Li phin vn-chng si to pan-lan-chhan , ng Carolyn Bertozzi, PhD, was one of three scientists to be awarded the 2022 Nobel Prize in Chemistry earlier today for the development of click chemistry and bio-orthogonal chemistry. Finally, we demonstrate that the cell-surface Staudinger ligation is compatible with hydrazone formation from metabolically introduced ketones. Using this new method, the glycome analysis of cell membranes isolated from human embryonic stem cells and somatic cell lines was performed. In this reaction, activated sulfate in the context of adenosine-5'-phosphosulfate (APS) or 3'-phosphoadenosine 5'-phosphosulfate (PAPS) is converted to sulfite with reducing equivalents from thioredoxin. We employed the recently introduced aldehyde tag method to obtain a recombinant protein with the aldehyde-bearing formylglycine residue at a specific site. Activity across tissues was highly restricted to the HEVs within peripheral lymph node.The restricted expression of the GlcNAc-6-0-sulfotransferase activity to lymph node HEVs strongly suggestions a role in the biosynthesis of L-selection ligands. We further show that proteins containing azidohomoalanine can be selectively modified in the presence of other cellular proteins by means of Staudinger ligation with triarylphosphine reagents. Mucins and trans-sialidase (TS) are substrate and enzyme, respectively, of the glycobiological system that scavenges sialic acid from the host in a crucial interplay for T. cruzi life cycle. Attachment via these "cell-adhesion barcodes" is rapid and specific, with close-packed arrays of cells forming within minutes. Kumar, P., Schelle, M. W., Jain, M., Lin, F. L., Petzold, C. J., Leavell, M. D., Leary, J. The second-order rate constant for PAP was determined to be over 3 orders of magnitude greater than those determined for myo-inositol 1-phosphate (IMP) and fructose 1,6-bisphosphate (FBP), previously considered to be the primary substrates of this enzyme. We demonstrate here that a previously uncharacterized sulfated molecule, termed S881, is localized to the outer envelope of M. tuberculosis and negatively regulates the virulence of the organism in two mouse infection models. Furthermore, we show that the biosynthesis of S881 relies on the universal sulfate donor 3'-phosphoadenosine-5'-phosphosulfate and a previously uncharacterized sulfotransferase, stf3. We applied this strategy to the GlcNAc-6-sulfotransferases GlcNAc6ST-1 and GlcNAc6ST-2, which collaborate in the sulfation of L-selectin ligands. Sialic acid is a major determinant of carbohydrate-receptor interactions in many systems pertinent to human health and disease. Imaging analysis of glycan trafficking revealed dramatic reorganization of glycans on the second time scale, including rapid migration to the cleavage furrow of mitotic cells. Additionally, the isotopic signature imparted by the dibromide tag was detectable on a 12-kDa protein, suggesting applications in identifying large peptide fragments, such as those containing multiple or large posttranslational modifications (e.g., glycosylation). Here we show that the cytosolic enzyme N-glycanase 1 (NGLY1, the human PNGase) is essential for Nrf1 activation in response to proteasome inhibition. The sulfation of trehalose is required for the biosynthesis of sulfolipid-1, the most abundant sulfated metabolite found in Mycobacterium tuberculosis. Mukkamala, R., Kushner, A. M., Bertozzi, C. R. Constructing azide-labeled cell surfaces using polysaccharide biosynthetic pathways. These technological hurdles are especially troublesome in detecting antibodies that bind nonlinear or conformational epitopes, such as anti-insulin antibodies in type 1 diabetes patients and anti-thyroglobulin antibodies associated with thyroid cancers. Grossman, H. L., Myers, W. R., Vreeland, V. J., Bruehl, R., Alper, M. D., Bertozzi, C. R., Clarke, J. Modular assembly of glycoproteins: Towards the synthesis of GlyCAM-1 by using expressed protein ligation, A strategy for functional proteomic analysis of glycosidase activity from cell lysates, Biomimetic engineering of carbon nanotubes by using cell surface mucin mimics. However, little is known about how alterations in O-GlcNAc cycling affect human embryonic stem cell (hESC) neural differentiation. View details for PubMedCentralID PMC5675001. Using a multicolor, time-resolved imaging strategy, we found that the distribution and dynamics of the glycans varied anatomically and with respect to developmental stage. Zurich, 2011 Tetrahedron Young Investigator Award for Bioorganic and Medicinal Chemistry, 2012 Honorary Doctorate of Science from, 2018 Foreign Member of the Royal Society (ForMemRS), 2020 John J. Carty Award for the Advancement of Science, 2020 F. A. VDAC2(-/-) cells resist the mitochondrial dysfunction and apoptosis caused by global O-GlcNAc perturbation, demonstrating afunctional connection between O-GlcNAc signaling and mitochondrial physiology through VDAC2. 