, García-Carmona F (2013) Kinetic study of hydroxytyrosol oxidation and its related compounds by red globe grape polyphenol oxidase. J Agric Food Chem 61(25):6050–6055

    Article  PubMed  Google Scholar 

  • Gibson DG, Young L, Chuang R-Y, Venter JC, Hutchison CA, Smith HO (2009) Enzymatic assembly of DNA molecules up to several hundred kilobases. Nat Methods 6(5):343–345

    Article  CAS  PubMed  Google Scholar 

  • Granados-Principal S, El-azem N, Pamplona R, Ramirez-Tortosa C, Pulido-Moran M, Vera-Ramirez L, Quiles JL, Sanchez-Rovira P, Naudí A, Portero-Otin M (2014) Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer. Biochem Pharmacol 90(1):25–33

  • Hamza M, Khoufi S, Sayadi S (2012) Fungal enzymes as a powerful tool to release antioxidants from olive mill wastewater. Food Chem 131(4):1430–1436

    Article  CAS  Google Scholar 

  • Hayes J, Allen P, Brunton N, O’Grady M, Kerry J (2011) Phenolic composition and in vitro antioxidant capacity of four commercial phytochemical products: olive leaf extract (Olea europaea L.), lutein, sesamol and ellagic acid. Food Chem 126(3):948–955

    Article  CAS  Google Scholar 

  • Hazelwood LA, Daran J-M, van Maris AJ, Pronk JT, Dickinson JR (2008) The Ehrlich pathway for fusel alcohol production: a century of research on Saccharomyces cerevisiae metabolism. Appl Environ Microbiol 74(8):2259–2266

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hodgman CE, Jewett MC (2012) Cell-free synthetic biology: thinking outside the cell. Metab Eng 14(3):261–269

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hu T, He X-W, Jiang J-G, Xu X-L (2014) Hydroxytyrosol and its potential therapeutic effects. J Agric Food Chem 62(7):1449–1455

    Article  CAS  PubMed  Google Scholar 

  • Jerman Klen T, Mozetič Vodopivec B (2011) Ultrasonic extraction of phenols from olive mill wastewater: comparison with conventional methods. J Agric Food Chem 59(24):12725–12731

    Article  CAS  PubMed  Google Scholar 

  • Kalogerakis N, Politi M, Foteinis S, Chatzisymeon E, Mantzavinos D (2013) Recovery of antioxidants from olive mill wastewaters: a viable solution that promotes their overall sustainable management. J Environ Manag 128:749–758

    Article  CAS  Google Scholar 

  • Kaminaga Y, Schnepp J, Peel G, Kish CM, Ben-Nissan G, Weiss D, Orlova I, Lavie O, Rhodes D, Wood K (2006) Plant phenylacetaldehyde synthase is a bifunctional homotetrameric enzyme that catalyzes phenylalanine decarboxylation and oxidation. J Biol Chem 281(33):23357–23366

    Article  CAS  PubMed  Google Scholar 

  • Kotler P (2011) Reinventing marketing to manage the environmental imperative. J Mark 75(4):132–135

    Article  Google Scholar 

  • Larrosa M, Espín JC, Tomás-Barberán FA (2003) Antioxidant capacity of tomato juice functionalised with enzymatically synthesised hydroxytyrosol. J Sci Food Agric 83(7):658–666

    Article  CAS  Google Scholar 

  • Liebgott P-P, Amouric A, Comte A, Tholozan J-L, Lorquin J (2009) Hydroxytyrosol from tyrosol using hydroxyphenylacetic acid-induced bacterial cultures and evidence of the role of 4-HPA 3-hydroxylase. Res Microbiol 160(10):757–766

    Article  CAS  PubMed  Google Scholar 

  • Mateos R, Trujillo M, Pereira-Caro G, Madrona A, Cert A, Espartero JL (2008) New lipophilic tyrosyl esters. Comparative antioxidant evaluation with hydroxytyrosyl esters. J Agric Food Chem 56(22):10960–10966

    Article  CAS  PubMed  Google Scholar 

  • Mazzei R, Drioli E, Giorno L (2012) Enzyme membrane reactor with heterogenized β-glucosidase to obtain phytotherapic compound: optimization study. J Membr Sci 390–391:121–129

    Article  Google Scholar 

  • Mazzei R, Giorno L, Mazzuca S, Spadafora A, Drioli E (2006) β-Glucosidase separation from Olea europaea fruit and its use in membrane bioreactors for hydrolysis of oleuropein. Desalination 200(1–3):483–484

