Skip to main content

Advertisement

Log in

Microbial hyaluronic acid production

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

Abstracts

Hyaluronic acid (HA) is a commercially valuable medical biopolymer increasingly produced through microbial fermentation. Viscosity limits product yield and the focus of research and development has been on improving the key quality parameters, purity and molecular weight. Traditional strain and process optimisation has yielded significant improvements, but appears to have reached a limit. Metabolic engineering is providing new opportunities and HA produced in a heterologous host is about to enter the market. In order to realise the full potential of metabolic engineering, however, greater understanding of the mechanisms underlying chain termination is required.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5a–c
Fig. 6

Similar content being viewed by others

References

  • Abbe K, Takahashi S, Yamada T (1982) Involvement of oxygen-sensitive pyruvate-formate-lyase in mixed acid fermentation by Streptococcus mutans under strictly anaerobic conditions. J Bacteriol 152:175–182

    CAS  PubMed  Google Scholar 

  • Armstrong DC (1997) The molecular weight properties of hyaluronic acid produced Streptococcus zooepidemicus. PhD. Thesis, University of Queensland

  • Armstrong DC, Johns MR (1997) Culture conditions affect the molecular weight properties of hyaluronic acid produced by Streptococcus zooepidemicus. Appl Environ Microbiol 63:2759–2764

    CAS  Google Scholar 

  • Asari A, Miyauchi S (2000) Medical applications of Hyaluronan. Glycoforum - Hyaluronan Today. http://www.glycoforum.gr.jp/science/hyaluronan/HAIZ/HAIZE.html

  • Ashbaugh CD, Alberti S, Wessels MR (1998) Molecular analysis of the capsule gene region of group A streptococcus: the hasAB genes are sufficient for capsule expression. J Bacteriol 180:4955–4959

    CAS  PubMed  Google Scholar 

  • Balazs EA, Leshchiner E, Larsen NE, Band P (1993) Application of hyaluronan and its derivatives. In: Gebelein CG (ed) Biotechnological polymers. Technomic, Lancaster, pp 41–65

    Google Scholar 

  • Cleary PP, Larkin A (1979) Hyaluronic acid capsule: strategy for oxygen resistance in group A streptococci. J Bacteriol 140:1090–1097

    CAS  PubMed  Google Scholar 

  • Cooney MJ, Goh LT, Lee PL, Johns MR (1999) Structured model-based analysis and control of the hyaluronic acid fermentation by Streptococcus zooepidemicus: Physiological implications of glucose and complex nitrogen-limited growth. Biotechnol Prog 15:898–910

    CAS  PubMed  Google Scholar 

  • Crater DL, Dougherty BA, van de Rijn I (1995) Molecular characterization of hasC from an operon required for hyaluronic acid synthesis in group A streptococci. Demonstration of UDP- glucose pyrophosphorylase activity. J Biol Chem 270:28676–28680

    CAS  PubMed  Google Scholar 

  • Cywes C, Wessels MR (2001) Group A Streptococcus tissue invasion by CD44-mediated cell signalling. Nature 414:648–652

    Article  CAS  PubMed  Google Scholar 

  • DeAngelis PL, Papaconstantinou J, Weigel PH (1993a) Isolation of a Streptococcus-Pyogenes gene locus that directs hyaluronan biosynthesis in acapsular mutants and in heterologous bacteria. J Biol Chem 268:14568–14571

    CAS  PubMed  Google Scholar 

  • DeAngelis PL, Papaconstantinou J, Weigel PH (1993b) Molecular cloning, identification, and sequence of the hyaluronan synthase gene from group A Streptococcus pyogenes. J Biol Chem 268:19181–19184

    CAS  PubMed  Google Scholar 

  • DeAngelis PL, Weigel PH (1994) Immunochemical confirmation of the primary structure of streptococcal hyaluronan synthase and synthesis of high molecular weight product by the recombinant enzyme. Biochemistry 33:9033–9039

