Although the early steps in SL-1 biosynthesis are known, the machinery underlying the final acylation reactions is not understood. Phagocytosis is initiated by lateral clustering of receptors, which in turn activates Src-family kinases (SFKs). By incorporating sulfate esters on the analogous positions of the disaccharide lactose, we generated a simple small molecule (lactose 6',6-disulfate) with greater inhibitory potency for L-selectin than sialyl Lewis x. Screening of the library identified an inhibitor with a K(i) value of 11 microM. Genetic complementation experiments showed that each of the three pathways was able to recover the mutant in the absence of trehalose, even at elevated temperatures. 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. Metabolic incorporation of d-alanine derivatives and click chemistry detection constitute a facile, modular platform that facilitates unprecedented spatial and temporal resolution of PG dynamics in vivo. Bhat, R., Belardi, B., Mori, H., Kuo, P., Tam, A., Hines, W. C., Le, Q., Bertozzi, C. R., Bissell, M. J. She coined the term "bioorthogonal chemistry"[2] for chemical reactions compatible with living systems. Antibody reactivity was lost by antigen treatment with sulfatase or preincubation with soluble tyrosine sulfate, indicating its specificity. View details for Web of Science ID 000430563200441. Sialic Acid Glycobiology Unveils Trypanosoma cruzi Trypomastigote Membrane Physiology. These data show that the normal distribution of surface glycosylation requires IL-1R, but not MyD88, and is not sufficient to prevent bacterial binding. Fine-tuning of glycan biosynthetic pathways is further accomplished by specific associations among glycosyltransferases. A., Bertozzi, C. R. Incorporation of azides into recombinant proteins for chemoselective modification by the Staudinger ligation. All mucin-associated [(35)S]sulfate was incorporated as GlcNAc-6-sulfate or Galbeta1-->4GlcNAc-6-sulfate. To tackle this issue, we followed an unnatural sugar approach as bioorthogonal chemical reporters, where the use of azidosialyl residues allowed identifying the acquired sugar. A., Gray, M. A., Bertozzi, C. R., Rabuka, D., Bassik, M. C. Quantitative super-resolution microscopy of the mammalian glycocalyx. Methods for targeting of small molecules to cellular proteins can allow imaging with fluorophores that are smaller, brighter, and more photostable than fluorescent proteins. Strikingly, we found that cholesterylamine (CholA) anchored glycopolymers are internalized into vesicles that serve as depots for delivery back to the cell surface, allowing for the display of cell-surface glycopolymers for at least ten days, even while the cells are dividing. A., Bertozzi, C. R. Isotype-specific agglutination-PCR (ISAP): Asensitive and multiplex method for measuring allergen-specific IgE. In particular, we focused on biarylazacyclooctynone (BARAC) because it reacts with azides faster than any other reported cyclooctyne and its modular synthesis facilitated rapid access to analogues. Such metabolic interference can block the expression of oligosaccharides or alter the structures of the sugars presented on cells. Woo, C. M., Iavarone, A. T., Spiciarich, D. R., Palaniappan, K. K., Bertozzi, C. R. The cancer glycocalyx mechanically primes integrin-mediated growth and survival. View details for DOI 10.1074/jbc.M111.315473, View details for Web of Science ID 000301349400015. Hotsclaw, C. M., Sogi, K. M., Gilmore, S. A., Scheller, M. W., Leavell, M. D., Bertozzi, C. R., Leary, J. The simplicity and generality of this method make it well suited for use in the study of carbohydrate-mediated cell surface interactions. Thus, cell assembly can be highly controlled, enabling the design of microtissues with defined cell composition and stoichiometry. Previously, we reported a method for the attachment of living cells to surfaces through the hybridization of synthetic DNA strands attached to their plasma membrane. The biological study of O-linked glycosylation is particularly problematic, as chemical tools to control this modification are lacking. B., Carlevaro, G., Araoz, B., Ruiz Diaz, P., Camara, M. d., Buscaglia, C. A., Bossi, M., Yu, H., Chen, X., Bertozzi, C. R., Mucci, J., Campetella, O. Ultrasensitive Antibody Detection by Agglutination-PCR (ADAP). We demonstrated the noninvasive imaging of glycans in live developing zebrafish, using a chemical reporter strategy. Upon exposure to mycobacterial cell wall lipids, 166 macrophage proteins showed differential expression. There is growing interest in extending this progress to O-glycoproteomics, which necessitates comparisons of method performance for the two classes of glycopeptides. We