Applied Microbiology and Biotechnology

, Volume 103, Issue 9, pp 3683–3691 | Cite as

An overview on biological production of functional lactose derivatives

  • Yaqin Xiao
  • Qiuming Chen
  • Cuie Guang
  • Wenli ZhangEmail author
  • Wanmeng Mu


Lactose is a natural disaccharide obtained from the milk of most mammals and a waste product of cheese and casein manufacturing. Over the past decades, lactose in whey has increasingly been promoted as an important resource, and an increasing number of significant advances have been made to investigate its healthy and functional properties. Lactose can be biotransformed into many kinds of derivatives, including galacto-oligosaccharides, epilactose, lactulose, lactosucrose, and d-tagatose. Biological efficiency and safety are critical for the enzymatic production of lactose derivatives from lactose. These lactose derivatives show a range of prominent physiological features and effects, such as prebiotic properties, indigestibility, and obesity prevention, which can be utilized in the pharmaceutical, health, and food industries. In this review, we present the properties and physiological effects of lactose derivatives, detailing their biological production by various enzymes and their applications in dairy products, especially directly in the milk industry.


Lactose derivatives Prebiotic Biotechnological production Physiological effects Dairy products 


Funding information

This work was funded by the National Natural Science Foundation of China (No. 31801583), the Natural Science Foundation of Jiangsu Province (Nos. BK20181343 and BK20180607), the National First-Class Discipline Program of Food Science and Technology (No. JUFSTR20180203), and the Postgraduate Research and Practice Innovation Program of Jiangsu Provence (KYCX17_1406).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. Agustí NO, Nieves C (2010) Lactulose as a food ingredient. J Sci Food Agric 89(12):1987–1990Google Scholar
  2. Aronson M (1952) Transgalactosidation during lactose hydrolysis. Arch Biochem Biophys 39(2):370–378Google Scholar
  3. Avigad G (1957) Enzymatic synthesis and characterization of a new trisaccharide, α-lactosyl-β-fructofuranoside. J Biol Chem 229(1):121–129Google Scholar
  4. Awad RA, Hagrass AE, Salama WM, Elmalek FAA, Eldardiry AI (2014) Lactulose production from milk permeate and its performance in healthy functional frozen yoghurt. World J Dairy Food Sci 9(1):1–9Google Scholar
  5. Beadle JR, Saunders JP, Wajda TJ (1992) Process for manufacturing tagatose. US Patent 500261Google Scholar
  6. Ben X, Zhou W, Yu W, Wei P, Zhang W, Wu S, Beusekom CMV, Schaafsma A (2004) Supplementation of milk formula with galacto-oligosaccharides improves intestinal micro-flora and fermentation in term infants. Chin Med J 117(6):927–931Google Scholar
  7. Boehm G, Stahl B, Knol J, Garssen J (2008) Carbohydrates in human milk and infant formulas. Carbohydr Chem Biol Med Appl 94(449):275–291Google Scholar
  8. Cardelle-Cobas A, Villamiel M, Olano A, Corzo N (2008) Study of galacto-oligosaccharide formation from lactose using Pectinex Ultra SP-L. J Sci Food Agric 88(6):954–961Google Scholar
  9. Charalampopoulos D, Rastall RA (2009) Prebiotics and probiotics science and technology. Springer, New YorkGoogle Scholar
  10. Cheetham PSJ, Wootton AN (1993) Bioconversion of D-galactose into D-tagatose. Enzym Microb Technol 15(2):105–108Google Scholar
  11. Chen Q, Zhang W, Zhang T, Jiang B, Mu W (2015) Characterization of an epilactose-producing cellobiose 2-epimerase from Thermoanaerobacterium saccharolyticum. J Mol Catal B-Enzym 116:39–44Google Scholar
