Carolyn R. Bertozzi
Carolyn R. BertozziHoward Hughes Investigator and Professor of Chemistry and of Biochemistry and Molecular BiologyE-mail: bertozzi@cchem.berkeley.edu |
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Full Directory InformationResearch Interests
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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 comprises three major project areas: (1) development of chemical approaches for perturbing and studying glycan function within the context of living cells; (2) investigating the roles of microbial glycoconjugates in pathogenesis, with an emphasis on Mycobacterium tuberculosis; and (3) development of tools for proteomics analysis of protein glycosylation.
Current Projects
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Chemical approaches to glycobiology: 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 presentation of specific carbohydrate epitopes is a reflection of the biosynthetic machinery within the secretory compartments of the cell. Organized among the membranes of the endoplasmic reticulum (ER) and Golgi cisternae, the glycosyltrasnferases act in an assembly line to generate functional oligosaccharide structures. The organization of these enzymes within subcellular compartments can be a key determinant of cell surface glycosylation patterns and, accordingly, cell-cell interactions. We have developed a strategy for modulating the activities of glycosyltransferases with small molecules that affect their Golgi localization. We separate their catalytic and localization domains and fuse these to engineered protein modules that will associate in the presence of a synthetic molecule. Thus, the enzymes are conditionally localized in the Golgi compartment by the small molecule drug, and inactive in its absence. We are applying this technique to study the biological functions of glycosyltransferases in cells and in model organisms.
Another chemical strategy we employ to study glycosylation involves metabolic engineering of unnatural sugar structures. When fed to cells or introduced into laboratory animals, unnatural metabolic precursor sugars can be incorporated into cell surface glycans, thereby altering their biological activities. For example, recognition of sugars by the immune system can be altered by metabolic introduction of unnatural modifications into their structures. We are applying this phenomenon to thedevelopment of a tumor vaccine strategy that targets unusual glycans found only on tumor cells. In addition, we can deliver novel chemical functional groups into glycans by metabolism and target these with exogenous probes by covalent reaction. Applications to tumor targeting with non-invasive imaging reagents are under investigation.
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.
Proteomics analysis of protein glycosylation: Glycosylation is the most common and complex form of posttranslational modification in eukaryotes. For most glycoproteins, the structures of the glycans and their specific sites of attachment are not known. We are applying the technique of metabolic glycan engineering to the systems-level analysis of protein glycosylation, with a focus on O-linked glycosylation of membrane proteins and GlcNAcylation of nuclear and cytosolic proteins.
Selected Publications
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Discovery of Sulfated Metabolites in Mycobacteria With a Genetic and Mass Spectrometric Approach. [J. D. Mougous, M. D. Leavell, R. H. Senaratne, C. D. Leigh, S. J. Williams, L. Riley, J. A. Leary, C. R. Bertozzi (2002) Proc. Natl. Acad. Sci. U.S.A 99, 17037-17042]
A Small-Molecule Modulator of Poly-a2,8-Sialic Acid Expression on Cultured Neurons and Tumor Cells. [L. K. Mahal, N. W. Charter, K. Angata, M. Fukuda, D. E. Koshland Jr., and C. R. Bertozzi (2001) Science 294, 380-382]
Chemical Glycobiology. [C. R. Bertozzi and L. L. Kiessling (2001) Science, 291, 2357-2364]
Cell Surface Engineering by a Modified Staudinger Reaction. [E. Saxon and C. R. Bertozzi (2000) Science 287, 2007-2010]
Engineering Chemical Reactivity on Cell Surfaces Through Oligosaccharide Biosynthesis. [L. K. Mahal, K. J. Yarema, and C. R. Bertozzi (1997) Science 276, 1125-1128]
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