report the discovery that boron nitride nanotubes (BNNTs), isosteres of CNTs with unique physical properties, are inherently noncytotoxic. To verify the quantitation and localization of glycans on the human embryonic stem cell membranes, flow cytometry and immunocytochemistry were performed. [7] In 2010, she was the first woman to receive the prestigious Lemelson-MIT Prize faculty award. A., Engleman, E. G., Bertozzi, C. R. A bulky glycocalyx fosters metastasis formation by promoting G1 cell cycle progression. Mechanistic and theoretical studies inspired the design of a series of cyclooctyne compounds bearing fluorine substituents, fused rings, and judiciously situated heteroatoms, with the goals of optimizing azide cycloaddition kinetics, stability, solubility, and pharmacokinetic properties. This observation stood in stark contrast to the slow kinetics associated with 1,3-dipolar cycloaddition of azides with unstrained, linear alkynes, the conventional Huisgen process. Bertozzi, C. R., SINGER, M. S., ROSEN, S. D. L-selectin-carbohydrate interactions: Relevant modifications of the Lewis x trisaccharide. Regrettably, conventional biochemical and genetic methods often fall short for the study of glycans, because their structures are often not precisely defined at the genetic level. Islet autoantibodies are predominantly measured by radioassay to facilitate risk assessment and diagnosis of type 1 diabetes. We structurally assigned 32 N-glycopeptides and over 500 intact and fully elaborated O-glycopeptides from 250 proteins across three human cancer cell lines and also discovered unexpected peptide sequence polymorphisms (pSPs). Methods for directing the cell surface expression of novel protein-based and oligosaccharide-based epitopes are stimulating new directions in biotechnology and biomedical research. Carolyn Bertozzi. The prokaryotic homolog exhibits remarkable structural similarity to human FGE, including the position of catalytic cysteine residues. Vertebrate glycans constitute a large, important, and dynamic set of post-translational modifications that are notoriously difficult to manipulate and image. Here, we report the synthesis and evaluation of a novel azacyclooctyne, 6,7-dimethoxyazacyclooct-4-yne (DIMAC). View details for Web of Science ID 000167417700020. Here we studied the function of novel germline variants in CSF3R at amino acid N610. Her father, William Bertozzi, was a physics professor at MIT. This heterogeneity precludes enrichment strategies that can be universally beneficial for all glycan classes. Breidenbach, M. A., Palaniappan, K. K., Pitcher, A. Protein-based assemblies with ordered nanometer-scale features in three dimensions are of interest as functional nanomaterials but are difficult to generate. Only complex 1 with the {Au(PPh3)}+ moiety exhibits significant bactericidal activity against both strains. The glycan-binding proteins, or lectins, that interact with mucins are often oligomeric receptors with multiple ligand binding domains. Notably, we observed that the transcription factors c-JUN and JUNB show higher levels of O-GlcNAc glycosylation and higher levels of expression in activated T cells. In the This challenging process made her dream of Beatty, K. E., Williams, M., Carlson, B. L., Swarts, B. M., Warren, R. M., van Helden, P. D., Bertozzi, C. R. Synthesis and Reactivity of Dibenzoselenacycloheptynes. The active cuprous FGE complex was interrogated directly by X-ray absorption spectroscopy. To discover the molecular basis of this unusual role for a G protein, we biochemically characterized and solved the X-ray crystal structure of a complex between Pseudomonas syringae ATPS (CysD) and its associated regulatory G protein (CysN). A novel and efficient enzyme kinetics assay using electrospray ionization mass spectrometry was developed and applied to the bacterial carbohydrate sulfotransferase (NodST). A., Smart, B. P., Spiciarich, D. R., Iavarone, A. T., Bertozzi, C. R. The Regulation of Sulfur Metabolism in Mycobacterium tuberculosis, Metabolic Labeling of Fucosylated Glycans in Developing Zebrafish. Flynn, R. A., Pedram, K., Malaker, S. A., Batista, P. J., Smith, B. This Account summarizes chemoselective approaches for assembling homogeneous glycoconjugates that attempt to reduce the barriers to their synthesis. View details for Web of Science ID 000174151500001. N610 was also the primary site of sialylation of the receptor. Strategies to ameliorate GBM tissue tension offer a therapeutic approach to reduce mortality due to GBM. Stanford University biochemist Carolyn Bertozzi is a highly admired scientist, entrepreneur, and advocate for diversity, particularly for LGBTQ+ people. It is anticipated that the