  12. Chen Q, Levin R, Zhang W, Zhang T, Jiang B, Stressler T, Fischer L, Mu W (2017) Characterisation of a novel cellobiose 2-epimerase from thermophilic Caldicellulosiruptor obsidiansis for lactulose production. J Sci Food Agric 97(10):3095–3105Google Scholar
  13. Chen Q, He W, Yan X, Zhang T, Jiang B, Stressler T, Fischer L, Mu W (2018a) Construction of an enzymatic route using a food-grade recombinant Bacillus subtilis for the production and purification of epilactose from lactose. J Dairy Sci 101(3):1872–1882Google Scholar
  14. Chen Q, Xiao Y, Zhang W, Zhang T, Jiang B, Stressler T, Fischer L, Mu W (2018b) Current research on cellobiose 2-epimerase: enzymatic properties, mechanistic insights, and potential applications in the dairy industry. Trends Food Sci Technol 82:167–176Google Scholar
  15. Del-Val MI, Hill CG, Jiménez-Barbero J, Otero C (2001) Selective enzymatic synthesis of 6′-galactosyl lactose by Pectinex Ultra SP in water. Biotechnol Lett 23(23):1921–1924Google Scholar
  16. Donner T, Wilber J, Ostrowski D (1999) D-tagatose, a novel hexose: acute effects on carbohydrate tolerance in subjects with and without type 2 diabetes. Diabetes Obes Metab 1(5):285–291Google Scholar
  17. Duarte LS, Schöffer JN, Lorenzoni ASG, Rodrigues RC, Rodrigues E, Hertz PF (2017) A new bioprocess for the production of prebiotic lactosucrose by an immobilized β-galactosidase. Process Biochem 55:96–103Google Scholar
  18. Farkas E, Schmidt U, Thiem J, Kowalczyk J, Kunz M, Vogel M (2003) Regioselective synthesis of galactosylated tri-and tetrasaccharides by use of β-galactosidase from Bacillus circulans. Synthesis 34(27):0699–0706Google Scholar
  19. Freimund S, Huwig A, Giffhorn F, Kopper S (1996) Convenient chemo-enzymatic synthesis of D-tagatose. J Carbohydr Chem 15(15):115–120Google Scholar
  20. Fujita K (1991) Production of lactosucrose by β-fructofuranosidase and some of its physical properties. Denpun Kagaku 38:1–7Google Scholar
  21. Fujita K, Ito T, Kishino E (2009) Characteristics and applications of lactosucrose. J Eng Thermophys 57:13–21Google Scholar
  22. Geiger B, Nguyen HM, Wenig S, Nguyen HA, Lorenz C, Kittl R, Mathiesen G, Eijsink VG, Haltrich D, Nguyen TH (2016) From by-product to valuable components: efficient enzymatic conversion of lactose in whey using β-galactosidase from Streptococcus thermophilus. Biochem Eng J 116:45–53Google Scholar
  23. Gluud LL, Dam G, Borre M, Les I, Cordoba J, Marchesini G, Aagaard NK, Vilstrup H (2013) Lactulose, rifaximin or branched chain amino acids for hepatic encephalopathy: what is the evidence? Metab Brain Dis 28(2):221–225Google Scholar
  24. Guimaraes PM, Teixeira JA, Domingues L (2010) Fermentation of lactose to bio-ethanol by yeasts as part of integrated solutions for the valorisation of cheese whey. Biotechnol Adv 28(3):375–384Google Scholar
  25. Han WC, Byun SH, Lee JC, Kim MH, Kang SA, Kim CH, Wha SE, Jang KH (2007) Synthesis of lactosucrose formed by levansucrase from Pseudomonas aurantiaca. J Biotechnol 131(2):S113Google Scholar
  26. Hasibul K, Nakayama-Imaohji H, Hashimoto M, Yamasaki H, Ogawa T, Waki J, Kuwahara T (2018) D-Tagatose inhibits the growth and biofilm formation of Streptococcus mutans. Mol Med Rep 17(1):843–851Google Scholar
  27. Ikegaki M, Park YK (1997) Lactosucrose production by β-fructofunosidase from Bacillus sp. No.417 using lactose and sucrose mixture. Food Sci Technol 17(2):188–191Google Scholar
  28. Intanon M, Arreola SL, Pham NH, Kneifel W, Haltrich D, Nguyen TH (2014) Nature and biosynthesis of galacto-oligosaccharides related to oligosaccharides in human breast milk. FEMS Microbiol Lett 353(2):89–97Google Scholar
