Abstract
Mannitol, a naturally occurring polyol (sugar alcohol), is widely used in the food, pharmaceutical, medical, and chemical industries. The production of mannitol by fermentation has become attractive because of the problems associated with its production chemically. A number of homo- and heterofermentative lactic acid bacteria (LAB), yeasts, and filamentous fungi are known to produce mannitol. In particular, several heterofermentative LAB are excellent producers of mannitol from fructose. These bacteria convert fructose to mannitol with 100% yields from a mixture of glucose and fructose (1:2). Glucose is converted to lactic acid and acetic acid, and fructose is converted to mannitol. The enzyme responsible for conversion of fructose to mannitol is NADPH- or NADH-dependent mannitol dehydrogenase (MDH). Fructose can also be converted to mannitol by using MDH in the presence of the cofactor NADPH or NADH. A two enzyme system can be used for cofactor regeneration with simultaneous conversion of two substrates into two products. Mannitol at 180 g l−1 can be crystallized out from the fermentation broth by cooling crystallization. This paper reviews progress to date in the production of mannitol by fermentation and using enzyme technology, downstream processing, and applications of mannitol.
Similar content being viewed by others
References
Aarnikunnas I, von Weymarn N, Ronnholm K, Leisola M, Palva A (2003) Metabolic engineering of Lactobacillus fermentum for production of mannitol and pure l-lactic acid or pyruvate. Biotechnol Bioeng 82:653–663
Adachi O, Toyama H, Matsushita K (1999) Crystalline NADP-dependent D-mannitol dehydrogenase from Gluconobacter suboxydans. Biosci Biotechnol Biochem 63:402–407
Baumchen C, Bringer-Meyer S (2007) Expression of glf Z.m increases D-Mannitol formation in whole cell biotransformation with resting cells of Corynebacterium glutamicum. Appl Microbiol Biotechnol 76:545–552
Baumchen C, Roth AHFJ, Biedendieck R, Malten M, Follmann M, Sahm H, Bringer-Meyer S, Jahn D (2007) d-Mannitol production by resting state whole cell biotransformation of d-fructose by heterologous mannitol and formate dehydrogenase gene expression in Bacillus megentarium. Biotechnol J 2:1408–1416
Boosaeng V, Sullivan PA, Shepherd MG (1976) Mannitol production in fungi during glucose catabolism. Can J Microbiol 22:808–816
Brunker P, Altenbuchner J, Kulbe KD, Mattes R (1997) Cloning, nucleotide sequence and expression of a mannitol dehydrogenase gene from Pseudomonas fluorescens DSM 50106 in Escherichia coli. Biochim Biophys Acta 1351:157–167
Busse M, Kindel PK, Gibbs M (1961) The heterolactic fermentation: 3. Positions of 13 C in the products of fructose dissimilation by Leuconostoc mesenteroides. J Biol Chem 236:2850–2853
Chalfan Y, Levy R, Mateles RI (1975) Detection of mannitol formation by bacteria. Appl Microbiol 30:476
Chenault HK, Whitesides GM (1987) Regeneration of nicotinamide cofactors for use in organic synthesis. Appl Biochem Biotechnol 14:147–197
Costenoble R, Adler L, Niklasson C, Liden G (2003) Engineering of the metabolism of Saccharomyces cerevisiae for anaerobic production of mannitol. FEMS Yeast Res 3:17–25
Datta R, Tsai S-P (1997) Lactic acid production and potential uses: a technology and economic assessment. In: Saha BC, Woodward J (eds) Fuels and chemicals from biomass. American Chemical Society, Washington, DC, pp 224–236
Daviskas E, Anderson SD, Jaques A, Charlton B (2010) Inhaled mannitol improves the hydration and surface properties of sputum in patients with cystic fibrosis. Chest 137:861–868
De Zeeuw JR, Tynan III EJ (1973) Fermentation process for the production of d-mannitol. U.S. Patent 3,736,229
Debord B, Lefebvre C, Guypt-Hermann AM, Hubert J, Bouche R, Guyot JC (1987) Study of different forms of mannitol: comparative behavior under compression. Drug Dev Ind Pharm 13:1533–1546
