Abstract
The production of microbial polysaccharides has recently gained much interest because of their potential biotechnological applications. Several pathogenic bacteria are known to produce capsular polysaccharides, which provide a protection barrier towards harsh environmental conditions, and towards host defences in case of invasive infections. These capsules are often composed of glycosaminoglycan-like polymers. Glycosaminoglycans are essential structural components of the mammalian extracellular matrix and they have several applications in the medical, veterinary, pharmaceutical and cosmetic field because of their peculiar properties. Most of the commercially available glycosaminoglycans have so far been extracted from animal sources, and therefore the structural similarity of microbial capsular polysaccharides to these biomolecules makes these bacteria ideal candidates as non-animal sources of glycosaminoglycan-derived products. One example is hyaluronic acid which was formerly extracted from hen crests, but is nowadays produced via Streptococci fermentations. On the other hand, no large scale biotechnological production processes for heparin and chondrotin sulfate have been developed. The larger demand of these biopolymers compared to hyaluronic acid (tons vs kilograms), due to the higher titre in the final product (grams vs milligrams/dose), and the scarce scientific effort have hampered the successful development of fermentative processes. In this paper we present an overview of the diverse applications and production methods of chondroitin reported so far in literature with a specific focus on novel microbial biotechnological approaches.
Similar content being viewed by others
References
Adebowale A, Du J, Liang Z, Leslie JL, Eddington ND (2002) The bioavailability and pharmacokinetics of glucosamine hydrochloride and low molecular weight chondroitin sulfate after single and multiple doses to beagle dogs. Biopharm Drug Dispos 23(6):217–225. doi:10.1002/bdd.315
Alkhalil A, Achur RN, Valiyaveettil M, Ockenhouse CF, Gowda DC (2000) Structural requirements for the adherence of Plasmodium falciparum-infected erythrocytes to chondroitin sulphate proteoglycans of human placenta. J Biol Chem 277(11):8882–8889. doi:10.1074/jbc.M006399200
Amano Enzyme USA, Ltd (2009) Microbial derived chondroitin sulfate. PCT WO2009/149155 A1
Bali JP, Cousse H, Neuzil E (2001) Biochemical basis of the pharmacologic action of chondroitin sulphates on the osteoarticular system. Semin Arthritis Rheum 31:58–68
Belcher C, Yaqub R, Fawthrop F, Bayliss M, Doherty M (1997) Synovial fluid chondroitin and keratan sulphate epitopes, glycosaminoglycans, and hyaluronan in arthritic and normal knees. Ann Rheum Dis 56(5):299–307
Bergefall K, Trybala E, Johansson M, Uyama T, Naito S, Yamada S, Kitagawa H, Sugahara K, Bergström T (2005) Chondroitin sulfate characterized by the E-disaccharide unit is a potent inhibitor of herpes simplex virus infectivity and provides the virus binding sites on gro2C cells. J Biol Chem 280(37):32193–32199. doi:10.1074/jbc.M503645200
Borsig L, Wang L, Cavalcante MC, Cardilo-Reis L, Ferreira PL, Mourao PA, Esko JD, Pvao MS (2007) Selectin blocking activity of a fucosylated chondroitin sulphate glycosaminoglycan from sea cucumber. Effect on tumor metastasis and neutrophil recruitment. J Biol Chem 282(20):14984–14991. doi:10.1074/jbc.M610560200
Boyce JD, Chung JY, Adler B (2000) Pasteurella multocida capsule: composition, function and genetics. J Biotechnol 83(1–2):153–60
Carter GR, Annau E (1953) Isolation of capsular polysaccharides from colonial variants of Pasteurella multocida. Am J Vet Res 14(52):475–478
Chong BF, Blank LM, Mclaughlin R, Nielsen LK (2005) Microbial hyaluronic acid production. Appl Microbiol Biotechnol 66(4):341–51. doi:10.1007/s00253-004-1774-4
Chung JY, Boyce JD, Townsend KM, Frost AJ, Ghoddusi M, Adler B (2001) Role of capsule in the pathogenesis of fowl cholera caused by Pasteurella multocida Serogroup A. Infect Immun 69:2487–2492. doi:10.1128/IAI.69.4.2487-2492.2001