ability of this technique to create virtually any type of 2D heterogeneous cell pattern should prove highly useful for the examination of key questions in cell signaling, including stem cell differentiation and cancer metastasis. These findings identify an osmosensory pathway orchestrated by PknD, Rv0516c, and SigF that enables adaptation to osmotic stress through cell wall remodeling and virulence factor production. View details for Web of Science ID 000309335000008, View details for PubMedCentralID PMC3466019. She is a member of the National Academy of Sciences (2005), the Institute of Medicine (2011), and the National Academy of Inventors (2013). WebBertozzi is a professor of Humanities and Sciences, and of Chemical and Systems Biology and of Radiology. A., Bertozzi, C. R. Metabolic selection of glycosylation defects in human cells, Polymerized liposome assemblies: Bifunctional macromolecular selectin inhibitors mimicking physiological selectin ligands. We previously described a chemical method to image glycans during zebrafish larval development; however, we were unable to detect glycans during the first 24 hours of embryogenesis, a very dynamic period in development. View details for DOI 10.1073/pnas.0811481106, View details for Web of Science ID 000262263900006, View details for PubMedCentralID PMC2629201. Furthermore, perturbation of MMCoA metabolism attenuated pathogen replication in mice. To determine whether PapA3 participates in PAT assembly, we expressed the protein heterologously and evaluated its acyltransferase activity in vitro. Unnatural intermediates are used to challenge a specific pathway, and cell surface expression of their metabolic products provides a readout of flux in that pathway and a basis for selecting genetic mutants. We disabled key enzymes required for each of the three pathways in M. smegmatis by allelic replacement. Bruehl, R. E., Dasgupta, F., Katsumoto, T. R., Tan, J. H., Bertozzi, C. R., Spevak, W., Ahn, D. J., ROSEN, S. D., Nagy, J. O. Biosynthesis of L-selectin ligands: Sulfation of sialyl Lewis x-related oligosaccharides by a family of GlcNAc-6-sulfotransferases. These two strategies provide a means to selectively modify cell-surface glycans with exogenous probes. These cells were used as substrates to examine the effect of inhibiting PSA synthesis on the development of neurons derived from the chick dorsal root ganglion. Complementation of the mutant strain restored PAT production, demonstrating that PapA3 is essential for the biosynthesis of this glycolipid in vivo. Kramer, J. R., Onoa, B., Bustamante, C., Bertozzi, C. R. Systemic Fluorescence Imaging of Zebrafish Glycans with Bioorthogonal Chemistry. Similarly, the ability to perceive the spatial organization of glycans could transform our understanding of their role in development, infection, and disease progression. These multivalent arrays are 4 orders of magnitude better than the monovalent carbohydrate. Cell surface glycans govern numerous cell-cell interactions are therefore key determinants of multicellular biology. The Gal/GalNAc/GlcNAc-6-O-sulfotransferases (GSTs) are a recently discovered family of carbohydrate sulfotransferases that share significant sequence homology at the amino acid level and mediate a number of different biological processes such as leukocyte adhesion at sites of chronic inflammation. The objective of these methods is to make glycoconjugate synthesis accessible to a broader community, thereby accelerating progress in glycobiology. Further, we propose that the method reported here could find widespread use in investigating the functional consequences of O-GlcNAcylation. Link, A. J., Vink, M. K., Agard, N. J., Prescher, J. In the presence of thiols, 1 gives rise to free PZA and {Au(PPh3)}-thiol polymeric species. B., Moore, K. L., Ellman, J. The building block was incorporated into a synthetic peptide derived from the active site of a Mycobacterium tuberculosis sulfatase. [6] In 1999, while working with HHMI and at Berkeley, she founded the field of bioorthogonal chemistry and coined the term in 2003. This approach enables two measurements: glycocalyx height and the distribution of individual sugars distal from the membrane. Finally, we generated an Rv3406 mutant (rv3406) in Mtb to study the sulfatase's role in sulfate scavenging. Based on sequence homology with a previously cloned human GlcNAc 6-O-sulfotransferase, we have identified an open reading frame (ORF) encoding a novel member of the Gal/GalNAc/GlcNAc 6-O-sulfotransferase (GST) family termed GST-5 on the human X chromosome (band Xp11). We introduced an exogenous GlcNAc salvage pathway into yeast, allowing cells to metabolize GlcNAc provided as a supplement to the culture medium. 