Deusing I, Buchholz K, Bliesener K (1996) Isolierung von fermentativ hergestelltem d-mannit mittels elektrodialyse und kristallisation. Chem Ing Tech 68:1436–1438
Devos F (1995) Process for the production of mannitol. U.S. Patent 5,466,795
Domelsmith LN, Klich MA, Goynes WR (1988) Production of mannitol by fungi from cotton dust. Appl Environ Microbiol 54:1784–1790
El-Kady LA, Moubasher MH, Mostafa ME (1995) Accumulation of sugar alcohols by filamentous fungi. Folia Microbiol 40:481–486
Erten H (1998) Metabolism of fructose as an electron acceptor by Leuconostoc mesenteroides. Proc Biochem 33:735–739
Fontes CPM, Honorato TL, Rabelo MC, Rodrigues S (2009) Kinetic study of mannitol production using cashew apple juice as substrate. Bioprocess Biosyst Eng 32:493–499
Forain T, Schauck AN, Delcour J (1996) 13 C nuclear magnetic resonance analysis of glucose and citrate end products in an IdhL-IdhD double-knockout strain of Lactobacillus plantarum. J Bacteriol 178:7311–7315
Galkin A, Kulakova L, Tishkov V, Esaki N, Soda K (1995) Cloning of formate dehydrogenase gene from a methanol-utilizing bacterium Mycobacterium vaccae N10. Appl Microbiol Biotechnol 44:479–483
Gaspar P, Neves AR, Ramos A, Gasson MJ, Shearman CA, Santos H (2004) Engineering Lactococcus lactis for production of mannitol: high yields from food-grade strains deficient in lactate dehydrogenase and the mannitol transport system. Appl Environ Microbiol 70:1466–1474
Ghoreishi SM, Shahrestani RG (2009) Innovative strategies for engineering mannitol production. Trends Food Sci Technol 20:263–270
Grobben GJ, Peters SWPG, Wisselink HW, Weusthuis RA, Hoefnagel MHN, Hugenholtz J, Eggink G (2001) Spontaneous formation of a mannitol-producing variant of Leuconostoc pseudomesenteroides grown in the presence of fructose. Appl Environ Microbiol 67:2867–2870
Groleau D, Chevalier P, Tse Hing Yuen TLS (1995) Production of polyols and ethanol by the osmophilic yeast Zygosaccharomyces rouxii. Biotechnol Lett 17:315–320
Hahn G, Kaup B, Bringer-Meyer S, Sahm H (2003) A zinc-containing mannitol-2-dehydrogenase from Leuconostoc pseudomesenteroides ATCC 12291: purification of the enzyme and cloning of the gene. Arch Microbiol 179:101–107
Haltrich D, Nidetzky B, Miemietz G, Gollhofer D, Sabine L, Stolz P, Kulbe KD (1996) Simultaneous enzymatic synthesis of mannitol and gluconic acid: I. Characterization of the enzyme system. Biocatal Biotransformation 14:31–45
Hammes WP, Stolz P, Ganzle M (1996) Metabolism of lactobacilli in traditional sourdoughs. Adv Food Sci 18:176–184
Hattori K, Suzuki T (1974) Large scale production of erythritol and its conversion to d-mannitol production by n-alkane grown Candida zeylanoides. Agric Biol Chem 38:1203–1208
Helanto M, Aarnikunnas J, von Weymarn N, Airaksinen U, Palva A, Leisola M (2005) Improved mannitol production by a random mutant of Leuconostoc pseudomesenteroides. J Biotechnol 116:283–294
Hendriksen HV, Mathiasen TE, Alder-Nissen J, Frisvad JC, Emborg C (1988) Production of mannitol by Penicillium strains. J Chem Technol Biotechnol 43:223–228
Hols P, Ramos A, Hugenholtz J, Delcour J, de Vos WM, Santos H, Kleerebezem M (1999) Acetate utilization in Lactococcus lactis deficient in lactate dehydrogenase: a rescue pathway for maintaining redox balance. J Bacteriol 181:5521–5526
Howaldt M, Gottlob A, Kulbe K, Chmiel H (1988) Simultaneous conversion of glucose/fructose mixtures in a membrane reactor. Ann NY Acad Sci 542:400–404
Hustede H, Haberstroh HJ, Schinig E (1989) Gluconic acid. In: Ullmann’s encyclopedia of industrial chemistry, vol. A12. VCK, Weinheim, pp 449–456
Itoh Y, Tanaka A, Araya H, Ogasawara K, Inaba H, Sakamoto Y, Koga J (1992) Lactobacillus sp. B001 and method of producing mannitol, acetic acid and lactic acid. European Patent 486024
Johnson JC (1976) Sugar alcohols and derivatives. In: Specialized sugars for the food industry. Noyes Data Corporation, NJ, p 313
