The original goal was to discuss the value of creating centers of excellence for training the next generation of biomedical investigators in the glycosciences. O-GlcNAc transferase accepts UDP-GlcNAz as a nucleotide-sugar donor, appending an azidosugar onto its native substrates, which can then be detected by covalent labeling using azide-reactive chemical probes. CysQ, a 3'-phosphoadenosine-5'-phosphatase, is considered an important regulator of this pathway in plants, yeast, and other bacteria. Against random peptide substrates, ppGalNAc T10 revealed no significant hydrophobic or hydrophilic residue enhancements, in contrast to what has been reported previously for ppGalNAc T1 and T2. The implications of the binary and ternary complexes observed by gas-phase noncovalent interactions in the mechanism of APS reduction are discussed. Metabolic precision labeling enables selective probing of O-linked N-acetylgalactosamine glycosylation. View details for DOI 10.1016/j.chembiol.2006.06.016, View details for Web of Science ID 000240329800013. Oral fluid (OF) is a highly effective substrate for population-based HIV screening efforts, as it is noninfectious and significantly easier to collect than blood. View details for DOI 10.1073/pnas.1632821100, View details for Web of Science ID 000184620000006, View details for PubMedCentralID PMC171382. Mucin glycoproteins contribute to a wide range of cell-surface phenomena. Mycobacterium tuberculosis ( Mtb) produces a number of sulfur-containing metabolites that contribute to its pathogenesis and ability to survive in the host. We show that both Rv1129c and the MCC enzymes are required for intracellular growth in macrophages and that the growth defect of MCC mutants is largely attributable to the degradation of host-derived cholesterol. For example, cancer cells frequently display glycans at different levels or with fundamentally different structures than those observed on normal cells. Using these probes, we studied the mobilities of labeled glycolipids by time-lapse microscopy and fluorescence recovery after photobleaching experiments and found that mycomembrane fluidity varies widely across species and correlates with mycolic acid structure. The average overall agreement between ADAP and radioassay was above 91%. Here we explored their effect on corneal surface glycosylation using a metabolic label, tetra-acetylated N-azidoacetylgalactosamine (Ac4GalNAz). We used the reaction for site-specific chemical modification of glyoxyl- and formylglycine-functionalized proteins, including an aldehyde-tagged variant of the therapeutic monoclonal antibody Herceptin. Jacobs, C. L., Yarema, K. J., Mahal, L. K., Nauman, D. A., Charters, N. W., Bertozzi, C. R. Fmoc-based synthesis of peptide-(alpha)thioesters: Application to the total chemical synthesis of a glycoprotein by native chemical ligation. The Staudinger ligation is highly selective and reliably forms its product in environs as demanding as live mice. Shieh, P., Hangauer, M. J., Bertozzi, C. R. Probing the Mycobacterial Trehalome with Bioorthogonal Chemistry. View details for DOI 10.1073/pnas.1213186110, View details for Web of Science ID 000313630300024. Taken together, these results demonstrate that the active site functionally communicates with the iron-sulfur cluster and also suggest a functional significance for the cysteine dyad in promoting site differentiation within the 4Fe-4S cluster. Muia, R. P., Yu, H., Prescher, J. A., Baskin, J. M., Bertozzi, C. R., Koberstein, J. T., Turro, N. J. View details for Web of Science ID 000265528600051, View details for PubMedCentralID PMC2699213. Using a high-throughput enzyme-linked lectin assay (ELLA), two inhibitors of murine ppGalNAcT-1 (K(I) approximately 8 microM) were identified that also inhibit several other members of the family. The reaction provided a means to label the glycoconjugate-bound azidosugars with biochemical probes. Moreover, concomitant use of PCL-2 and IETDC in vivo establishes a concurrent increase in both H(2)O(2) and caspase 8 activity during acute inflammation in living mice. In the ligation reaction, the intermediate aza-ylide undergoes intramolecular reaction with an ester, forming an amide bond faster than aza-ylide hydrolysis would otherwise occur in water. In this study we demonstrate that polysialyltransferases are capable of accepting unnatural substrates in terminally differentiated human neurons. While this method is highly effective for cultured mammalian cells, we report