Cimini D, Restaino OF, Catapano A, De Rosa M, Schiraldi C (2010) Production of capsular polysaccharide from Escherichia coli K4 for biotechnological applications. Appl Miccrobiol Biotechnol 85(6):1779–1787. doi:10.1007/s00253-009-2261-8
Conte A, Volpi N, Palmieri L, Bahous I, Ronca G (1995) Biochemical and pharmacokinetic aspects of oral treatment with chondroitin sulfate. Arzneimittelforschung 45:918–925
De Angelis PL (2003) Chondroitin synthase gene and methods of making and using same. United States Patent Application 20030104601
De Angelis PL (2009) Chondroitin synthase gene and methods of making and using same. United States Patent 7569386
De Angelis PL (2010) Methods of ex pressing Gram-negative glycosaminoglycan synthase genes in Gram-positive hosts. United States Patent 7,642,071 B2
DeAngelis PL, Padgett-McCue AJ (2000) Identification and molecular cloning of a chondroitin synthase from Pasteurella multocida type F. J Biol Chem 275(31):24124–24129. doi:10.1074/jbc.M003385200
DeAngelis PL, Jing W, Drake RR, Achyuthan AM (1998) Identification and molecular cloning of a unique hyaluronan synthase from Pasteurella multocida. J Biol Chem 273(14):8454–8458
DeAngelis PL, Gunay NS, Toida T, Mao W, Linhardt RJ (2002) Identification of the capsular polysaccharides of type D and F Pasteurella multocida as unmodified heparin and chondroitin respectively. Car Res 337:1547–1552
Du J, White N, Eddington ND (2004) The bioavailability and pharmacokinetics of glucosamine hydrochloride and chondroitin sulfate after oral and intravenous single dose administration in the horse. Biopharm Drug Dispos 25(3):109–16. doi:10.1002/bdd.392
Fraser PE, Darabie AA, McLaurin JA (2001) Amyloid-beta interactions with chondroitin sulphate-derived monosaccharides and disaccharides. Implications for drug development. J Biol Chem 273(9):6412–6419. doi:10.1074/jbc.M008128200
Gilbert ME, Kirker KR, Gray SD, Ward PD, Szakacs JG, Prestwich GD, Orlandi RR (2004) Chondroitin sulfate hydrogel and wound healing in rabbit maxillary sinus mucosa. Laryngoscope 114(8):1406–1409
Habuchi O (2000) Diversity and functions of glycosaminoglycan sulfotransferases. Biochim Biophys Acta 1474:115–127
Hiraoka N, Misra A, Belot F, Hindsgaul O, Fukuda M (2001) Molecular cloning and expression of two distinct human N-acetylgalactosamine 4-O-sulfotransferases that transfer sulfate to GalNAc beta 1–>4GlcNAc beta 1–>R in both N- and O-glycans. Glycobiology 11(6):495–504
Iovu M, Dumais G, du Souich P (2008) Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage 16:S14–S18
Krahulec J, Krahulcovà J, Medovà M, Vladimir V (2005) Influence of KfoG on capsular polysaccharide structure in Escherichia coli K4 strain. Mol Biotechnol 30:129–134. doi:10.1385/MB:30:2:129
Lauder RM (2009) Chondroitin sulphate: a complex molecule with potential impacts on a wide range of biological systems. Complement Ther Med 17:56–62. doi:10.1016/j.ctim.2008.08.004
Luo XM, Fosmire GJ, Leach RM (2002) Chicken keel cartilage as a source of chondroitin sulphate. Poult Sci 81:1086–1089
Malavaki C, Mizumoto S, Karamanos N, Sugahara K (2008) Recent advances in the structural study of functional chondroitin sulfate and dermatan sulfate in health and disease. Connect Tissue Res 49:133–139. doi:10.1080/03008200802148546
Manzoni M, Bergomi S, Molinari F, Cavazzoni V (1996) Production and purification of an extracellularly produced K4 polysaccharide from Escherichia coli. Biotechnol Lett 18(4):383–386
Mellata M, Dho-Moulin M, Dozois CM, Curtiss R 3rd, Lehoux B, Fairbrother JM (2003) Role of avian pathogenic Escherichia coli virulence factors in bacterial interaction with chicken heterophils and macrophages. Infect Immun 71:494–503
McAlindon TE, LaValley MP, Gulin JP, Felson DT (2000) Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 283(11):1469–1475
McCarty MF, Russel AL, Seed MP (2000) Sulphated glycosaminoglycans and glucosamine may sinergize in promoting synovial hyaluronic acid synthesis. Med Hypotheses 54:798–802. doi:10.1054/mehy.1999.0954
Michel BA, Brühlmann P, Stucky G, Uebelhart D (2002) Chondroprotection through chondroitin 4 & 6 sulphate (Condrosulf®): the Zurich study. IBSA Satellite Symposium held at the Annual European Congress of Rheumatology (EULAR), Stockholm, 12-5 June 2002
