The Brockhausen lab aims to understand the biochemical mechanisms underlying diseases such as inflammation, infections and cancer. We also hope to develop novel therapeutic interventions based on our knowledge and inhibition of glycosyltransferase enzymes that glycosylate proteins in humans, and assemble the O-antigenic and other polysaccharides in pathogenic bacteria as well as in pathogenic fungi. Newly developed assays for glycosyltransferases help to discover novel enzymes, characterize enzymes, reveal protein structure and function relationships and contribute to our understanding of the underlying biosynthetic mechanisms. This work is the basis for the design of specific inhibitors that could 1. Reduce inflammation, 2. Reduce cancer metastasis and 3. Act as new antibacterial or antifungal agents. A world-wide network of collaborators helps to achieve these goals.
Thousands of different structures of sugar chains are found on glycoproteins, however, the role of these glycans in health and disease is largely undefined. The longterm goal of our research is to obtain knowledge of the molecular mechanisms controlling the biosynthesis of glycoprotein-bound glycans, and to understand the role of glycans in cell growth, cell death and cell adhesion. These biological processes are important in inflammatory diseases such as rheumatoid arthritis, in cystic fibrosis, inflammatory bowel disease, cancer, and other diseases.
The large polysaccharide capsule of the pathogenic fungus Cryptococcus neoformans is a major virulence factor. We are involved in discovering the enzymes that assemble these capsules.
A major focus in the lab is the biochemistry of bacterial polysaccharides that are also important virulence factors. These complex carbohydrates function in the protection of microbes and in the communication mechanisms with the host. We have discovered a number of novel enzymes that transfer sugars in the biosynthesis of O antigens. We develop specific biochemical assays for these enzymes in order to develop inhibitors as anti-biotic drug candidates.
- Selected Reviews
- I Brockhausen, J Schutzbach, W Kuhns. Glycoproteins and their relationship to human disease. (1998) Acta Anat. 161: 36-78
- I Brockhausen. Pathways of O-glycan biosynthesis in cancer cells. (1999) Biochim. Biophys. Acta, 1473: 67-95
- I Brockhausen. The role of galactosyltransferases in cell surface functions and in the immune system. (2006) Drug News and Perspectives 19(7): 401-409
- J Schutzbach, H Ankel, I Brockhausen. Synthesis of cell envelope glycoproteins of Cryptococcus laurentii. (2007) Carbohydr. Res.342:881-893
- Glycobiology Protocols in Methods in Molecular Biology. I. Brockhausen Ed. (2006) Humana Press.
- I Brockhausen. Biochemical Aspects: Biosynthesis of O-glycans. In Comprehensive Glycosciences, From Chemistry to Systems Biology. (2007) Elsevier.
- I Brockhausen. Structure and function of glycosyltransferases specific for O-glycan processing. (2007) In Glycobiology, Scion Publ. Woodbury NY.
- J. Schutzbach, I Brockhausen. Inhibition of glycosyltransferase activities as the basis for drug development. (2009) Methods in Molecular Biology, Humana Press, Totowa, NY. 534: 1-15
- I Brockhausen. biosynthesis of complex mucin-type O-glycans. (2009) Comprehensive Natural Products Chemistry II Volume 5, Carbohydrates, nucleosides and nucleic acids. G. Wang Ed. Elsevier.
- I Brockhausen, Y Gao. Structural Glycobiology: applications in cancer research. Chapter 8. (2012) Ed. E. Yurevics. CRC Press, Taylor & Francis Group, Abingdon, UK, pp177-213
- I Brockhausen. Role of glycans in cell death: a deadly relationship. In: Glycosignals in Cancer: Mechanisms of malignant phenotypes. (2016) Ed M. Fukuda, K. Furukawa,Springer Japan.pp163-193
- Glycobiology Protocols in Methods in Molecular Biology. (2006) I Brockhausen Ed. Humana Press, Totowa NY.
- Glycosyltransferases, Methods and Protocols’ in Methods in Molecular Biology.(2013) I Brockhausen Ed. Series ed. John Walker, Springer, Humana Press, Totowa NY.
- Bacterial polysaccharides. Methods and Protocols’ in Methods in Molecular Biology. (2019) I Brockhausen Ed. Series ed. John Walker, Springer, Humana Press, Totowa NY.