    CAS  PubMed  Google Scholar 

  • de Ruyter P, Kuipers OP, de Vos WM (1996) Controlled gene expression systems for Lactococcus lactis with the food-grade inducer nisin. Appl Environ Microbiol 62:3662–3667

    PubMed  Google Scholar 

  • Dougherty BA, van de Rijn I (1993) Molecular characterization of hasB from an operon required for hyaluronic acid synthesis in group A streptococci. Demonstration of UDP- glucose dehydrogenase activity. J Biol Chem 268:7118–7124

    CAS  PubMed  Google Scholar 

  • Dougherty BA, van de Rijn I (1994) Molecular characterization of hasA from an operon required for hyaluronic acid synthesis in group A streptococci. J Biol Chem 269:169–175

    CAS  PubMed  Google Scholar 

  • Ellwood DC, Evans CGT, Dunn GM, McInnes N et al (1995) Production of hyaluronic acid. US Patent 5411874

  • Ellwood DC, Evans CGT, Dunn GM, McInnes N et al (1996) Production of hyaluronic acid. US Patent 5411874

  • Fong Chong B (2002) Improving the cellular economy of Streptococcus zooepidemicus through metabolic engineering. PhD Thesis, The University of Queensland

  • Fong Chong B, Nielsen LK (2003a) Aerobic cultivation of Streptococcus zooepidemicus and the role of NADH oxidase. Biochem Eng J 16:153–162

    Article  Google Scholar 

  • Fong Chong B, Nielsen LK (2003b) Amplifying the cellular reduction potential of Streptococcus zooepidemicus. J Biotechnol 100:33–41

    Article  PubMed  Google Scholar 

  • Forsee WT, Cartee RT, Yother J (2000) Biosynthesis of type 3 capsular polysaccharide in Streptococcus pneumoniae—enzymatic chain release by an abortive translocation process. J Biol Chem 275:25972–25978

    Article  CAS  PubMed  Google Scholar 

  • Fouissac E, Milas M, Rinaudo M (1993) Shear rate, concentration, molecular weight and temperature viscosity dependences of hyaluronate, a wormlike polyelectrolytes. Macromolecules 26:6945–6951

    CAS  Google Scholar 

  • Goh L-T (1998) Effect of culture conditions on rates of intrinsic hyaluronic acid production by Streptococcusequi subsp. zooepidemicus. PhD Thesis. University of Queensland

  • Heldermon C, DeAngelis PL, Weigel PH (2001) Topological organization of the hyaluronan synthase from Streptococcus pyogenes. J Biol Chem 276:2037–2046

    Article  CAS  PubMed  Google Scholar 

  • Heldermon C, Kumari K, Tlapak-Simmons V, Weigel PH (2000) Streptococcal hyaluronan synthases and the synthesis of “designer” hyaluronan. In: Abatangelo G, Weigel PH (eds) New frontiers in medical sciences: redefining hyaluronan. Elsevier, New York

    Google Scholar 

  • Jacques M, Graham L (1989) Improved preservation of bacterial capsule for electron microscopy. J Electron Microsc Tech 11:167–169

    CAS  PubMed  Google Scholar 

  • Johns MR, Goh LT, Oeggerli A (1994) Effect of pH, agitation and aeration on hyaluronic-acid production by Streptococcus-Zooepidemicus. Biotechnol Lett 16:507–512

    CAS  Google Scholar 

  • Kim JH, Yoo SJ, Oh DK, Kweon YG et al. (1996) Selection of a Streptococcus equi mutant and optimization of culture conditions for the production of high molecular weight hyaluronic acid. Enzyme Microb Technol 19:440–445

    Article  CAS  Google Scholar 

  • Kitchen JR, Cysyk RL (1995) Synthesis and release of hyaluronic acid by Swiss 3T3 fibroblasts. Biochem J 309:649–656