Michel BA, Stucki G, Frey D, De Vathaire F, Vignon E, Bruehlmann P, Uebelhart D (2005) Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: a randomized, controlled trial. Arthritis Rheum 52(3):779–786. doi:10.1002/art.20867
Mitchell C, Navison M, Jackson LF, Fox R, Lee DC, Campbell JS, Fausto N (2005) Heparin binding epidermal growth factor links hepathocyte priming with cell cycle progression during liver regeneration. J Biol Chem 280(4):2562–2568
Narimatsu H, Kimata K, Yada T, Sato T, Goto M (2007) Chondroitin synthase and nucleic acid encoding the enzyme. United States Patent 7(232):676
Ninomiya T, Sugiura N, Tawada A, Sugimoto K, Watanabe H, Kimata K (2002) Molecular cloning and characterization of chondroitin polymerase from Escherichia coli strain K4. J Biol Chem 277:21567–21575. doi:10.1074/jbc.M201719200
Osawa T, Sugiura N, Shimada H, Hirooka R, Tsuji A, Shirakawa T, Fukuyama K, Kimura M, Kimata K, Kakuta Y (2009) Crystal structure of chondroitin polymerase from Escherichia coli K4. Biochem Biophys Res Commun 378:10–14. doi:10.1016/j.bbrc.2008.08.121
Petrucci F, Zoppetti G, Oreste P, Cipolletti G (2001) Process for the preparation of the polysaccharides K4 and K5 from Escherichia coli. WO0102597 (A1)
Pothacharoen P, Siriaunkgul S, Ong-Chai S, Supabandhu J, Kumja P, Wanaphirak C, Sugahara K, Hardingham T, Kongtawelert P (2006) Raised Serum Chondroitin Sulfate Epitope Level in Ovarian Epithelial Cancer. J Biochem 140(4):517–524. doi:10.1093/jb/mvj181
Prydz K, Dalen KT (2000) Synthesis and sorting of proteoglycans. J Cell Sci 113:193–205
Pumphrey CY, Theus AM, Li S, Parrish RS, Sanderson RD (2002) Neoglycans, carbodiimide-modified glycosaminoglycans:a new class of anticancer agents that inhibit cancer cell proliferation and induce apoptosis. Cancer Res 62(13):3722–3728
Rimler RB (1994) Presumptive identification of Pasteurella multocida serogroups A, D and F by capsule depolymerisation with mucopolysaccharidases. Vet Rec 134(8):191–192
Rimler RB, Register KB, Magyar T, Ackermann MR (1995) Influence of chondroitinase on indirect hemagglutination titers and phagocytosis of Pasteurella multocida serogroups A, D and F. Vet Microbiol 47:287–294
Roberts IS (1996) The biochemistry and genetics of capsulated polysaccharide production in bacteria. Annu Rev Microbiol 50:285–315. doi:10.1146/annurev.micro.50.1.285
Roberts IS, Mountford R, Hodge R, Jann KB, Boulnois GJ (1988) Common organization of gene clusters for production of different capsular polysaccharides (K antigens) in Escherichia coli. J Bacteriol 170:1305–1310
Rodriguez ML, Jann B, Jann K (1988) Structure and serological characteristics of the capsular K4 antigen of Escherichia coli O5:K4:H4, a fructose-containing polysaccharide with a chondroitin backbone. Eur J Biochem 177:117–124
Rolls A, Avidan H, Cahalon L, Shori H, Bakalash S, Litvak V, Lev S, Lider O, Schwartz M (2004) A disaccharide derived from chondroitin sulphate proteoglycan promotes central nervous system repair in rats and mice. Eur J Neurosci 20(8):1973–1983. doi:10.1111/j.1460-9568.2004.03676.x
Ronca F, Palmieri L, Panicucci P, Ronca G (1998) Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage 6(Suppl A):14–21
Rosner H, Grimmecke HD, Knirel YA, Shashkov AS (1992) Hyaluronic acid and a (1–4)-beta-D-xylan, extracellular polysaccharides of Pasteurella multocida (Carter type A) strain 880. Carbohydr Res 223:329–333
Sakko AJ, Butler MS, Byers S, Reinboth BJ, Stahl J, Kench JG, Horvath LG, Sutherland RL, Stricker PD, Henshall SM, Marshall VR, Tilley WD, Horsfall DJ, Ricciardelli C (2008) Immunohistochemical level of unsulfated Chondroitin disaccharides in the cancer stroma is an independent predictor of prostate cancer relapse. Cancer Epidemiol Biomark Prev 17:2488–2497
Silbert JE, Sugumaran G (2002) Biosynthesis of chondroitin/dermatan sulfate. IUBMB Life 54(4):177–186. doi:10.1080/15216540214923
Smetsers TF, van de Westerlo EM, ten Dam GB, Overes IM, Schalkwijik J, van Muijen GN, van Kuppevelt TH (2004) Human single-chain antibodies reactive with native chondroitin sulphate detect chondroitin sulphate alterations in melanoma and psoriasis. J Invest Dermatol 122(3):701–716