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. Thus, BARAC is a promising reagent for in vivo imaging. Data from two independent probes, fluorophores conjugated directly to the polymer backbone and fluorescent proteins bound to the sugar groups, unexpectedly show that the mucin mimic molecules lie flat along the membrane. By contrast, only GlcNAc-6-SO(4) appears to contribute to MECA-79 binding. However, its superior polarity and water solubility reduced nonspecific binding, thereby improving the sensitivity of azide detection. Despite reports detailing a suite of sulfated glycolipids in many mycobacteria, a corresponding family of sulfotransferase genes remains uncharacterized. Key advantages of DNA-directed cell binding include the ability to immobilize both adherent and non-adherent cells, to capture cells selectively from a mixed population, to tune the binding properties of the cells, and to reuse substrates prepared with widely available DNA printing technologies. Furthermore, their dynamic behavior in synthetic membranes mirrored that of natural biomolecules. View details for DOI 10.1073/pnas.1201504109, View details for Web of Science ID 000307551700033, View details for PubMedCentralID PMC3420203. Flynn, R. A., Belk, J. We found that extension of the N-acyl chain to six, seven, or eight carbon atoms dramatically reduced utilization by the biosynthetic machinery. Factors including glycan heterogeneity, low abundance, and low occupancy can complicate site mapping. This system provides a unique framework with which to study the behavior of mucin-like macromolecules in a controlled, cell surface-mimetic environment. Here we demonstrate that a methionine surrogate, azidohomoalanine, is activated by the methionyl-tRNA synthetase of Escherichia coli and replaces methionine in proteins expressed in methionine-depleted bacterial cultures. View details for Web of Science ID 000243895200017. Schumann, B., Debets, M., Wisnovsky, S., Agbay, A., Wagner, L., Choi, J., Gray, M., Bertozzi, C. Quantitative super-resolution microscopy reveals the architecture of the mammalian glycocalyx and its changes during cancer progression. The inhibitory activity of 1-68A and a panel of synthetic analogues identified moieties necessary for inhibition. View details for Web of Science ID 000392525600001, View details for PubMedCentralID PMC5255568. Here we describe a method for the site-specific introduction of aldehyde groups into recombinant proteins using the 6-amino-acid consensus sequence recognized by the formylglycine-generating enzyme. Bertozzi completed her undergraduate degree in Chemistry at Harvard University and her Ph.D. at UC Berkeley, focusing on the chemical synthesis of oligosaccharide analogs. Godula, K., Umbel, M. L., Rabuka, D., Botyanszki, Z., Bertozzi, C. R., Parthasarathy, R. Glycopeptide-preferring Polypeptide GalNAc Transferase 10 (ppGalNAc T10), Involved in Mucin-type O-Glycosylation, Has a Unique GalNAc-O-Ser/Thr-binding Site in Its Catalytic Domain Not Found in ppGalNAc T1 or T2. The review discusses the significance of mucin-type O-linked glycosylation initiated by the polypeptide N-acetylgalactosaminyltransferases in biology and development of chemical tools to study these enzymes and their substrates. Walton, E. M., Cronan, M. R., Cambier, C. J., Rossi, A., Marass, M., Foglia, M. D., Brewer, W., Poss, K. D., Stainier, D. R., Bertozzi, C. R., Tobin, D. M. A tension-mediated glycocalyx-integrin feedback loop promotes mesenchymal-like glioblastoma. We describe a chemical strategy directed toward identifying O-GlcNAc-modified proteins from living cells or proteins modified in vitro. Antibodies bind to and agglutinate synthetic antigen-DNA conjugates, enabling ligation of the DNA strands and subsequent quantification by qPCR. Biomolecules labeled with azides can be detected through Cu-free click chemistry with cyclooctyne probes, but their intrinsic hydrophobicity can compromise bioavailability. [22][26] She has been an investigator with HHMI since 2000. View details for DOI 10.1002/cbic.201100649, View details for Web of Science ID 000299834900004, View details for PubMedCentralID PMC3385855. The sulfotransferases that generate specific carbohydrate 'sulfoforms' have recently been recognized as key modulators of these processes and therefore represent potential therapeutic targets. Our glycan-specific assay can be paired with traditional proximity ligation assays to simultaneously determine the change in total protein levels. The advantage of this ELISA over previous assays is that a macromolecular physiological ligand is employed, rather than a fortuitous or simplified carbohydrate ligand. View details for Web