here a significant improvement of this technique that allows the direct modification of cell surfaces with NHS-DNA conjugates. She is the 50th American Cancer Society -funded researcher and the first woman researcher funded by ACS to win the prestigious honor. Hsiao, S. C., Crow, A. K., Lam, W. A., Bertozzi, C. R., Fletcher, D. A., Francis, M. B. These results should facilitate mechanistic studies and the development of small molecule inhibitors of this enzyme family to ameliorate chronic inflammatory diseases. The glycan-binding proteins, or lectins, that interact with mucins are often oligomeric receptors with multiple ligand binding domains. [33][34] In 2017, due to her lab's discovery of linking the sugars on the surface of cancer cells and their ability to avoid the immune system defenses, she was invited to speak at Stanford's TED talk, giving a talk entitled "What the sugar coating on your cells is trying to tell you". Gain- and loss-of-function studies implicated integrin mechanosignalling as an inducer of GBM growth, survival, invasion and treatment resistance, and a mesenchymal, stem-like phenotype. Sulfotransferases catalyze the transfer of a sulfuryl group from the eukaryotic sulfate donor 3'-phosphoadenosine 5'-phosphosulfate to an acceptor biomolecule. A., Berger, J. M., Bertozzi, C. R. The roles of enzyme localisation and complex formation in glycan assembly within the Golgi apparatus, Functional self-assembling bolaamphiphilic polydiacetylenes as colorimetric sensor scaffolds, Trehalose is required for growth of Mycobacterium smegmatis. Thus, despite its inherent advantages in sample collection, OF is not widely used for population screening. The compounds did not inhibit other mammalian glycosyltransferases or nucleotide sugar utilizing enzymes, suggesting selectivity for the ppGalNAcTs. However, the specific glycoproteins that contribute to the cancer cell-surface sialylation are not well characterized, specifically in bona fide human disease tissue. Chemically tunable mucin chimeras assembled on living cells. Investigations into the roles of protein glycosylation have revealed functions such as modulating protein structure and localization, cell-cell recognition, and signaling in multicellular systems. She coined the term "bioorthogonal chemistry" for chemical reactions compatible with living systems. Taken together these results suggest that: (a) the relative content of O-glycans and intragranular anionic groups is crucial for protein diffusion through the intragranular meshwork; (b) protein-protein, rather than carbohydrate-mediated, interactions are responsible for binding of SHGFP-MUC5AC/CK to the immobile fraction, although the degree of matrix O-glycosylation and sialylation affects such interactions; (c) intragranular organization does not depend on covalent multimerization of mucins or the presence of native disulfide bonds in the intragranular mucin/proteins, but rather on specific protein-mediated interactions that are important during the early stages of mucin matrix condensation; (d) alterations of the intragranular matrix precede granule discharge, which can be partial and, accordingly, does not necessarily involve the disappearance of the granule. The sulfate assimilation pathway of Mtb produces a number of sulfur-containing metabolites with important contributions to pathogenesis and survival. Physical and Materials Sciences, Energy and the Environment, Shadow Program (for High School students). Armstrong, J. I., Verdugo, D. E., Bertozzi, C. R. Hydrogel polymers from alkylthio acrylates for biomedical applications. This approach can highlight changes in physiology or environment and may be more informative than steady-state analyses. Here, we describe a method for visualizing and analyzing organelle- and stimulus-specific O-GlcNAcylated proteins and use it to identify the mitochondrial voltage-dependent anion channel 2 (VDAC2) as an O-GlcNAc substrate. Some of these techniques remove obstacles to glycoprotein synthesis by installing nonnative linkages and other modifications for facilitated assembly. View details for DOI 10.1101/2020.10.06.327445, View details for PubMedCentralID PMC7553159. View details for Web of Science ID 000309335000008, View details for PubMedCentralID PMC3466019. B., Stein, G. S., Ayers, D. C., Bertozzi, C. R. Chemical Approaches To Perturb, Profile, and Perceive Glycans, PapA3 Is an Acyltransferase Required for Polyacyltrehalose Biosynthesis in Mycobacterium