Kaup B, Bringer-Meyer S, Sahm H (2004) Metabolic engineering of Escherichia coli: construction of an efficient biocatalyst for d-mannitol formation in a whole-cell biotransformation. Appl Microbiol Biotechnol 64:333–339
Kaup B, Bringer-Meyer S, Sahm H (2005) d-Mannitol formation from glucose in a whole-cell biotransformation with recombinant Escherichia coli. Appl Microbiol Biotechnol 69:397–403
Khan A, Bhide A, Gadre R (2009) Mannitol production from glycerol by resting cells of Candida magnoliae. Bioresour Technol 100:4911–4913
Korakli M, Schwarz E, Wolf G, Hammes WP (2000) Production of mannitol by Lactobacillus sanfranciscensis. Adv Food Sci 22:1–4
Kulbe KD, Schwab U, Gudernatsch W (1987) Enzyme-catalyzed production of mannitol and gluconic acid. Product recovery by various procedures. Ann NY Acad Sci 506:552–568
Lee WH (1967) Carbon balance of a mannitol fermentation and the biosynthetic pathway. Appl Microbiol 15:1206–1210
Lee JK, Oh DK, Song HY, Kim IW (2007) Ca2+ and Cu2+ supplementation increases mannitol production by Candida magnoliae. Biotechnol Lett 29:291–294
Lee JK, Song JY, Kim SY (2003a) Controlling substrate concentration in fed-batch Candida magnoliae culture increases mannitol production. Biotechnol Prog 19:768–775
Lee JK, Koo BS, Kim SY, Hyun HH (2003b) Purification and characterization of a novel mannitol dehydrogenase from a newly isolated strain of Candida magnoliae. Appl Environ Microbiol 69:4438–4447
Liu S, Saha B, Cotta M (2005) Cloning, expression, purification, and analysis of mannitol dehydrogenase gene mtlK from Lactobacillus brevis. Appl Biochem Biotechnol 121–124:391–402
Loesche WJ, Kornman KS (1976) Production of mannitol by Streptococcus mutants. Arch Oral Biol 21:551–553
Makkee M, Kieboom APG, Van Bekkum H (1985) Production methods of d-mannitol. Starch/Stärke 37:136–141
Martinez GH, Barker A, Horecker BL (1963) A specific mannitol dehydrogenase from Lactobacillus brevis. J Biol Chem 238:1598–1603
Miller G (2002) Drug targeting. Breaking down barriers. Science 297(5584):1116–1118
Nelson GEN, Johnson DE, Ciegler A (1971) Production of d-mannitol by conidia of Aspergillus candidus. Appl Microbiol 22:484–485
Neves AR, Ramos A, Shearman C, Gasson M, Almeida JS, Santos H (2000) Metabolic characterization of Lactococcus lactis deficient in lactate dehydrogenase using in vivo 13 C-NMR. Eur J Biochem 267:3859–3868
Nidetzky B, Haltrich D, Schmidt K, Schmidt H, Weber A, Kulbe KD (1996) Simultaneous enzymatic synthesis of mannitol and gluconic acid: II. Development of a continuous process for a coupled NAD(H)-dependent enzyme system. Biocatal Biotransformation 14:46–53
Niehaus WG Jr, Dilts RP (1982) Purification and characterization of mannitol dehydrogenase from Aspergillus parasiticus. J Bacteriol 1151:243–250
Ojamo H, Koivikko H, Heikkila H (2003) Process for the production of mannitol by immobilized micro-organisms. U.S. Patent 6,602,691 B1
O’Neill H, Woodward J (2000) The nicotinamide cofactors: applications in biotechnology. In: Saha BC, Demirjian DC (eds) Applied biocatalysis in specialty chemical and pharmaceuticals. American Chemical Society, Washington, DC, pp 103–130
Onishi H, Suzuki T (1968) Production of d-mannitol and glycerol by yeasts. Appl Microbiol 16:1847–1852
Onishi H, Suzuki T (1970) Microbial production of d-mannitol and d-fructose from glycerol. Biotechnol Bioeng 12:913–920
Parker C, Barnell WO, Snoep JL, Ingram LO, Conway T (1995) Characterization of the Zymomonas mobilis glucose facilitator gene product (glf) in recombinant Escherichia coli: examination of the transport mechanism, kinetics and the role of glucokinase in glucose transport. Mol Microbiol 15:759–802
Parmentier S, Arnaut F, Soetaert W, Vandamme EJ (2005) Enzymatic production of D-mannitol with Leuconostoc pseudomesenteroides mannitol dehydrogenase coupled to a coenzyme regeneration system. Biocatal Biotransformation 23:1–7