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. We evaluated a panel of four lectins (Soybean agglutinin (SBA), Wisteria floribunda lectin (WFL), Vicia villosa-B-4 agglutinin (VVA), and Helix pomatia agglutin (HPA)) with specificity for -N-acetylgalactosamine (-GalNAc), an epitope displayed on mucins overexpressed in many adenocarcinomas. Here we describe a versatile platform that can accomplish this goal through DNA hybridization. Our data show that over 50% of O-glycopeptides in our sample generated from combined digestion using OpeRATOR and trypsin contain multiple O-glycosites, indicating that collision-based fragmentation alone is not sufficient. Tastan, O. Y., Debets, M. F., Malaker, S. A., Wisnovsky, S. P., Angelis, N., Wagner, L. S., Choi, J., Browne, W. M., Bineva-Todd, G., Cioce, A., Agbay, A. J., Li, Z., Briggs, D. C., Flynn, H., Roustan, C., Fernandez, D., Douglas, H. L., Kjaer, S., Snijders, A. P., Li, V. W., Bertozzi, C. R., Schumann, B. View details for DOI 10.1073/pnas.0610634104, View details for Web of Science ID 000245256700066, View details for PubMedCentralID PMC1829275. The controlled addition of structurally defined components to live cell membranes can facilitate the molecular level analysis of cell surface phenomena. The prokaryotic homolog exhibits remarkable structural similarity to human FGE, including the position of catalytic cysteine residues. Kohler, J. J., Czlapinski, J. L., Laughlin, S. T., Schelle, M. W., de Graffenried, C. L., Bertozzi, C. R. Metabolic functionalization of recombinant glycoproteins. Multicellular organs comprise differentiated cell types with discrete yet interdependent functions. Rv3406 was identified based on its homology to the alkyl sulfatase AtsK from Pseudomonas putida. T-cell progenitors originate in the bone marrow and are mobilized to the blood at regular intervals by unknown signals. We further generated rapamycin-inducible chimeric enzymes comprising the localization domain of a sulfotransferase and the catalytic domain of a glycosyltransferase, demonstrating the generality of the system among other Golgi enzymes. Collectively, these results indicate that the distortion/interaction model combined with bond angle analysis will enable predictions of cyclooctyne reactivity and the rational design of new reagents for copper-free click chemistry. The selectins are a family of three adhesion molecules (L-, P-, and E-) that direct the interaction of circulating leukocytes with endothelial cells during the first step in recruitment to tissue sites. This system enables the production of glycoproteins that are functionalized for specific chemical modifications at their glycosylation sites. Circular dichroism of unglycosylated diptericin indicated that the peptide lacked structure both in plain buffer and in the presence of liposomes. The installation of sulfate groups on the carbohydrate residues of glycoproteins, glycolipids, and glycosaminoglycans is a critical posttranslational modification that occurs in all higher eukaryotes. Changes in glycosylation are often associated with disease progression, but the genetic and metabolic basis of these events is rarely understood in detail at a molecular level. Yet, our understanding of the invivo ligands and function for most lectins is still incomplete. She completed her undergraduate degree in Chemistry from Harvard University in 1988 and her Ph.D. in Chemistry from UC Berkeley in 1993. Professor of Chemical & Systems Biology and Radiology Examples of sulfated metabolites as mediators of interactions between bacteria and plants suggest that sulfation is a key modulator of extracellular signaling between prokaryotes and eukaryotes. This provides orthogonal cleavage relative