    Article  CAS  Google Scholar 

  • Merra E, Calzaretti G, Bobba A, Storelli MM, Casalino E (2014) Antioxidant role of hydroxytyrosol on oxidative stress in cadmium-intoxicated rats: different effect in spleen and testes. Drug Chem Toxicol 37(4):420–426

    Article  CAS  PubMed  Google Scholar 

  • Napora-Wijata K, Robins K, Osorio-Lozada A, Winkler M (2014) Whole-cell carboxylate reduction for the synthesis of 3-hydroxytyrosol. ChemCatChem 6(4):1089–1095

    Article  CAS  Google Scholar 

  • Nozzi NE, Desai SH, Case AE, Atsumi S (2014) Metabolic engineering for higher alcohol production. Metab Eng 25:174–182

    Article  CAS  PubMed  Google Scholar 

  • Oral RA, Doğan M, Sarioğlu K (2014) Recovery of bioactive phenolic compounds from olive mill waste water, pomegranate peel, and european cranberrybush (viburnum opulus l.) juice by preparative MPLC. J Liq Chromatogr Relat Technol 37(13):1827–1836

    Article  CAS  Google Scholar 

  • Orenes-Piñero E, García-Carmona F, Sánchez-Ferrer Á (2013) A new process for obtaining hydroxytyrosol using transformed Escherichia coli whole cells with phenol hydroxylase gene from Geobacillus thermoglucosidasius. Food Chem 139(1):377–383

    Article  PubMed  Google Scholar 

  • Pérez-Bonilla M, Salido S, van Beek TA, Altarejos J (2013) Radical-scavenging compounds from olive tree (Olea europaea L.) wood. J Agric Food Chem 62(1):144–151

    Article  PubMed  Google Scholar 

  • Purcaro G, Codony R, Pizzale L, Mariani C, Conte L (2014) Evaluation of total hydroxytyrosol and tyrosol in extra virgin olive oils. Eur J Lipid Sci Technol 116(1):805–811

    CAS  Google Scholar 

  • Quirantes-Piné R, Lozano-Sánchez J, Herrero M, Ibáñez E, Segura-Carretero A, Fernández-Gutiérrez A (2013) HPLC–ESI–QTOF–MS as a powerful analytical tool for characterising phenolic compounds in olive-leaf extracts. Phytochem Anal 24(3):213–223

    Article  PubMed  Google Scholar 

  • Rafehi H, Smith AJ, Balcerczyk A, Ziemann M, Ooi J, Loveridge SJ, Baker EK, El-Osta A, Karagiannis TC (2012) Investigation into the biological properties of the olive polyphenol, hydroxytyrosol: mechanistic insights by genome-wide mRNA-Seq analysis. Genes Nutr 7(2):343–355

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rietjens SJ, Bast A, Haenen GR (2007) New insights into controversies on the antioxidant potential of the olive oil antioxidant hydroxytyrosol. J Agric Food Chem 55(18):7609–7614

    Article  CAS  PubMed  Google Scholar 

  • Rigane G, Bouaziz M, Baccar N, Abidi S, Sayadi S, Ben Salem R (2012) Recovery of hydroxytyrosol rich extract from two-phase Chemlali olive pomace by chemical treatment. J Food Sci 77(10):C1077–C1083

    Article  CAS  PubMed  Google Scholar 

  • Roig A, Cayuela M, Sánchez-Monedero M (2006) An overview on olive mill wastes and their valorisation methods. Waste Manag (Oxford) 26(9):960–969

    Article  CAS  Google Scholar 

  • Romero C, Brenes M (2012) Analysis of total contents of hydroxytyrosol and tyrosol in olive oils. J Agric Food Chem 60(36):9017–9022

    Article  CAS  PubMed  Google Scholar 

  • Sánchez-Fidalgo S, de Ibargüen LS, Cárdeno A, de la Lastra CA (2012) Influence of extra virgin olive oil diet enriched with hydroxytyrosol in a chronic DSS colitis model. Eur J Nutr 51(4):497–506

    Article  PubMed  Google Scholar 

  • Santos M, Piccirillo C, Castro PM, Kalogerakis N, Pintado M (2012) Bioconversion of oleuropein to hydroxytyrosol by lactic acid bacteria. World J Microbiol Biotechnol 28(6):2435–2440