Perry FR, Green DW, Maloney JO (1997) Perry’s chemical engineers’ handbook, 7th edn. McGraw-Hill, New York, pp 2–40
Pimentel MS, Silva MH, Cortes I, Faia AM (1994) Growth and metabolism of sugar and acids of Leuconostoc oenos under different conditions of temperature and pH. J Appl Bacteriol 76:42–48
Quain DE, Boulton CA (1987) Growth and metabolism of mannitol by strains of Saccharomyces cerevisiae. J Gen Microbiol 133:1675–1684
Racine FM, Saha BC (2007) Production of mannitol by Lactobacillus intermedius NRRL B-3693 in fed-batch and continuous cell-recycle fermentations. Process Biochem 42:1609–1613
Rapoport SI (2001) Advances in osmotic opening of the blood-brain barrier to enhance CNS chemotherapy. Expert Opin Investig Drugs 10:1809–1818
Saha BC (2003) Production of mannitol by fermentation. In: Saha BC (ed) Fermentation biotechnology. American Chemical Society, Washington, DC, pp 67–85
Saha BC, Nakamura LK (2003) Production of mannitol and lactic acid by fermentation with Lactobacillus intermedius NRRL B-3693. Biotechnol Bioeng 82:864–871
Saha BC (2004) Purification and characterization of a novel mannitol dehydrogenase from Lactobacillus intermedius. Biotechnol Prog 20:537–542
Saha BC (2006a) A low-cost medium for mannitol production by Lactobacillus intermedius NRRL B-3693. Appl Microbiol Biotechnol 72:676–680
Saha BC (2006b) Effect of salt nutrients on mannitol production by Lactobacillus intermedius NRRL B-3693. J Ind Microbiol Biotechnol 33:887–890
Saha BC (2006c) Production of mannitol from inulin by simultaneous enzymatic saccharification and fermentation with Lactobacillus intermedius NRRL B-3693. Enzyme Microb Technol 39:991–995
Saha BC, Racine FM (2008) Production of mannitol by lactic acid bacteria: a review. In: Hou CT, Shaw JF (eds) Biocatalysis and bioenergy. Wiley, Hoboken, pp 391–404
Saha BC, Racine FM (2010) Effects of pH and corn steep liquor variability on mannitol production by Lactobacillus intermedius NRRL B-3693. Appl Microbiol Biotechnol 87:553–560
Sakai S, Yamanaka K (1968) Crystalline d-mannitol: NAD+ oxidoreductase from Leuconostoc mesenteroides. Biochim Biophys Acta 151:684–686
Salou P, Divies C, Cardona R (1994) Growth and energetics of Leuconostoc oenos during cometabolism of glucose with citrate or fructose. Appl Environ Microbiol 60:1459–1466
Sasaki Y, Laivenieks M, Zeikus JG (2005) Lactobacillus reuteri ATCC 53608 mdh gene cloning and recombinant mannitol dehydrogenase characterization. Appl Microbiol Biotechnol 68:36–41
Schneider KH, Giffhom F (1989) Purification and properties of a polyol dehydrogenase from the phototrophic bacterium Rhodobacter sphaeroides. Eur J Biochem 1184:15–19
Schneider KH, Giffhorn F, Kaplan S (1993) Cloning, nucleotide sequence and characterization of the mannitol dehydrogenase gene from Rhodobacter sphaeroides. J Gen Microbiol 139:2475–2484
Schwarz E (1994) In: Elvers B, Hawkins S, Russey W (eds) Ulman’s encyclopedia of industrial chemistry, Vol. A25, 5th edn. VCH, Weinheim, pp 423–426
Shen B, Jensen RG, Bohnert HJ (1997) Mannitol protects against oxidation by hydroxyl radicals. Plant Physiol 115:527–532
Slatner M, Nagl G, Haltrich D, Kulbe KD, Nidetzky B (1998) Enzymatic production of pure d-mannitol at high productivity. Biocatal Biotransform 16:351–363
Smiley KL, Cadmus MC, Liepins P (1967) Biosynthesis of d-mannitol from d-glucose by Aspergillus candidus. Biotechnol Bioeng 9:365–374
Soetaert W (1990) Production of mannitol with Leuconostoc mesenteroides. Med Fac Landbouww Rijksuniv Gent 55:1549–1552
Soetaert W, Buchholz K, Vandamme EJ (1995) Production of d-mannitol and d-lactic acid by fermentation with Leuconostoc mesenteroides. Agro Food Ind Hi Tech 6:41–44
Soetaert W, Vanhooren PT, Vandamme EJ (1999) The production of d-mannitol by fermentation. Meth Biotechnol 10:261–275
