Special Issue "Synthesis and Biological Applications of Glycoconjugates Ⅱ"
Deadline for manuscript submissions: 31 January 2019
Prof. Dr. Lothar Elling
Laboratory for Biomaterials, Institute of Biotechnology and Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstraße 20, 52074 Aachen, Germany
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Interests: glycoconjugates; enzyme cascade reactions; chemo-enzymatic synthesis; glycosyltransferases; nucleotide sugars; galectins; lectins; glycopolymers; biosensors; biomaterials
Glycoconjugates (glycoproteins, glycolipids, proteoglycans) are involved in numerous biological recognition events. Their glycans encode the specific information to trigger protein–glycan interactions. Intercellular crosstalk and pathogen–host interactions are examples and are directly related to the vast chemical diversity of glycan structures. Glycan synthesis via chemical and/or enzymatic approaches are therefore challenging. Novel and efficient procedures for glycan-based products need to be developed and optimized. Multi-enzyme cascade reactions are key for the production of glycans in a larger scale. Protein engineering of enzymes serve to tailor biocatalysts with favorable and novel properties. Most importantly, the combination of chemo- and biocatalysis expands the spectrum of novel synthetic routes. In this way, complex glycans and neo-glycoconjugates will be accessible for biological applications. Multivalency is a key factor for decoding glycan information by carbohydrate recognizing molecules such as lectins and antibodies leading to many applications in biomedicine, biomaterial research, and advanced material sciences. Examples have been seen already in the first Special Issue “Synthesis and Biological Applications of Glycoconjugates” in Molecules in 2017.
I cordially invite you to contribute and share your recent research results in the upcoming second Special Issue on all aspects of the synthesis and biological applications of glycoconjugates.
Prof. Dr. Lothar Elling
Manuscript Submission Information
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- cascade reactions
- chemo-enzymatic synthesis
- glycoconjugates in tissue engineering
- glycoconjugates of the microbiome
- glycoconjugates in host-pathogen interaction
- Synthesis and Biological Applications of Glycoconjugates in Molecules (7 articles)
The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.
Title: β-N-Acetylhexosaminidase in the synthesis of bioactive glycans: protein and reaction engineering
Authors: Pavla Bojarová, Vladimír Křen et al.
Affiliation: Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic
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Abstract: N-Acetylhexosamine oligosaccharides terminated with GalNAc are attractive synthetic targets since they act as selective ligands of galectin-3, a biomedically important human lectin. β-N-Acetylhexosaminidases (EC 22.214.171.124) used as synthetic tools have the advantage of tolerating a number of functional groups incorporated in both the donor and acceptor carbohydrate molecule. Thus, oligosaccharides carrying desired structural modifications may be prepared . Such modifications at glycan C-1 may be applied for, e.g., covalent attachment of glycans to a multivalent carrier, resulting in glycomimetics with enhanced affnity to galectins .
β-N-Acetylhexosaminidases exhibit dual specificity for both N-acetylglucosamine and N-acetylgalactosamine moieties (and thus have both GlcNAcase and GalNAcase activities); this may complicate synthetic applications especially in combination with a side substrate hydrolysis that may occur in the reaction. A point mutation of active-site amino acid Tyr to other amino acid residues, especially Phe, His and Asn, has previously been shown to strongly suppress the hydrolytic activity of β-N-acetylhexosaminidases and substantially increase the synthetic yields . In the present work, we have found that Tyr470 is also an important mutation hotspot for altering the ratio of GlcNAcase/GalNAcase activity, resulting in mutant enzymes with various affinity to GlcNAc/ GalNAc substrates. The enzyme selectivity may also be manipulated by altering the reaction medium upon changing pH or adding selected organic co-solvents. As a result, we are able to fine-tune the β-N-acetylhexosaminidase affinity and selectivity, resulting in a high-yield production of the desired functionalized GalNAcβ4GlcNAc epitope. The present work will show the protein and reaction engineering on a model β-N-acetylhexosaminidase from Talaromyces flavus, recombinantly expressed in Pichia pastoris. The result of the one-step engineered reaction is the production of this carbohydrate epitope in a close-to-quantitative yield, comparable to the synthesis by glycosyltransferases. The impact of this point mutation on the enzyme GlcNAcase/GalNAcase activity will be explained by a detailed molecular modelling and substrate docking study.
1. Bojarová, P., Křen, V. Trends Biotechnol. 2009, 27, 199-209.
2. Bojarová, P., Chytil. P., Mikulová, B., Bumba, L., Konefal, R., Pelantová, H., Krejzová, J., Slámová, K., Petrásková, L., Kotrchová, L., Cvačka, J., Etrych, T., Křen, V., Polym. Chem. 2017, 8, 2647-2658.
3. Slámová, K., Krejzová, J., Marhol, P., Kalachova, L., Kulik, N., Pelantová, H., Cvačka, J., Křen, V. Adv. Synth. Catal. 2015, 357, 1941-1950.
Title: Screening of a library of oligosaccharides targeting Lectin LecB of Pseudomonas aeruginosa and synthesis of oligoglycoclusters of high affinity
Authors: Yann Chevolot and François Morvan
Affiliation: Université de Lyon, Ecole centrale de Lyon, CNRS, Institut des Nanotechnologies de Lyon (INL), UMR CNRS 5270, Site Ecole Centrale de Lyon, Ecully cedex, France
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Abstract: The gram negative bacterium Pseudomonas aeruginosa (PA) is an opportunistic bacterium that causes severe and chronic infection of immune-depressed patient. It has the ability to form a biofilm that gives a selective advantage to the bacteria with respect to antibiotherapy and host defenses. During the formation of the biofilm, several virulent factors are involved. Among these virulence factor, lectins play a key role. Therefore, molecules inhibiting these lectins are envisioned as new anti-bacterial agents. Herein, we have focused on LecB. LecB is a tetrameric soluble lectin involved in bacterium adherence to host cells, biofilm formation, cytotoxicity. It binds to L-fucose, D-mannose and glycan exposing terminal fucose or mannose. Herein, using a competitive assay on microarray, 156 oligosaccharides and polysaccharides issued from fermentation or from the biomass were screened toward their affinity to LecB. Next, the five best ligands (Lewisa, Lewisb, Lewisx, siayl-Lewisx and 3-fucosyllactose) were derivatized with a propargyl aglycon allowing the synthesis of multivalent constructions thanks to copper catalyzed azide alkyne cycloaddition. The binding of the resulting oligoglycoclusters to LecB was determined using a microarray.