    Article  CAS  PubMed  Google Scholar 

  • Satoh Y, Tajima K, Munekata M, Keasling JD, Lee TS (2012) Engineering of L-tyrosine oxidation in Escherichia coli and microbial production of hydroxytyrosol. Metab Eng 14(6):603–610

    Article  CAS  PubMed  Google Scholar 

  • Scoditti E, Nestola A, Massaro M, Calabriso N, Storelli C, De Caterina R, Carluccio MA (2014) Hydroxytyrosol suppresses MMP-9 and COX-2 activity and expression in activated human monocytes via PKCα and PKCβ1 inhibition. Atherosclerosis 232(1):17–24

  • Shin JH, Kim HU, Kim DI, Lee SY (2013) Production of bulk chemicals via novel metabolic pathways in microorganisms. Biotechnol Adv 31(6):925–935

    Article  CAS  PubMed  Google Scholar 

  • Sun L, Luo C, Liu J (2014) Hydroxytyrosol induces apoptosis in human colon cancer cells through ROS generation. Food Func 5:1909–1914

    Article  CAS  Google Scholar 

  • Szakály Z, Szente V, Kövér G, Polereczki Z, Szigeti O (2012) The influence of lifestyle on health behavior and preference for functional foods. Appetite 58(1):406–413

    Article  PubMed  Google Scholar 

  • Tabernero M, Sarriá B, Largo C, Martínez-López S, Madrona A, Espartero JL, Bravo L, Mateos R (2014) Comparative evaluation of the metabolic effects of hydroxytyrosol and its lipophilic derivatives (hydroxytyrosyl acetate and ethyl hydroxytyrosyl ether) in hypercholesterolemic rats. Food Funct 5(7):1556–1563

  • Takeda Y, Bui VN, Iwasaki K, Kobayashi T, Ogawa H, Imai K (2014) Influence of olive-derived hydroxytyrosol on the toll-like receptor 4-dependent inflammatory response of mouse peritoneal macrophages. Biochem Biophys Res Commun 446(4):1225–1230

    Article  CAS  PubMed  Google Scholar 

  • Trincone A, Pagnotta E, Tramice A (2012) Enzymatic routes for the production of mono-and di-glucosylated derivatives of hydroxytyrosol. Bioresour Technol 115:79–83

    Article  CAS  PubMed  Google Scholar 

  • Visioli F (2012) Olive oil phenolics: where do we stand? Where should we go? J Sci Food Agric 92(10):2017–2019

    Article  CAS  PubMed  Google Scholar 

  • Weng C-J, Yen G-C (2012) Chemopreventive effects of dietary phytochemicals against cancer invasion and metastasis: phenolic acids, monophenol, polyphenol, and their derivatives. Cancer Treat Rev 38(1):76–87

    Article  CAS  PubMed  Google Scholar 

  • Woodley JM, Bisschops M, Straathof AJ, Ottens M (2008) Future directions for in‐situ product removal (ISPR). J Chem Technol Biotechnol 83(2):121–123

    Article  CAS  Google Scholar 

  • Yangui T, Dhouib A, Rhouma A, Sayadi S (2009) Potential of hydroxytyrosol-rich composition from olive mill wastewater as a natural disinfectant and its effect on seeds vigour response. Food Chem 117(1):1–8

    Article  CAS  Google Scholar 

  • Zhang Z-L, Chen J, Xu Q, Rao C, Qiao C (2012) Efficient synthesis of hydroxytyrosol from 3, 4-dihydroxybenzaldehyde. Synth Commun 42(6):794–798

    Article  CAS  Google Scholar 

  • Zhao B, Ma Y, Xu Z, Wang J, Wang F, Wang D, Pan S, Wu Y, Pan H, Xu D (2014) Hydroxytyrosol, a natural molecule from olive oil, suppresses the growth of human hepatocellular carcinoma cells via inactivating AKT and nuclear factor-kappa B pathways. Cancer Lett 347(1):79–87

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, 3200003, Israel

    Yigal Achmon & Ayelet Fishman

Authors
  1. Yigal Achmon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ayelet Fishman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ayelet Fishman.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Achmon, Y., Fishman, A. The antioxidant hydroxytyrosol: biotechnological production challenges and opportunities. Appl Microbiol Biotechnol 99, 1119–1130 (2015). https://doi.org/10.1007/s00253-014-6310-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00253-014-6310-6

Keywords

Search

Navigation