Smith AN, Boulnois GJ, Roberts IS (1990) Molecular analysis of the Escherichia coli K5 kps locus: identification and characterization of an inner-membrane capsular polysaccharide transport system. Mol Microbiol 4:1863–1869
Sugiugura N, Koji K (2009) Novel process for preparation of chondroitin fraction. United States Patent 2009/0155851
Sutherland IW (1988) Bacterial surface polysaccharide: structure and function. Int Rev Cytol 113:187–231
Suzuki K (2008) Chondroitin producing bacterium and method of producing chondroitin. PCT WO 2008/13350 A1
Tadashi E (2005) Sodium Chondroitin sulfat, chondroitin sulfat containing materila and processes for producing the same. European Patent Application EP1557472
Townsend KM, Boyce JD, Chung JY, Frost AJ, Adler B (2001) Genetic organization of Pasteurella multocida cap Loci and development of a multiplex capsular PCR typing system. J Clin Microbiol 39(3):924–929. doi:10.1128/JCM.39.3.924-929.2001
Toyoki Y, Yoshihara S, Sasaki M, Konn M (1997) Characterization of glycosaminoglycans in regenerating canine liver. J Hepatol 26(5):1135–1140
Volpi N (2002) Oral bioavailability of chondroitin sulfate (Condrosulf) and its constituents in healthy male volunteers. Osteoarthritis Cartilage 10(10):768–777
Volpi N (2009) Quality of different chondroitin sulphate preparations in relation to their therapeutic activity. J Pharm Pharmac 1271-1277. doi:10.1211/jpp/61.10.0002
Volpi N (2010) High-performance liquid chromatography and on-line mass spectrometry detection for the analysis of chondroitin sulfates/hyaluronan disaccharides derivatized with 2-aminoacridone. Anal Biochem 397(1):12–23. doi:10.1016/j.ab.2009.09.030
Wang TW, Sun JS, Wu HC, Tsuang YH, Wang W, Lin FH (2006) The effect of gelatin–chondroitin sulfate–hyaluronic acid skin substitute on wound healing in SCID mice. Biomaterials 27:5689–5697
Wessels MR, Goldberg JB, Moses AE, DiCesare TJ (1994) Effects on virulence of mutations in a locus essential for hyaluronic acid capsule expression in Group A streptococci. Infect Immun 62:433–441
Whitfield C (2006) Biosynthesis and assembly of capsular polysaccharides in Escherichia coli. Annu Rev Biochem 75:39–68. doi:10.1146/annurev.biochem.75.103004.142545
Whitfield C, Roberts IS (1999) Structure, assembly and regulation of expression of capsules in Escherichia coli. Mol Microbiol 31:1307–1320
Yamada S, Sugahara K (2008) Potential therapeutic application of chondroitin sulfate/dermatan sulphate. Curr Drug Discov Technol 5(4):289–301
Yamada T, Ohtake S, Sato M, Habuchi O (2004) Chondroitin 4-sulphotransferase-1 and chondroitin 6-sulphotransferase-1 are affected differently by uronic acid residues neighbouring the acceptor GalNAc residues. Biochem J 15;384(Pt 3):567-75. doi:10.1042/BJ20040965
Yamaguchi K, Tamaki H, Fukui S (2006) Detection of oligosaccharide ligands for hepatocyte growth factor/scatter factor (HGF/SF), keratinocyte growth factor (KGF/FGF-7), RANTES and heparin cofactor II by neoglycolipid microarrays of glycosaminoglycan-derived oligosaccharide fragments. Glycoconj J 23(7–8), 513–523
Zoppetti G, Oreste P (2004) Process for the preparation of chondroitin sulfates from K4 polysaccharide and obtained products. United States Patent 6(777):398
Zoppetti G, Pasqua O, Cipolletti G (2001) O-sulfated bacterial polysaccharides. United States Patent 6,288,044
Zou XH, Foong WC, Cao T, Bay BH, Wand OH, Yip GW (2004) Chondroitin Sulfate in Palatal Wound Healing. J Dent Res 83(11):880–885. doi:10.1177/154405910408301111
Zou XH, Jiang YZ, Zhang GR, Jin HM, Nguyen TM, Ouyang HW (2009) Specific interactions between human fibroblasts and particular chondroitin sulfate molecules for wound healing. Acta Biomater 5(5):1588–1595. doi:10.1016/j.actbio.2008.12.001
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Schiraldi, C., Cimini, D. & De Rosa, M. Production of chondroitin sulfate and chondroitin. Appl Microbiol Biotechnol 87, 1209–1220 (2010). https://doi.org/10.1007/s00253-010-2677-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00253-010-2677-1