    CAS  PubMed  Google Scholar 

  • Kumari K, Weigel PH (1997) Molecular cloning, expression, and characterization of the authentic hyaluronan synthase from group C Streptococcus equisimilis. J Biol Chem 272:32539–32546

    Article  CAS  PubMed  Google Scholar 

  • Lander ES, Linton LM, Birren B, Nusbaum C et al. (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921

    Article  PubMed  Google Scholar 

  • Leonard BA, Woischnik M, Podbielski A (1998) Production of stabilized virulence factor-negative variants by group A streptococci during stationary phase. Infect Immun 66:3841–3847

    CAS  PubMed  Google Scholar 

  • Lertwerawat Y (1993) Hyaluronic acid production and its instability in Streptococcus zooepidemicus. PhD Thesis. University of Queensland

  • Maguin E, Prevost H, Ehrlich SD, Gruss A (1996) Efficient insertional mutagenesis in lactococci and other Gram-positive bacteria. J Bacteriol 178:931–935

    CAS  PubMed  Google Scholar 

  • Matsubara C, Kajiwara M, Akasaka H, Haze S (1991) Carbon-13 nuclear magnetic resonance studies on the biosynthesis of hyaluronic acid. Chem Pharm Bull 39:2446–2448

    CAS  Google Scholar 

  • Mausolf A, Jungmann J, Robenek H, Prehm P (1990) Shedding of hyaluronate synthase from streptococci. Biochem J 267:191–196

    CAS  PubMed  Google Scholar 

  • Meyer K, Palmer JW (1934) The polysaccharide of the vitreous humor. J Biol Chem 107:629–634

    CAS  Google Scholar 

  • O’Regan M, Martini I, Crescenzi F, De Luca C et al (1994) Molecular Mechanisms and genetics of hyaluron Biosynthesis. Int J Biol Macromol 16:283–286

    Article  CAS  PubMed  Google Scholar 

  • Praest BM, Helmut G, Rudiger K (1997) Effects of oxygen-derived free radicals on the molecular weight and the polydispersity of hyaluronan solutions. Carbohydr Res 303:153–157

    Article  CAS  Google Scholar 

  • Prehm P (1984) Hyaluronate is synthesised at plasma membrane. Biochem J 220:597–600

    CAS  PubMed  Google Scholar 

  • Saettone MF, Giannaccini B, Chetoni P, Torracca MT et al (1991) Evaluation of high-molecular-weight and low-molecular-weight fractions of sodium hyaluronate and an ionic complex as adjuvants for topical ophthalmic vehicles containing pilocarpine. Int J Pharm 72:131–139

    CAS  Google Scholar 

  • Sakamoto M, Komagata K (1996) Aerobic growth of and activities of NADH oxidase and NADH peroxidase in lactic acid bacteria. J Ferment Bioeng 82:210–216

    CAS  Google Scholar 

  • Salzberg SL, White O, Peterson J, Eisen JA (2001) Microbial genes in the human genome: lateral transfer or gene loss? Science 292:1903–1906

    CAS  PubMed  Google Scholar 

  • Saso L, Bonanni G, Grippa E, Gatto MT et al (1999) Interaction of hyaluronic acid with mucin, evaluated by gel permeation chromatography. Res Commun Mol Pathol Pharmacol 104:277–284

    CAS  PubMed  Google Scholar 

  • Schmidt KH, Gunther E, Courtney HS (1996) Expression of both M protein and hyaluronic acid capsule by group A streptococcal strains results in a high virulence for chicken embryos. Med Microbiol Immunol 184:169–173

    CAS  PubMed  Google Scholar 

  • Scott JE, Heatley F (1999) Hyaluronan forms specific stable tertiary structures in aqueous solution: a C-13 NMR study. Proc Natl Acad Sci USA 96:4850–4855

    CAS  PubMed  Google Scholar 

  • Snoep JL, de Graef MR, de Mattos MJT, Neijssel OM (1992) Pyruvate catabolism during transient state conditions in chemostat cultures of Enterococcus faecalis NCTC 775: importance of internal pyruvate concentrations and NADH/NAD+ ratios. J Gen Microbiol 138:2015–2020

