Carolyn R. Bertozzi
Howard Hughes Medical Institute Investigator and Professor of Biochemistry, Biophysics and Structural Biology*
A major lesson from eukaryotic genome sequencing projects is that the absolute number of genes an organism's genome encodes is not the best parameter for defining biological complexity. Instead, the complex functions associated with human health and disease are determined by combinatorial expansion of genomic information in the form of posttranslational modifications. Of these, the most ubiquitous is glycosylation, highlighting the importance of glycobiology in the postgenomic era. Our research group is pursuing three major areas: (1) development of chemical tools for glycomics research; (2) investigating the roles of microbial metabolites in pathogenesis, with an emphasis on Mycobacterium tuberculosis; and (3) development of novel imaging tools using nanotechnology.
Chemical tools for glycomics research. Cell surface oligosaccharides are major determinants of cell-cell interactions during development, the immune response, and pathogenic processes such as microbial infection and tumor cell metastasis. The goal of this program is to develop chemical tools for profiling glycans in cells and living organisms and for elucidating their functions with respect to human disease. One such tool is a chemical reporter system for visualizing glycans within cell-based systems. We developed two chemical reactions that employ the azide as a bioorthogonal chemical handle. The azide can be delivered to specific glycan types via metabolism of synthetic azido sugars. Once incorporated into cellular glycans, the azido sugars can be selectively reacted with probes for detection, enrichment or visualization. We are applying this technology to proteomic analysis of protein glycosylation, the identification of glycan tumor biomarkers, and to non-invasive imaging of glycosylation changes in animal disease models.
Mycobacterial metabolites involved in pathogenesis: Mycobacterium tuberculosis is the causative agent of TB and is responsible for around 3 million deaths per year. Current treatment protocols are lengthy and complicated, and multidrug resistant strains have arisen in recent years that remain impossible to treat. Mycobacteria have many unusual features, including a complex cell wall structure comprising sulfated trehalose metabolites that are thought to mediate host-pathogen interactions. We are interested in the biological activities of these metabolites and their biosynthetic origin inside the bacterial cell, with an eye for identifying new avenues for drug development. Toward this end, we are knocking the genes, identified using bioinformatics techniques, that encode key biosynthetic enzymes, analyzing their phenotypes in mouse models of TB, and screening compound libraries for inhibitor leads. We are also pursuing X-ray crystal structures of the most promising enzyme targets.
Nanoscience tools for biological imaging. Carbon nanotubes (CNTs) have remarkable electrical, magnetic, optical and mechanical properties that are potentially useful in biological sensing and imaging applications. However, CNTs are not compatible with living cells due to their lack of water-solubility and intrinsic toxicity. We are developing synthetic coatings and chemical modification strategies that cloak CNTs in a layer of biomimetic materials. The coated CNTs are rendered non-toxic and are suitable for integration into cell-based biosensors and imaging platforms.
Kumar, P.; Schelle, M. W.; Jain, M.; Lin, F. L.; Petzold, C. J.; Leavell, M. D.; Leary, J. A.; Cox, J. S.; Bertozzi, C. R. PapA1 and PapA2 are Acyltransferases Essential for the Biosynthesis of the Mycobacterium tuberculosis Virulence Factor Sulfolipid-1. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 11221-11226
Chang, P. V.; Prescher, J. A.; Hangauer, M. J.; Bertozzi, C. R. Imaging Cell Surface Glycans with Bioorthogonal Chemical Reporters. J. Am. Chem. Soc. 2007, 129, 8400-8401.
Chen, X.; Kis, A.; Zettl, Z.; Bertozzi, C. R. A Cell Nanoinjector Based on Carbon Nanotubes. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 8218-8222.
Dube, D. H.; Prescher, J. A.; Quang, C. N.; Bertozzi, C. R. Probing Mucin-type O-linked Glycosylation in Living Animals. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 4819-24.
Prescher, J. A.; Bertozzi, C. R. Chemical Technologies for Probing Glycans. Cell 2006, 126, 851-854.
Mougous, J. D.; Senaratne, R. H.; Petzold, C. J.; Jain, M.; Lee, D. H.; Schelle, M. W.; Leavell, M. D.; Cox, J. S.; Leary, J. A.; Riley, L. W.; Bertozzi, C. R. A Novel Sulfated Metabolite Produced by stf3 Negatively Regulates the Virulence of Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 4258-63.
Mougous, J. D.; Lee, D. H.; Hubbard, S. C.; Schelle, M. W.; Vocadlo, D. J.; Berger, J. M.; Bertozzi, C. R. Molecular Basis for G protein Control of ATP Sulfurylase in Bacteria. Molecular Cell 2006, 21, 109-122.
Prescher JA, Dube DH, Bertozzi CR. Chemical remodelling of cell surfaces in living animals. Nature. 2004, 430, 873-7.
Vocadlo, D. J.; Bertozzi, C. R. A Strategy for Functional Proteomic Analysis of Glycosidase Activity from Cell Lysates. Angew. Chem. Int. Ed. 2004, 43, 5338-5342.
de Graffenried, C. L.; Laughlin, S. T.; Kohler, J. J.; Bertozzi, C. R. A Small-Molecule Switch for Golgi Sulfotransferases. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 16715-16720.
Last Updated 2007-07-31