Song HS, Vielle C (2009) Recent advances in the biological production of mannitol. Appl Microbiol Biotechnol 84:55–62
Song HS, Ahluwalia N, Leduc Y, Delbaere LT, Vielle C (2008) Thermotoga maritima TMO 298 is a highly thermostable mannitol dehydrogenase. Appl Microbiol Biotechnol 81:485–495
Song KH, Lee JK, Song JY, Hong SG, Baek H, Kim SY, Hyun HH (2002) Production of mannitol by a novel strain of Candida magnoliae. Biotechnol Lett 24:9–12
Stankovic L, Bilik V, Matulova M (1989) Production of d-mannitol from d-aldopentoses by the yeast Rhodotorula minuta. Folia Microbiol 34:511–514
Stoop JMH, Williamson JD, Conkling MA, MacKay JJ, Pharr DM (1998) Characterization of NAD-dependent mannitol dehydrogenase from celery as affected by ions, chelators, reducing agents and metabolites. Plant Sci 131:43–51
Strandberg GW (1969) d-Mannitol metabolism by Aspergillus candidus. J Bacteriol 97:1305–1309
Takemura M, Iijima M, Tateno Y, Osada Y, Maruyama H (1978) Process for preparing d-mannitol. U.S. Patent 4,083,881
Vandamme EJ, Derycke DG (1983) Microbial inulinases: fermentation process, properties, and applications. Adv Appl Microbiol 29:139–176
Vandamme EJ, Soetaert W (1995) Biotechnical modification of carbohydrates. FEMS Microbiol Rev 16:163–186
Viikari L, Korhola M (1986) Fructose metabolism in Zymomonas mobilis. Appl Microbiol Biotechnol 24:471–476
von Weymarn FNW, Hujanen M, Leisola MSA (2002a) Production of D-mannitol by heterofermentative lactic acid bacteria. Proc Biochem 37:1207–1213
von Weymarn N, Kiviharju K, Leisola M (2002b) High-level production of d-mannitol with membrane cell-recycle bioreactor. J Ind Microbiol Biotechnol 29:44–49
von Weymarn FNW, Kiviharju KJ, Jaaskelainen SP, Leisola MSA (2003) Scale-up of a new bacterial mannitol production process. Biotechnol Prog 19:815–821
Weisser P, Kramer R, Sahm H, Sprenger GA (1995) Functional expression of the glucose transporter of Zymomonas mobilis leads to restoration of glucose and fructose uptake in Escherichia coli mutants and provides evidence for its facilitator action. J Bacteriol 177:3351–3354
Wichmann R, Wandrey C, Buckmann AF, Kula MR (1981) Continuous enzymatic transformation in an enzyme membrane reactor with simultaneous NAD(H) regeneration. Biotechnol Bioeng 23:2789–2802
Wisselink HW, Weusthuis RA, Eggink G, Hugenholtz J, Grobben GJ (2002) Mannitol production by lactic acid bacteria: a review. Int Dairy J 12:151–161
Wisselink HW, Mars AE, van der Meer P, Eggink G, Hugenholtz J (2004) Metabolic engineering of mannitol production in Lactococcus lactis: influence of overexpression of mannitol-1-phosphate dehydrogenase in different genetic backgrounds. Appl Environ Microbiol 76:4286–4292
Yamada H, Okamoto K, Kodama K, Noguchi F, Tanaka S (1961) Enzymic studies on mannitol formation by Piricularia oryzae. J Biochem Tokyo 49:40–410
Yun JW, Song SK (1994) Production of extracellular polyols in Aureobasidium pullulans. Biotechnol Lett 16:949–954
Yun JW, Kim DH (1998) A comparative study of mannitol production by two lactic acid bacteria. J Ferment Bioeng 85:203–208
Yun JW, Kang SC, Song SK (1996a) Mannitol accumulation during fermentation of kimchi. J Ferment Bioeng 81:279–280
Yun JW, Kang SC, Song SK (1996b) Microbial transformation of fructose to mannitol by Lactobacillus sp. KY-107. Biotechnol Lett 18:35–40
Author information
Authors and Affiliations
Corresponding author
Additional information
Mention of trade names or commercial products in this article is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the U.S. Department of Agriculture.
Rights and permissions
About this article
Cite this article
Saha, B.C., Racine, F.M. Biotechnological production of mannitol and its applications. Appl Microbiol Biotechnol 89, 879–891 (2011). https://doi.org/10.1007/s00253-010-2979-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00253-010-2979-3