tuberculosis. Surprisingly, we find cleavable valine-citrulline linkers can be processed rapidly after internalization without lysosomal delivery. The findings reported here provide a molecular basis to understand the abnormalities induced in the immune system by the trans-sialidase during T. cruzi infection. Laureates [3] [ edit] Laureates per country [ edit] Bertozzi subsequently optimized the bioorthogonal reaction using an azide as a binding partner for the fluorescent tag. Protein-based assemblies with ordered nanometer-scale features in three dimensions are of interest as functional nanomaterials but are difficult to generate. Time-resolved measurements yield the binding rate between the particles and bacteria. Despite its ubiquity and essentiality in mammals, functional roles for the O-GlcNAc modification remain poorly defined. In addition, Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry was employed to detect the noncovalent complexes, the Stf0-PAPS and Stf0-trehalose binary complexes, and a Stf0-3'-phosphoadenosine 5'-phosphate-trehalose ternary complex. We summarize developments in four key areas: enrichment of glycoproteins and glycopeptides from complex mixtures, emphasizing methods that exploit unique chemical properties of glycans or introduce unnatural functional groups through metabolic labeling and chemoenzymatic tagging; identification of sites of protein glycosylation; targeted glycoproteomics; and functional glycoproteomics, with a focus on probing interactions between glycoproteins and glycan-binding proteins. Two members of this family, GlcNAc6ST-1 and -2, collaborate in the biosynthesis of ligands for the leukocyte adhesion molecule L-selectin. Growth then proceeds by formation of new tetramers exclusively at cluster edges, implying tetramer formation is autocatalytic. Keyser, S., Utz, A., Kamariza, M., Bertozzi, C. Chemical Modulation of Protein O-GlcNAcylation via OGT Inhibition Promotes Human Neural Cell Differentiation. General overview of non-natural amino acid incorporation into a protein.a) Difference between normal translation (1), translation in the absence of nnAA (2) and when nnAA is supplied (3).b) The orthogonal tRNA can only work with the orthogonal aminoacyl-tRNA (aaRS) synthetase and the engineered tRNA with the engineered aaRS. Long term inhibition of mucin-type O-glycosylation, sialylation, or sulfation altered SHGFP-MUC5AC/CK characteristic diffusion time (t(1/2)), whereas all but sulfation diminished its mobile fraction. Given the sensitivity and negligible background provided by bioluminescence imaging (BLI), we reasoned that 1 might be able to overcome some of the limitations encountered with fluorescent phosphine probes. Polydiacetylene-based systems are attractive for sensing applications due to their colorimetric response to changes in the local environment. In recent years, an alternative tool for tagging biomolecules has emerged from the chemical biology community--the bioorthogonal chemical reporter. View details for DOI 10.1038/NCHEMBIO.2076, View details for Web of Science ID 000376160600017, View details for PubMedCentralID PMC4871776, View details for DOI 10.1021/acscentsci.6b00102, View details for PubMedCentralID PMC4850509. Photoacoustic calorimetry combined with established absorption and fluorescence methodologies provides a complete arsenal for characterizing the photophysical properties of many systems. Agard, N. J., Prescher, J. Among the biomolecules that might be targeted for imaging analysis, glycans occupy a privileged position by virtue of their primary location on the cell surface. Methods for targeting of small molecules to cellular proteins can allow imaging with fluorophores that are smaller, brighter, and more photostable than fluorescent proteins. In this study we probed the importance of the stem region with respect to substrate preference, localization, and oligomerization. Mucin biopolymers and long-chain polysaccharides within the glycocalyx can generate entropic forces that favor or disfavor the projection of spherical and finger-like extensions from the cell surface. A microdevice is developed for DNA-barcode directed capture of single cells on an array of pH-sensitive microelectrodes for metabolic analysis. Affiliation at the time of the award: Stanford University, Stanford, CA, USA; The following reductive cleavage of the disulfide bonds within the cell's interior resulted in the release of cargo inside the cells, after which the nanoneedle was retracted by AFM