Hyaluronic acid (HA) is a polyanionic polymer consisting of repeating disaccharide units of d-glucuronic acid (GlcA) and N-acetyl-d-glucosamine (GlcNAc) (4GlcAβ1,3GlcNAcβ1). In vertebrates HA is involved in water homeostasis, passage of molecules in connective tissues and lubrication of joints. Certain pathogenic streptococci strains use HA as component of their polysaccharide capsule to escape the host's immune system.
Tha lacking immunogenicity makes HA attractive for the development of new biomaterials and pharmaceuticals. It is expected that the demand for effective HA products will constantly rise with the growth of ageing population. In ophthalmology and orthopedics polymeric HA with a molecular weight (MW) > 1 MDa is used. However, the availability of unmodified HA in this MW range is limited because of its low biomechanical stability and fast in vivo degradation. Therefore, high MW HA with the lowest possible dispersity is needed. At the present time, HA is either extracted from rooster combs using large amounts of organic solvents or is obtained from the fermentation of pathogenic streptococci. Both processes are not sustainable and result in polydisperse HA. Still there is no process available which can avoid either the use of animal tissue, fermentation of pathogenic bacteria or chemical crosslinking.
The joint project "Hyaluronan Polymer" includes three RWTH Aachen University partners (Biomaterials, Biotechnology, Microbiology) as well as the company GALAB Laboratories GmbH and aims at the development of such a process using a microbial host. The new process is also evaluated in terms of sustainability by the ifu Hamburg GmbH (institute of environmental informatics). In particular, the partners develop new enzyme modules for the short metabolic access to the HA building blocks GlcA and GlcNAc, optimize HA synthases with regard to MW by means of protein engineering, focus on metabolic engineering of the microbial host and develop HA analytics and downstream processing. By combining these approaches, it is planned to develop a sustainable fermentation process for the production of long-chain HA with reduced environmental impact.
The project "Hyaluronan Polymer" was funded by the DBU (Deutsche Bundesstiftung Umwelt) and BMBF (KMU-Innovative).
Univ.-Prof. Dr. rer. nat. Lothar Elling (project coordination)
Laboratory of Biomaterials, Institute of Biotechnology and Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University
Univ.-Prof. Dr.-Ing. Lars Blank
M. Sc. Sandra Schulte
Institute of Applied Microbiology, RWTH Aachen University
Univ.-Prof. Dr. rer. nat. Ulrich Schwaneberg
Dr. Felix Jakob
M. Sc. John Mandawe
Institute of Biotechnology, RWTH Aachen University
Dr. Jürgen Kuballa
Publications from the "Hyaluronan Polymer" project:
Eisele, A., Zaun, H., Kuballa, J., Elling, L. (2018)
In Vitro One-Pot Enzymatic Synthesis of Hyaluronic Acid from Sucrose and N-Acetylglucosamine: Optimization of the Enzyme Module System and Nucleotide Sugar Regeneration
ChemCatChem 10, 2969-2981 https://doi.org/10.1002/cctc.201800370.
Mandawe, J., Infanzon, B., Eisele, A., Zaun, H., Kuballa, J., Davari, M.D., Jakob, F., Elling, L., Schwaneberg, U. (2018)
Directed Evolution of Hyaluronic Acid Synthase from Pasteurella multocida towards High-Molecular-Weight Hyaluronic Acid
ChemBioChem 19, 1414-1423. https://doi.org/doi:10.1002/cbic.201800093.
Gottschalk, J., Zaun, H., Eisele, A., Kuballa, J., Elling, L. (2019)
Key Factors for A One-Pot Enzyme Cascade Synthesis of High Molecular Weight Hyaluronic Acid
Internat. J. Mol. Sci. 20, 5664. https://doi.org/10.3390/ijms20225664.
Gottschalk, J., Blaschke, L., Aßmann, M., Kuballa, J., Elling, L. (2021)
Integration of a Nucleoside triphosphate regeneration system in the one-pot synthesis of UDP-sugars and hyaluronic acid
ChemCatChem 13, 3074-3083. https://doi.org/10.1002/cctc.202100462.
Gottschalk, J., Elling, L. (2021)
Current state on the enzymatic synthesis of glycosaminoglycans
Curr. Opin. Chem. Biol. 61, 71-80. https://doi.org/10.1016/j.cbpa.2020.09.008.
Gottschalk, J., Aßmann, M., Kuballa, J., Elling, L. (2022)
Repetitive Synthesis of High-Molecular-Weight Hyaluronic Acid with Immobilized Enzyme Cascades
ChemSusChem 15, e202101071. https://doi.org/10.1002/cssc.202101071.