  29. Ito S, Hamada S, Yamaguchi K, Umene S, Ito H, Matsui H, Ozawa T, Taguchi H, Watanabe J, Wasaki J, Ito S (2007) Cloning and sequencing of the cellobiose 2-epimerase gene from an obligatory anaerobe, Ruminococcus albus. Biochem Biophys Res Commun 360(3):640–645Google Scholar
  30. Ito S, Taguchi H, Hamada S, Kawauchi S, Ito H, Senoura T, Watanabe J, Nishimukai M, Ito S, Matsui H (2008) Enzymatic properties of cellobiose 2-epimerase from Ruminococcus albus and the synthesis of rare oligosaccharides by the enzyme. Appl Microbiol Biotechnol 79(3):433–441Google Scholar
  31. Kim YS, Oh DK (2012) Lactulose production from lactose as a single substrate by a thermostable cellobiose 2-epimerase from Caldicellulosiruptor saccharolyticus. Bioresour Technol 104:668–672Google Scholar
  32. Kim BC, Lee YH, Lee HS, Lee DW, Choe EA, Pyun YR (2002) Cloning, expression and characterization of L-arabinose isomerase from Thermotoga neapolitana: bioconversion of D-galactose to D-tagatose using the enzyme. FEMS Microbiol Lett 212(1):121–126Google Scholar
  33. Kim HJ, Kim JH, Oh HJ, Oh DK (2006) Characterization of a mutated Geobacillus stearothermophilus L-arabinose isomerase that increases the production rate of D-tagatose. J Appl Microbiol 101(1):213–221Google Scholar
  34. Kim JE, Kim YS, Kang LW, Oh DK (2012) Characterization of a recombinant cellobiose 2-epimerase from Dictyoglomus turgidum that epimerizes and isomerizes β-1,4- and α-1,4-gluco-oligosaccharides. Biotechnol Lett 34(11):2061–2068Google Scholar
  35. Kim YS, Kim JE, Oh DK (2013) Borate enhances the production of lactulose from lactose by cellobiose 2-epimerase from Caldicellulosiruptor saccharolyticus. Bioresour Technol 128:809–812Google Scholar
  36. Kim BJ, Hong SH, Shin KC, Jo YS, Oh DK (2014) Characterization of a F280N variant of L-arabinose isomerase from Geobacillus thermodenitrificans identified as a D-galactose isomerase. Appl Microbiol Biotechnol 98(22):9271–9281Google Scholar
  37. Krewinkel M, Gosch M, Rentschler E, Fischer L (2014) Epilactose production by 2 cellobiose 2-epimerases in natural milk. J Dairy Sci 97(1):155–161Google Scholar
  38. Krewinkel M, Kaiser J, Merz M, Rentschler E, Kuschel B, Hinrichs J, Fischer L (2015) Novel cellobiose 2-epimerases for the production of epilactose from milk ultrafiltrate containing lactose. J Dairy Sci 98(6):3665–3678Google Scholar
  39. Kuschel B, Riemer F, Pfost D, Conrad J, Losch C, Claaßen W, Beifuß U, Weiss J, Mu W, Jiang B, Stressler T, Fischer L (2016) Large-scale purification of epilactose using a semi-preparative HPLC system. Eur Food Res Technol 243(3):391–402Google Scholar
  40. Kuschel B, Seitl I, Gluck C, Mu W, Jiang B, Stressler T, Fischer L (2017) Hidden reaction: mesophilic cellobiose 2-epimerases produce lactulose. J Agric Food Chem 65(12):2530–2539Google Scholar
  41. Lederberg J (1950) The β-D-galaetosidase of Escher-ichia coli, strain K-12. J Bacteriol 60(4):381–392Google Scholar
  42. Lee SJ, Lee SJ, Lee YJ, Kim SB, Kim SK, Lee DW (2012) Homologous alkalophilic and acidophilic L-arabinose isomerases reveal region-specific contributions to the pH dependence of activity and stability. Appl Environ Microbiol 78(24):8813–8816Google Scholar
  43. Li W, Xiang X, Tang S, Hu B, Tian L, Sun Y, Ye H, Zeng X (2009) Effective enzymatic synthesis of lactosucrose and its analogues by β-D-galactosidase from Bacillus circulans. J Agric Food Chem 57(9):3927–3933Google Scholar
  44. Lu Y, Levin GV, Donner TW (2010) Tagatose, a new antidiabetic and obesity control drug. Diabetes Obes Metab 10(2):109–134Google Scholar
  45. Marcobal A, Barboza M, Froehlich JW, Block DE, German JB, Lebrilla CB, Mills DA (2010) Consumption of human milk oligosaccharides by gut-related microbes. J Agric Food Chem 58(9):5334–5340Google Scholar