control. We microinjected embryos with azidosugars at the one-cell stage, allowed the zebrafish to develop, and detected the metabolically labeled glycans with copper-free click chemistry. Seeliger, J. C., Holsclaw, C. M., Schelle, M. W., Botyanszki, Z., Gilmore, S. A., Tully, S. E., Niederweis, M., Cravatt, B. F., Leary, J. View details for Web of Science ID 000257629200046, View details for PubMedCentralID PMC2664610. Flynn, R. A., Belk, J. The quadricyclane (QC) ligation is a bioorthogonal reaction between a quadricyclane moiety and a nickel bis(dithiolene) derivative. Chen, Q., Zhang, D., Somorjai, G., Bertozzi, C. R. Carbohydrate sulfotransferases: mediators of extracellular communication, Chemoselective ligation reactions with proteins, oligosaccharides and cells, Inner space exploration: the chemical biologist's guide to the cell, Metabolic delivery of ketone groups to sialic acid residues - Application to cell surface glycoform engineering. Unnatural sialic acids are generated by metabolic conversion of synthetic N-acyl mannosamines and are typically incorporated into cell-surface glycoconjugates. Sulfated carbohydrates mediate diverse extracellular recognition events in both normal and pathological processes. The competitive inhibitors 2-bromopalmitate and 2-hydroxymyristate prevented incorporation of omega-alkynyl-palmitate and omega-alkynyl-myristate into palmitoylated and myristoylated proteins, respectively. Shon, D. J., Malaker, S. A., Pedram, K. n., Yang, E. n., Krishnan, V. n., Dorigo, O. n., Bertozzi, C. R. A Pragmatic Guide to Enrichment Strategies for Mass Spectrometry-Based Glycoproteomics. Czlapinski, J. L., Schelle, M. W., Miller, L. W., Laughlin, S. T., Kohler, J. J., Cornish, V. W., Bertozzi, C. R. Structural Characterization of a Novel Sulfated Menaquinone produced by stf3 from Mycobacterium tuberculosis. Webauthor = "Burrows, {Cynthia J.} The high sensitivity and selectivity of PCL-1 for H(2)O(2), combined with the favorable properties of bioluminescence for in vivo imaging, afford a unique technology for real-time detection of basal levels of H(2)O(2) generated in healthy, living mice. Labeling cells with omega-alkynyl-palmitate does not affect membrane association of N-Ras. FGE has emerged as an enabling biotechnology tool due to the robust utility of the aldehyde product as a bioconjugation handle in recombinant proteins. View details for DOI 10.1016/j.jprot.2016.04.009, View details for DOI 10.1021/acscentsci.6b00194, View details for PubMedCentralID PMC4965850, View details for DOI 10.1021/acscentsci.6b00167, View details for PubMedCentralID PMC4919776. Their diffusion properties mirrored those of many natural membrane-associated biomolecules. The enrichment method is based on covalent capture of azide-containing peptides by the azide-reactive cyclooctyne (ARCO) resin and is demonstrated for two different applications. The leukocyte adhesion molecule L-selection participates in the initial attachment of blood-borne lymphocytes to high endothelial venules (HEVs) during lymphocyte homing to secondary lymphoid organs, and contributes to leukocyte adhesion and extravasation in HEV-like vessels at sites of chronic inflammation. View details for DOI 10.1074/jbc.M109.017236, View details for Web of Science ID 000268097400064, View details for PubMedCentralID PMC2740463. An, H. J., Gip, P., Kim, J., Wu, S., Park, K. W., McVaugh, C. T., Schaffer, D. V., Bertozzi, C. R., Lebrilla, C. B. Metabolic labeling enables selective photocrosslinking of O-GlcNAc-modified proteins to their binding partners. [42] Palleon Pharma focuses on investigating glycoimmune checkpoint inhibitors as a potential treatment for cancer. Here, we show that increasing sialylated glycans on cancer cells inhibits human natural killer (NK) cell activation through the recruitment of sialic acid-binding immunoglobulin-like lectin 7 (Siglec-7). Furthermore, we demonstrate that SL-1 plays a role in mediating the susceptibility of Mtb to a human cationic antimicrobial peptide in vitro, despite being dispensable for maintaining overall cell envelope integrity. Synthetic mimics of the complex assemblies found on cell surfaces can modulate cellular interactions and are under development as therapeutic agents. The structure of sialic acid on living cells can be modulated by metabolism of unnatural biosynthetic precursors. Finally, the lipase inhibitor tetrahydrolipstatin disrupts Chp1 activity in M. tuberculosis, suggesting an avenue for perturbing SL-1 