of Science ID A1995TD84500001. The correlation of its abundance with the virulence of clinical isolates suggests a role for SL-I in pathogenesis, although its biological functions remain unknown. This review focuses on recent advances in chemical tools to study the specificity and dynamics of mammalian lectins in live cells. Delaveris, C. S., Wilk, A. J., Riley, N. M., Stark, J. C., Yang, S. S., Rogers, A. J., Ranganath, T., Nadeau, K. C., Blish, C. A., Bertozzi, C. R. Optimization of Metabolic Oligosaccharide Engineering with Ac4GalNAlk and Ac4GlcNAlk by an Engineered Pyrophosphorylase. We applied this "azido-ELISA" to the family of polypeptide alpha-N-acetylgalactosaminyltransferases (ppGalNAcTs), all of which were able to transfer N-azidoacetylgalactosamine (GalNAz) from the unnatural nucleotide sugar donor UDP-GalNAz. View details for Web of Science ID 000090003800038. The detailed quantitative parameters of ManLev metabolism in human and nonhuman-derived cell lines were determined to establish a foundation for the modification of cell surfaces with novel epitopes at defined cell-surface densities. Lin, F. L., Hoyt, H. M., van Halbeek, H., Bergman, R. G., Bertozzi, C. R. Synthetic glycopeptides and glycoproteins as tools for biology, Functional hydrogel-biomineral composites inspired by natural bone, Azido sialic acids can modulate cell-surface interactions, A small-molecule switch for Golgi sulfotransferases. Among her many honours are the Lemelson-MIT Prize (2010), the Arthur C. Cope Award of the American Chemical Society (2017), and the Wolf Prize in Chemistry (2022). Cotton Medal, Texas A&M University (2020); The Gustavus John Esselen Award for Chemistry in the Public Interest, Northeast Section of the ACS (2019); Max Tishler Prize, Harvard University Dept. The polyvalent display of carbohydrate groups found on cell surface glycoprotein structures may contribute to the enhanced binding strength of selectin-mediated adhesion. These data suggest that chemical inhibition of OGT and perturbation of protein O-GlcNAcylation accelerate the differentiation of hESCs along the neuronal lineage, thus providing further insight into the dynamic molecular mechanisms involved in neuronal development. We used this method to identify interaction partners for the O-GlcNAc-modified FG-repeat nucleoporins. Consistent with other studies, we find that O-GlcNAc sites in T cells lack a strict consensus sequence. View details for DOI 10.1073/pnas.0911116107, View details for Web of Science ID 000274296300006, View details for PubMedCentralID PMC2836626, View details for Web of Science ID 000278671100002. The approach has applications in tissue-selective imaging of glycans for clinical and basic research purposes. O-GlcNAc transferase (OGT) catalyzes the addition of N-acetylglucosamine (O-GlcNAc) onto a diverse array of intracellular proteins. Grunwell, J. R., Rath, V. L., Rasmussen, J., Cabrilo, Z., Bertozzi, C. R. Discovery of sulfated metabolites in mycobacteria with a genetic and mass spectrometric approach. WebCarolyn Ruth Bertozzi (born October 10, 1966) is an American chemist and Nobel laureate, known for her wide-ranging work spanning both chemistry and biology. Using this approach quantities of homogeneous material were obtained for structural and functional analysis. The loss of SL-1 (and SL(1278)) did not appear to affect bacterial replication or trafficking, suggesting that the functions of SL-1 are specific to human infection. Spiciarich, D. R., Nolley, R., Maund, S. L., Purcell, S. C., Herschel, J., Iavarone, A. T., Peehl, D. M., Bertozzi, C. R. Corneal surface glycosylation is modulated by IL-1R and Pseudomonas aeruginosa challenge but is insufficient for inhibiting bacterial binding. Thus, to advance insight into the role of O-GlcNAc in T cell activation, we performed glycosite mapping studies via direct glycopeptide measurement on resting and activated primary human T cells with a technique termed Isotope Targeted Glycoproteomics. GST-5 is the newest member of an emerging family of carbohydrate 6-O-sulfotransferases that includes chondroitin 6-sulfotransferase (GST-0), keratan-sulfate galactose 6-O-sulfotransferase (GST-1), the ubiquitously expressed GlcNAc 6-O-sulfotransferase (GST-2), high endothelial cell GlcNAc 6-O-sulfotransferase (GST-3), and intestinal GlcNAc 6-O-sulfotransferase (GST-4). Oligosaccharides or alter the structures of the library identified an inhibitor with a (. Generality of this method make it well suited for use in the presence of thiols, 1 gives to. Heterologously and evaluated its acyltransferase activity in vitro, demonstrating that PapA3 is essential for the of! 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