- Selected papers
- I Brockhausen, J Yang, J Burchell, C Whitehouse, J Taylor-Papadimitriou. Mechanism underlying aberrant glycosylation of the MUC1 mucin in breast cancer cells. (1995) Eur. J. Biochem., 233: 607-617
- C Whitehouse, J Burchell, S Gschmeissner, I Brockhausen, K Lloyd, J Taylor-Papadimitriou. A transfected sialyltransferase that is elevated in breast cancer and localizes to the medial/trans-Golgi apparatus inhibits the development of core 2-based O-glycans. (1997) J. Cell Biol., 137:1229-1241
- I Brockhausen, J Yang, N Dickinson, S Ogata, S Itzkowitz. Enzymatic basis for sialyl-Tn expression in human colon cancer cells. (1998) Glycoconj. J. 15: 595-603
- I Brockhausen, M Lehotay, J Yang, W Qin, D Young, J Lucien, J Coles, H Paulsen. Glycoprotein biosynthesis in porcine aortic endothelial cells and changes in the apoptotic cell population. (2002) Glycobiology, 12: 33-45
- X Yang, W Qin, M Lehotay, D Toki, P Dennis, J Schutzbach, I Brockhausen. Soluble human core 2 beta6-GlcNAc-transferase requires its conserved Cys residues for full activity (2003) Biochim. Biophys. Acta, 1648:62-74
- X Yang, M Lehotay, T Anastassiades, M Harrison, I Brockhausen. The effect of TNFalpha on glycosylation pathways in bovine synoviocytes. (2004) Biochemistry and Cell Biology, 82(5):559-568
- DS McBride, I Brockhausen. FWK Kan. Detection of glycosyltransferases in the golden hamster (Mesocricetus auratus) oviduct and evidence for the regulation of O-glycan biosynthesis during the estrus cycle. (2005) Biochim. Biophys. Acta, 1721:107-115.
- JG. Riley, M Menggad, P Montoya-Peleaz, WA. Szarek, CL Marolda, MA Valvano, JS Schutzbach, I Brockhausen. The wbbD gene of E. coli strain VW187 (O7:K1) encodes a UDP-Gal: GlcNAc(alpha)-pyrophosphate-R (beta)1,3-galactosyltransferase involved in the biosynthesis of O7-specific lipopolysaccharide. (2005) Glycobiology, 15: 605-613
- I Brockhausen, M Benn, S Bhat, S Marone, JG, Riley J, P Montoya-Peleaz, JZ Vlahakis, H Paulsen, JS Schutzbach, W Szarek. UDP-Gal: GlcNAc-R beta1,4-Galactosyltransferase - a target enzyme for drug design. Acceptor specificity and inhibition of the enzyme. (2006) Glycoconj. J., 23: 523-539
- X Yang, J Yip, T Anastassiades, M Harrison, I Brockhausen. The action of TNFalpha and TGFbeta include specific alterations of the glycosylation of bovine and human chondrocytes. (2007) Biochim. Biophys. Acta 1773 (2):264-272
- Y Li, X Yang, A Nguyen, I Brockhausen. Requirement of N-glycosylation for the secretion of recombinant extracellular domain of human Fas in heLa cells. (2007) Internat. J. Biochem. Cell Biol. 39: 1625-1636
- X Yang, J Yip, M Harrison, I Brockhausen. Primary human osteoblasts and bone cancer cells as models to study glycodynamics in bone.(2008) Internat J Biochem Cell Biol 40(3):471-483
- I Brockhausen, J Riley, M Joynt, X Yang, WA Szarek. Acceptor substrate specificity of UDP-Gal: GlcNAc-R b1,3-galactosyltransferase from Escherichia coli O7:K1. (2008) Glycoconj. J. 25: 663-673
- I Brockhausen, B Liu, B Ju, K Lau, W Szarek, L Wang, L Feng. Characterization of two UDP-GlcNAcNAc: beta1,3-glucosyltranferases from the Escherichia coli serotypes O56 and O152. (2008) J. Bacteriol. 190: 4922-4932