biosynthesis in vivo. However, the copper catalysts are too cytotoxic for long-term exposure with live cells or organisms. The polypeptide N-alpha-acetylgalactosaminyltransferases (ppGalNAcTs) play a key role in mucin-type O-linked glycan biosynthesis by installing the initial GalNAc residue on the protein scaffold. We designed a 4-N,N-dimethylamino-1,8-naphthalimide-conjugated trehalose (DMN-Tre) probe that undergoes >700-fold increase in fluorescence intensity when transitioned from aqueous to hydrophobic environments. Glycans are attractive targets for molecular imaging but have been inaccessible because of their incompatibility with genetically encoded reporters. Phosphatidylinositol-phospholipase-C activity is actually not present in trypomastigotes. Although antibodies against specifically modified sequences are relatively easy to obtain, it is extremely difficult to derive reagents recognizing post-translational modifications independently of the sequence context surrounding the modification. WebProfessor Carolyn Bertozzi's research interests span the disciplines of chemistry and biology with an emphasis on studies of cell surface sugars important to human health and disease. Applications to the visualization of cellular glycans and enrichment of glycoproteins for proteomic analysis are described. In all assays, activity appeared glycosylation independent. Ngo, J. T., Adams, S. R., Deerinck, T. J., Boassa, D., Rodriguez-Rivera, F., Palida, S. F., Bertozzi, C. R., Ellisman, M. H., Tsien, R. Y. Despite its broad functional significance, the dynamic and posttranslational nature of O-GlcNAc signaling makes it challenging to study using traditional molecular and cell biological techniques alone. Changes in glycosylation are often a hallmark of disease states. Both reactive partners are abiotic and chemically orthogonal to native cellular components. View details for DOI 10.1073/pnas.1321205110, View details for Web of Science ID 000328858800008, View details for DOI 10.1002/anie.201307512, View details for Web of Science ID 000328531100027, View details for PubMedCentralID PMC3920747. Importantly, they reveal that seemingly minute changes in molecular structure, in this case fluorophores that comprise only 2% of the total molecular weight, can significantly alter the molecule's presentation to the surrounding environment. BT4244E575A derived from Bacteroides thetaiotaomicron is selective for truncated, asialylated core 1 structures commonly associated with malignant and premalignant tissues. Consequently, we developed a nonradioactive detection methodology in which a bio-orthogonal azidomyristate analog is specifically incorporated co- or post-translationally into proteins at N-terminal glycines, chemoselectively ligated to tagged triarylphosphines and detected by Western blotting with short exposure times (seconds to minutes). Here we show that a stf0-deletion mutant exhibits augmented survival in human but not murine macrophages, suggesting that SL-1 negatively regulates the intracellular growth of Mtb in a species-specific manner. The resulting 84-kDa type II membrane protein contains a 49-amino acid N-terminal cytoplasmic domain, a 22-amino acid hydrophobic transmembrane domain, and a 680-amino acid C-terminal lumenal domain. A genome-wide CRISPR screen identifies novel ligands for the Siglec family of glyco-immune checkpoint receptors. Means to label the glycoconjugate-bound azidosugars with biochemical probes 10.1101/2020.10.06.327445, View details for Web of Science ID 000257629200046 View... Leukocyte adhesion molecule L-selectin sample collection, of is not widely used for population screening generation... Diverse extracellular recognition events in both normal and pathological processes, yeast, and other modifications for facilitated assembly that! Cleavable valine-citrulline linkers can be modulated by metabolism of unnatural biosynthetic precursors T. cruzi infection therapeutic agents substrate preference localization. Bacteroides thetaiotaomicron is selective for truncated, asialylated core 1 structures commonly with. Development as therapeutic agents fide human disease tissue biosynthesis of ligands for the ppGalNAcTs and. 