to canonical proteases (e.g., trypsin) for improved O-glycopeptide characterization with tandem mass spectrometry (MS/MS). Van de Bittner, G. C., Dubikovskaya, E. A., Bertozzi, C. R., Chang, C. J. A chimera comprising the localization domain of GlcNAc6ST-1 fused to the catalytic domain of GlcNAc6ST-2 was confined to the trans-Golgi network and adopted the substrate preference of GlcNAc6ST-1. The results support the hypothesis of a two-step mechanism in which the sulfonucleotide first undergoes rapid nucleophilic attack to form an enzyme-thiosulfonate (E-Cys-S-SO(3-)) intermediate. Since PSA is important in neural plasticity and development, this mechanism for modulating PSA structure might be useful for functional studies. View details for Web of Science ID 000268395000075, View details for PubMedCentralID PMC2716393. The combination of novel biochemical and metabolism-based approaches with emerging genomic methods promises to accelerate efforts to understand glycosylation. A., Bassik, M. C., Moerner, W. E., Bertozzi, C. R. Capture and visualization of live Mycobacterium tuberculosis bacilli from tuberculosis patient bioaerosols. In this approach, metabolic labeling substrates containing bioorthogonal functional groups are provided to cells for incorporation into biopolymers by endogenous biosynthetic machinery. However, the estimated barrier is much smaller than expected for folding of isolated S-layer proteins, suggesting an energetic rationale for this multistage pathway. An undecasaccharide mimetic was then readily generated by alkylation of this glycopeptide with an N-bromoacetamido trisaccharide. Paulick, M. G., Forstner, M. B., Groves, J. T., Bertozzi, C. R. Bioorthogonal click chemistry: Covalent labeling in living systems, Redirecting lipoic acid ligase for cell surface protein labeling with small-molecule probes. DMN-Tre labeling enabled the rapid, no-wash visualization of mycobacterial and corynebacterial species without nonspecific labeling of Gram-positive or Gram-negative bacteria. Hsiao, S. C., Crow, A. K., Lam, W. A., Bertozzi, C. R., Fletcher, D. A., Francis, M. B. We observed dramatic nanoscopic morphological transformations accompanying charge-induced chromatic transitions, suggesting that both side-chain disordering and main-chain rearrangement play important roles in altering the effective conjugation lengths of the poly(ene-yne). Although the chemical reporter strategy has been used in conjunction with bioorthogonal chemistry to image the external glycosylation state of live zebrafish and detect tumor-associated glycans in mice, the ability to image glycans systemically within a live organism has remained elusive. In one step, 35S-labeled by-products are then eluted from the membrane, leaving spatially separated 35S-labeled product "dots" for subsequent quantification. We used this strategy to construct a paracrine signaling network in isolated 3-dimensional microtissues. Here we investigate the conversion of a panel of azide-functionalized mannosamine and glucosamine derivatives into cell-surface sialosides. However, the diversity found in glycoproteins has undermined efforts to describe the intact glycoproteome via mass spectrometry (MS). In this work, we apply an aluminum "lift off" lithography method to allow the efficient generation of complex patterns comprising different DNA sequences. A major drawback to studying the sialylation kinetics and turnover of the trypomastigote glycoconjugates is the difficulty to identify and follow the recently acquired sialyl residues. 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. The generation of homogeneously glycosylated proteins is essential for defining glycoform-specific activity and improving protein-based therapeutics. Here we describe the characterization and application of a synthetic riboswitch-based system, which comprises a mycobacterial promoter for transcriptional control and a riboswitch for translational control. However, current bioaerosol sampling approaches have reported low detection yields in sputum-positive TB cases. Mtb capture was calculated per exhaled air volume sampled and bioaerosol volume for RASC-1 (n = 35) and for RASC-2 (n = 21). Ooi, Y. S., Majzoub, K., Flynn, R. A., Mata, M. A., Diep, J., Li, J. K., van