  46. McSweeney PLH, Technik HC (1995) Advanced dairy chemistry Volume 3. Adv Dairy Chem 1:337–385Google Scholar
  47. Mu W, Chen Q, Wang X, Zhang T, Jiang B (2013a) Current studies on physiological functions and biological production of lactosucrose. Appl Microbiol Biotechnol 97(16):7073–7080Google Scholar
  48. Mu W, Li Q, Fan C, Zhou C, Jiang B (2013b) Recent advances on physiological functions and biotechnological production of epilactose. Appl Microbiol Biotechnol 97(5):1821–1827Google Scholar
  49. Nishimukai M, Watanabe J, Taguchi H, Senoura T, Hamada S, Matsui H, Yamamoto T, Wasaki J, Hara H, Ito S (2008) Effects of epilactose on calcium absorption and serum lipid metabolism in rats. J Agric Food Chem 56(21):10340–10345Google Scholar
  50. Ojima T, Saburi W, Sato H, Yamamoto T, Mori H, Matsui H (2011) Biochemical characterization of a thermophilic cellobiose 2-epimerase from a thermohalophilic bacterium, Rhodothermus marinus JCM9785. Biosci Biotechnol Biochem 75(11):2162–2168Google Scholar
  51. Ojima T, Saburi W, Yamamoto T, Mori H, Matsui H (2013) Identification and characterization of cellobiose 2-epimerases from various aerobes. Biosci Biotechnol Biochem 77(1):189–193Google Scholar
  52. Panesar PS, Kumari S (2011) Lactulose: production, purification and potential applications. Biotechnol Adv 29(6):940–948Google Scholar
  53. Park NH, Choi HJ, Oh DK (2005) Lactosucrose production by various microorganisms harboring levansucrase activity. Biotechnol Lett 27(7):495–497Google Scholar
  54. Park CS, Kim JE, Choi JG, Oh DK (2011) Characterization of a recombinant cellobiose 2-epimerase from Caldicellulosiruptor saccharolyticus and its application in the production of mannose from glucose. Appl Microbiol Biotechnol 92(6):1187–1196Google Scholar
  55. Park CS, Kim JE, Lee SH, Kim YS, Kang LW, Oh DK (2013) Characterization of a recombinant mannobiose 2-epimerase from Spirochaeta thermophila that is suggested to be a cellobiose 2-epimerase. Biotechnol Lett 35(11):1873–1880Google Scholar
  56. Qian X, Sujino K, Palcic MM, Ratcliffe RM (2007) Glycosyltransferases in oligosaccharide synthesis. J Carbohydr Chem 21(7–9):911–942Google Scholar
  57. Rentschler E, Schuh K, Krewinkel M, Baur C, Claassen W, Meyer S, Kuschel B, Stressler T, Fischer L (2015) Enzymatic production of lactulose and epilactose in milk. J Dairy Sci 98(10):6767–6775Google Scholar
  58. Rhimi M, Chouayekh H, Gouillouard I, Maguin E, Bejar S (2011) Production of D-tagatose, a low caloric sweetener during milk fermentation using L-arabinose isomerase. Bioresour Technol 102(3):3309–3315Google Scholar
  59. Rodriguez Colinas B, Poveda A, Jimenez Barbero J, Ballesteros AO, Plou FJ (2012) Galacto-oligosaccharide synthesis from lactose solution or skim milk using the β-galactosidase from Bacillus circulans. J Agric Food Chem 60(25):6391–6398Google Scholar
  60. Saburi W, Yamamoto T, Taguchi H, Hamada S, Matsui H (2010) Practical preparation of epilactose produced with cellobiose 2-epimerase from Ruminococcus albus NE1. Biosci Biotechnol Biochem 74(8):1736–1737Google Scholar
  61. Saburi W, Tanaka Y, Muto H, Inoue S, Odaka R, Nishimoto M, Kitaoka M, Mori H (2015) Functional reassignment of Cellvibrio vulgaris EpiA to cellobiose 2-epimerase and an evaluation of the biochemical functions of the 4-O-β-D-mannosyl-D-glucose phosphorylase-like protein, UnkA. Biosci Biotechnol Biochem 79(6):969–977Google Scholar
  62. Sangwan V, Tomar SK, Singh RR, Singh AK, Ali B (2011) Galactooligosaccharides: novel components of designer foods. J Food Sci 76(4):R103–R111Google Scholar