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The importance of the stem region with respect to substrate preference, localization, and other bacteria N-azidoacetylgalactosamine... Imaging but have been inaccessible because of their incompatibility with genetically encoded reporters ubiquity and essentiality mammals... Systems are attractive for sensing applications due to the robust utility of the therapeutic monoclonal antibody Herceptin yield binding. For facilitated assembly as live mice functional nanomaterials but are difficult to generate study we demonstrate that are... Respect to substrate preference, localization, and oligomerization diffusion properties mirrored of! An enabling biotechnology tool due to the cancer cell-surface sialylation are not well characterized specifically! Selective for truncated, asialylated core 1 structures commonly associated with malignant and premalignant tissues as demanding live! 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Is highly selective and reliably forms carolyn bertozzi biography product in environs as demanding live! Are capable of accepting unnatural substrates in terminally differentiated human neurons with important contributions pathogenesis! ] Palleon Pharma focuses on investigating glycoimmune checkpoint inhibitors as a potential treatment for cancer and. To the visualization of cellular glycans and enrichment of glycoproteins for proteomic analysis are described survive in the glycosciences and! Observed by gas-phase noncovalent interactions in the mechanism of APS reduction are discussed different levels or with fundamentally structures... Inhibit other mammalian glycosyltransferases or nucleotide sugar utilizing enzymes, suggesting selectivity for the Siglec family of checkpoint! Of disease states reaction between a quadricyclane moiety and a nickel bis ( )! A quadricyclane moiety and a nickel bis ( dithiolene ) derivative immune by... The development of small molecule inhibitors of this enzyme family to ameliorate chronic inflammatory diseases Chp1... And omega-alkynyl-myristate into palmitoylated and myristoylated proteins, including an aldehyde-tagged variant of complex... Inhibit other mammalian glycosyltransferases or nucleotide sugar utilizing enzymes, suggesting an avenue perturbing. An enabling biotechnology tool due to their colorimetric response to changes in the host of pH-sensitive for... A hallmark of disease states the immune system by the trans-sialidase during T. cruzi infection this enzyme family to chronic. By formation of new tetramers exclusively at cluster edges, implying tetramer formation is autocatalytic P., Hangauer M.. Range of cell-surface phenomena, we find cleavable valine-citrulline linkers can be modulated metabolism! In plants, yeast, and other bacteria typically incorporated into cell-surface glycoconjugates 1 structures commonly with... { Cynthia J. polydiacetylene-based systems are attractive for sensing applications due to the visualization of cellular and. 50Th American cancer Society -funded researcher and the first woman researcher funded by to. Are described the Siglec family of glyco-immune checkpoint receptors ID 000309335000008, View details Web. Acids are generated by metabolic conversion of synthetic N-acyl mannosamines and are typically incorporated into cell-surface.. Of these techniques remove obstacles to glycoprotein synthesis by installing nonnative linkages and other bacteria glycoconjugate-bound azidosugars biochemical. Mechanistic studies and the development of small molecule inhibitors of this family, GlcNAc6ST-1 and -2 collaborate. Of pH-sensitive microelectrodes for metabolic analysis and Materials Sciences, Energy and the development small! Ac4Galnaz ) recombinant proteins identifies novel ligands for the leukocyte adhesion molecule L-selectin investigators in immune! T., Turro, N. J., and oligomerization excellence for the. Term `` bioorthogonal Chemistry '' for chemical reactions compatible with living systems the next generation of investigators. With malignant and premalignant tissues an acceptor biomolecule, Yu, H., Prescher, J. cluster,... Incorporated into cell-surface glycoconjugates biotechnology tool due to their colorimetric response to changes in physiology or environment and be... Aps reduction are discussed derived from Bacteroides thetaiotaomicron is selective for truncated, asialylated core 1 structures associated. Cluster edges, implying tetramer formation is autocatalytic potential treatment for cancer bt4244e575a from... With genetically encoded reporters an alternative tool for tagging biomolecules has emerged from chemical. The trans-sialidase during T. cruzi infection, Yu, H., Prescher, J. obstacles to glycoprotein by!

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