- I Brockhausen, T Dowler, H Paulsen. Site directed processing: Role of amino acid sequences and glycosylation of acceptor glycopeptides in the assembly of extended mucin type O-glycan core 2. (2009) Biochim. Biophys. Acta, 1790: 1244-1257
- J Riley, C Xu, I Brockhausen. Synthesis of acceptor substrate analogs for the study of glycosyltransferases involved in the second step of the biosynthesis of O antigen repeating units. (2010) Carbohydr. Res. (2010) 345:586-597
- G Picco, S Julien, I Brockhausen, R Beatson, A Antonopoulos, S Haslam, U Mandel, A Dell, S Pinder, J Taylor-Papadimitriou and J Burchell. Over-expression of ST3Gal-I promotes mammary tumorigenesis. (2010) Glycobiology 20:1241-1250
- Y Gao, Lazar C, WA. Szarek, I Brockhausen. Specificity of beta4galactosyltransferase inhibitor 2-naphthyl 2-butanamido-2-deoxy-1-thio-beta-D-glucopyranoside. (2010) Glycoconj J 27(7- 9):673- 684
- C Xu, B Liu, B Hu, Y Han, L Feng, J Allingham, WA Szarek, L Wang, I Brockhausen. Biochemical characterization of UDP-Gal:GlcNAc-pyrophosphate-lipid beta1,4 galactosyltransferase WfeD, a new enzyme from Shigella boydii type 14 that catalyzes the second step in O-antigen repeating-unit synthesis. (2011) J Bacteriol 193(2):449-459
- Y Gao, B Liu, S Strum, J Schutzbach, TN Druzhinina, NS Utkina, VI Torgov, LL Danilov, VV Veselovsky, JZ Vlahakis, WA Szarek, L Wang, I Brockhausen. Biochemical characterization of WbdN, a beta1,3-glucosyltransferase involved in O-antigen synthesis in enterohemorrhagic Escherichia coli O157. (2012) Glycobiology 22(8): 1092-1102
- Y Gao, V Chachadi, PW Chen, I Brockhausen. Glycosylation potential of human prostate cancer cell lines. (2012) Glycoconj J, 9(17): 525-537
- Y Gao, J Vlahakis, WA Szarek, I Brockhausen. Selective inhibition of glycosyltransferases by bivalent imidazolium salts. (2013) Bioorg Med Chem. 21:1305-1311
- S Wang, D Czuchry, B Liu, A Vinnikova, Y Gao, JZ Vlahakis, WA Szarek, L Feng, L Wang, I Brockhausen. Characterization of two UDP-Gal: GalNAc-diphosphate-lipid beta1,3-Galactosyltransferases WbwC from Escherichia coli Serotypes O104 and O5.
(2014) J. Bacteriol. 196(17):3122-3133
- I Brockhausen. Crossroads between bacterial and mammalian glycosyltransferases. (2014) Frontiers in Immunology. 5:492: 1-21
- S Wang, Y Hao, JS Lam, JZ Vlahakis, WA Szarek, A. Vinnikova, VV Veselovsky, I Brockhausen. Biosynthesis of the Common Polysaccharide Antigen of Pseudomonas aeruginosa PAO1: Characterization and role of WbpZ – a GDP-D-rhamnose:GlcNAc/GalNAc-diphosphate-lipid ?1,3-D-rhamnosyltransferase WbpZ. (2015) J Bacteriol. 197(12):2012-2019
- D Czuchry, P Desormeaux, M Stuart, D Jarvis, KL Matta, WA Szarek, I Brockhausen. Identification and biochemical characterization of the novel alpha2,3-sialyltransferase WbwA from pathogenic Escherichia coli serotype O104. (2015) J Bacteriol 197: 3760-3768
- Fiona F. Hager, Arturo LópezGuzmán, Simon Krauter, Markus Blaukopf, Mathias Polter, Inka Brockhausen, Paul Kosma, Christina Schäffer. Functional characterization of enzymatic steps involved in pyruvylation of bacterial secondary cell wall polymer fragments. (2018) Front Microbiol. 9:1356, 1-16
- S Sharma, Y Ding, KF. Jarrell, I Brockhausen. Identification and characterization of a 4-epimerase AglW from the archaeon Methanococcus maripaludis. Glycoconj J (2018) 35(6):525-535