Buuren, N., Rumachik, N., Johnson, A. G., Puschnik, A. S., Marceau, C. D., Mlera, L., Grabowski, J. M., Kirkegaard, K., Bloom, M. E., Sarnow, P., Bertozzi, C. R., Carette, J. E. A novel therapeutic modality of inhibiting the glyco-immune checkpoint axis to treat cancer. Here, we describe the computation-guided rational design of a cysteine- and lysine-containing 11-residue peptide sequence that reacts with 2-cyanobenzothiazole (CBT) derivatives. This work therefore extends the use of bioorthogonal labeling strategies to problems of clinical relevance. Finally, we found that metabolic labeling of both cell envelope structures reports on drug effects on cell physiology in two hours, far faster than a genetic sensor of cell envelope stress. Illumination of dye-labeled structures generates singlet oxygen to locally catalyze the polymerization of diaminobenzidine into an osmiophilic reaction product that is readily imaged by EM. This hypothesis reflects the known oligomeric states of the galectins themselves and their binding properties with multivalent ligands in vitro, but direct evidence of their ability to cross-link ligands on a cell surface is lacking. View details for Web of Science ID 000172448800001. Hudak, J. E., Canham, S. M., Bertozzi, C. R. Osmosensory signaling in Mycobacterium tuberculosis mediated by a eukaryotic-like Ser/Thr protein kinase. In this work, we undertook a mechanistic study of the Staudinger ligation with a focus on factors that affect reaction kinetics and on the identification of intermediates. We refer to these fascinating structures as "carbon nanohoops" due to their structural similarity to carbon nanotubes. Luchansky, S. J., Hang, H. C., Saxon, E., Grunwell, J. R., Danielle, C. Y., Dube, D. H., Bertozzi, C. R. Drug targeting Mycobacterium tuberculosis cell wall synthesis: Development of a microtiter plate-based screen for UDP-galactopyranose mutase and identification of an inhibitor from a uridine-based library. WebAbout our Founding. Malaker, S. A., Shon, J., Pedram, K., Riley, N. M., Bertozzi, C. R. AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. An RNA-centric dissection of host complexes controlling flavivirus infection. Proof of principle was performed by using various heparin/HS samples isolated from bovine and porcine tissues. The concepts outlined herein lay a foundation for future development of peptide tags in the context of site-selective modification of lysine residues within engineered microenvironments. Tomsia, A. P., Saiz, E., Song, J., Bertozzi, C. R. Synthesis of lipidated green fluorescent protein and its incorporation in supported lipid bilayers. While these lectins possess the ability to agglutinate A(1)-blood cells carrying the -GalNAc epitope and cross-link low valency glycoconjugates, only SBA showed a tendency to form intermolecular cross-links among the arrayed polyvalent mucin mimetics. 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. Directed proteomics applies mass spectrometry analysis to a subset of information-rich proteins. View details for DOI 10.1371/journal.pbio.0030250, View details for Web of Science ID 000231243800014, View details for PubMedCentralID PMC1175818. However, the mechanisms by which ADCs are internalized and activated remain unclear. View details for DOI 10.1074/jbc.M109.017236, View details for Web of Science ID 000268097400064, View details for PubMedCentralID PMC2740463. Preliminary screening has identified compounds that inhibit estrogen sulfotransferase (EST), an enzyme relevant to breast cancer. Generated in nine steps from a glucose analogue, DIMAC reacted with azide-labeled proteins and cells similarly to cyclooctynes. Manning, D. D., Bertozzi, C. R., ROSEN, S. D., Kiessling, L. L. C-glycosyl aldehydes: Synthons for C-linked disaccharides. A. Binda, O., Boyce, M., Rush, J. S., Palaniappan, K. K., Bertozzi, C. R., Gozani, O. Organelle Membrane Proteomics Reveals Differential Influence of Mycobacterial Lipoglycans on Macrophage Phagosome Maturation and Autophagosome Accumulation. View details for DOI 10.1038/s41467-019-12684-7. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. This complex could be stored as a lyophilized powder and then dissociated in organic solvents to produce free DIFBO for in situ kinetic and spectroscopic analysis. 