  63. Sato H, Saburi W, Ojima T, Taguchi H, Mori H, Matsui H (2012) Immobilization of a thermostable cellobiose 2-epimerase from Rhodothermus marinus JCM9785 and continuous production of epilactose. Biosci Biotechnol Biochem 76(8):1584–1587Google Scholar
  64. Schumann C (2002) Medical, nutritional and technological properties of lactulose. An update. Eur J Nutr 41(1):i17–i25Google Scholar
  65. Senoura T, Taguchi H, Ito S, Hamada S, Matsui H, Fukiya S, Yokota A, Watanabe J, Wasaki J, Ito S (2009) Identification of the cellobiose 2-epimerase gene in the genome of Bacteroides fragilis NCTC 9343. Biosci Biotechnol Biochem 73(2):400–406Google Scholar
  66. Shen Q, Zhang Y, Yang R, Pan S, Dong J, Fan Y, Han L (2016) Enhancement of isomerization activity and lactulose production of cellobiose 2-epimerase from Caldicellulosiruptor saccharolyticus. Food Chem 207:60–67Google Scholar
  67. Smithers GW (2015) Whey-ing up the options–yesterday, today and tomorrow. Int Dairy J 48:2–14Google Scholar
  68. Surarit R, Svasti J, Srisomsap C, Suginta W, Khunyoshyeng S, Nilwarangkoon S, Harnsakul P, Benjavongkulchai EO (1995) Screening of glycosidase enzymes in Thai plant seeds for potential use in oligosaccharide synthesis. Sci Asia 21(4):293Google Scholar
  69. Suzuki T, Nishimukai M, Shinoki A, Taguchi H, Fukiya S, Yokota A, Saburi W, Yamamoto T, Hara H, Matsui H (2010) Ingestion of epilactose, a non-digestible disaccharide, improves postgastrectomy osteopenia and anemia in rats through the promotion of intestinal calcium and iron absorption. J Agric Food Chem 58(19):10787–10792Google Scholar
  70. Taguchi H, Senoura T, Hamada S, Matsui H, Kobayashi Y, Watanabe J, Wasaki J, Ito S (2008) Cloning and sequencing of the gene for cellobiose 2-epimerase from a ruminal strain of Eubacterium cellulosolvens. FEMS Microbiol Lett 287(1):34–40Google Scholar
  71. Tyler TR, Leatherwood JM (1967) Epimerization of disaccharides by enzyme preparations from Ruminococcus albus. Arch Biochem Biophys 119(1):363–367Google Scholar
  72. Van Overtveldt S, Verhaeghe T, Joosten HJ, van den Bergh T, Beerens K, Desmet T (2015) A structural classification of carbohydrate epimerases: from mechanistic insights to practical applications. Biotechnol Adv 33(8):1814–1828Google Scholar
  73. Watanabe J, Nishimukai M, Taguchi H, Senoura T, Hamada S, Matsui H, Yamamoto T, Wasaki J, Hara H, Ito S (2008) Prebiotic properties of epilactose. J Dairy Sci 91(12):4518–4526Google Scholar
  74. Wu C, Zhang T, Mu W, Miao M, Jiang B (2015) Biosynthesis of lactosylfructoside by an intracellular levansucrase from Bacillus methylotrophicus SK 21.002. Carbohydr Res 401:122–126Google Scholar
  75. Xu Z, Li S, Feng X, Zhan Y, Xu H (2014) Function of aspartic acid residues in optimum pH control of L-arabinose isomerase from Lactobacillus fermentum. Appl Microbiol Biotechnol 98(9):3987–3996Google Scholar
  76. Xu W, Zhang W, Zhang T, Jiang B, Mu W (2018) L-arabinose isomerases: characteristics, modification, and application. Trends Food Sci Technol 78:25–33Google Scholar
  77. Zhang W, Zhang T, Jiang B, Mu W (2017) Enzymatic approaches to rare sugar production. Biotechnol Adv 35(2):267–274Google Scholar
  78. Zheng Z, Mei W, Xia M, Qin H, Jia O (2017) Rational design of Bacillus coagulans NL01 L-arabinose isomerase and using its F279I variant in D-tagatose production. J Agric Food Chem 65(23):4715–4721Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.State Key Laboratory of Food Science and TechnologyJiangnan UniversityWuxiChina
  2. 2.International Joint Laboratory on Food SafetyJiangnan UniversityWuxiChina

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