    CAS  PubMed  Google Scholar 

  • Spurlock SL, Spurlock GH, Bernstad S, Michanek P et al. (1999) Treatment of acute superficial flexor tendon injuries in performance horses with high molecular weight sodium hyaluronate. J Equine Vet Sci 19:338–344

    Google Scholar 

  • Stangohl S (2000) Methods and means for the production of hyaluronic acid. US Patent 6090596

  • Stangohl S (2003) Methods and means for the production of hyaluronic acid. US Patent 6537795

  • Suzuki Y, Yamaguchi T (1993) Effect of hyaluronic acid on macrophage phagacytosis and active oxygen release. Agents Actions 38:32–37

    CAS  PubMed  Google Scholar 

  • Thomas EL, Pera KA (1983) Oxygen metabolism of Streptococcus mutans: uptake of oxygen and release of superoxide and hydrogen peroxide. J Bacteriol 154:1236–1244

    CAS  PubMed  Google Scholar 

  • Thomas TD, Ellwood DC, Longyear VMC (1979) Change from homo- to heterolactic fermentation by Streptococcus lactis resulting from glucose limitation in anaerobic chemostat cultures. J Bacteriol 138:109–117

    CAS  PubMed  Google Scholar 

  • Tlapak-Simmons VL, Baggenstoss BA, Clyne T, Weigel PH (1999a) Purification and lipid dependence of the recombinant hyaluronan synthases from Streptococcus pyogenes and Streptococcus equisimilis. J Biol Chem 274:4239–4245

    Article  CAS  PubMed  Google Scholar 

  • Tlapak-Simmons VL, Baggenstoss BA, Kumari K, Heldermon C et al. (1999b) Kinetic characterization of the recombinant hyaluronan synthases from Streptococcus pyogenes and Streptococcus equisimilis. J Biol Chem 274:4246–4253

    Article  CAS  PubMed  Google Scholar 

  • Tlapak-Simmons VL, Kempner ES, Baggenstoss BA, Weigel PH (1998) The active streptococcal hyaluronan synthases (HASs) contain a single HAS monomer and multiple cardiolipin molecules. J Biol Chem 273:26100–26109

    Article  CAS  PubMed  Google Scholar 

  • van de Rijn I, Kessler RE (1980) Growth characteristics of group A streptococci in a new chemically defined medium. Infect Immun 27:444–448

    PubMed  Google Scholar 

  • Ward PN, Field TR, Ditcham WGF, Maguin E et al (2001) Identification and disruption of two discrete loci encoding hyaluronic acid capsule biosynthesis genes hasA, hasB, and hasC in Streptococcus uberis. Infect Immun 69:392–399

    Article  CAS  PubMed  Google Scholar 

  • Weigel PH (2002) Functional characteristics and catalytic mechanisms of the bacterial hyaluronan synthases. IUBMB Life 54:201–211

    CAS  PubMed  Google Scholar 

  • Weigel PH, Hascall VC, Tammi M (1997) Hyaluronan synthases. J Biol Chem 272:13997–14000

    Article  CAS  PubMed  Google Scholar 

  • Weissman B, Meyer K (1954) The structure of hyalobiuronic acid and of hyaluronic acid from umbilical cord. J Am Chem Soc 76:1753–1757

    Google Scholar 

  • Wessels MR, Moses A, Goldberg JB, DiCesare TJ (1991) Hyaluronic acid capsule is a virulence factor for mucoid group A streptococci. Proc Natl Acad Sci USA 88:8317–8321

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lars K. Nielsen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chong, B.F., Blank, L.M., Mclaughlin, R. et al. Microbial hyaluronic acid production. Appl Microbiol Biotechnol 66, 341–351 (2005). https://doi.org/10.1007/s00253-004-1774-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00253-004-1774-4

Keywords

Navigation