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. At 60 hours after fertilization, we observed an increase in de novo glycan biosynthesis in the jaw region, pectoral fins, and olfactory organs. Genome-wide CRISPR screens reveal a specific ligand for the glycan-binding immune checkpoint receptor Siglec-7. In cells, GlcNAc6ST-1 exists as a dimer; two cysteine residues within the stem and transmembrane domain were found to be critical for dimerization. The coating layers of macrophages and their targets hinder phagocytosis by both steric and electrostatic means. The most potent examined, 1-68A, is a pH-dependent, two-step, covalent inhibitor of Escherichia coli LpxC that competes with UDP to bind the enzyme in the first step of inhibition. Hudak, J. E., Barfield, R. M., de Hart, G. W., Grob, P., Nogales, E., Bertozzi, C. R., Rabuka, D. Synthesis of a Fluorogenic Cyclooctyne Activated by Cu-Free Click Chemistry, Protein Glycoengineering Enabled by the Versatile Synthesis of Aminooxy Glycans and the Genetically Encoded Aldehyde Tag, Cell surface glycoproteomic analysis of prostate cancer-derived PC-3 cells. View details for Web of Science ID 000169081700029. Under nondenaturing conditions, a distribution of the apoprotein, a 2Fe-2S intermediate, and the 4Fe-4S holoprotein were observed. View details for Web of Science ID 000264791600009, View details for PubMedCentralID PMC2657038. Here, we use metabolic oligosaccharide engineering to introduce a bioorthogonal functional group, the azide, into cellular and recombinant glycoproteins for subsequent chemical elaboration via Staudinger ligation. Mycobacterium tuberculosis (M. tuberculosis) is an intracellular pathogen possessing a complex mixture of cell wall lipids that are thought to modulate the activities of host macrophages. Macrophages continuously survey their environment in search of pathogens or apoptotic corpses or debris. After insertion into live cell membranes, the GPs' fluorescence lifetime and diffusion time were measured in the presence and absence of galectin-1. In this paper, we describe experiments in which the conformations of structurally well-defined polymers anchored to fluid lipid membranes were probed using Fluorescence Interference Contrast Microscopy (FLIC), an optical technique that provides topographic information with few-nanometer precision. 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. View details for Web of Science ID 000182331800019. Finally, the Delta papA2 and Delta papA1 mutants were screened for virulence defects in a mouse model of infection. A., Solomon, E. I., Bertozzi, C. R. Formylglycine-generating enzyme binds substrate directly at a mononuclear Cu(I) center to initiate O2 activation. Using high-performance liquid chromatography, we quantified the degree of accumulation and reversibility upon acidic compartment neutralization in macrophages and observed that accumulation was greater in infected than in uninfected macrophages. Some members of the family prefer previously gly co sylated peptides (ppGalNAc T7 and T10), whereas others are inhibited by neighboring gly co sy la tion (ppGalNAc T1 and T2). However, changes in the glycan structure significantly affected membrane mobility, with the loss of monosaccharide units correlating to decreased diffusion. Herein we describe a novel glycosyltransferase assay that exploits their unnatural substrate tolerance and the unique chemical reactivity of the azide. [27][28][29] This new field and technique allows researchers to chemically modify molecules in living organisms and not interrupt the processes of the cell. View details for Web of Science ID 000291896400004, View details for PubMedCentralID PMC3117394. Synthetic Riboswitches That Induce Gene Expression in Diverse Bacterial Species. This concise motif can be installed within heterologous proteins as a genetically encoded "aldehyde tag" for site-specific labeling with aminooxy- or hydrazide-functionalized probes. Both mutant synthetases label human, hamster, and mouse cell line proteins and selectively activate their azido-bearing amino acids over 10-fold above the canonical. A., Lo, A., Bertozzi, C. R. Metabolic labeling of glycans with azido sugars for visualization and glycoproteomics. View details for DOI 10.1074/jbc.M111.315473, View details for Web of Science ID 000301349400015. Varki, A., Cummings, R. D., Esko, J. D., Freeze, H. H., Stanley, P., Marth, J. D., Bertozzi, C. R., Hart, G. W., Etzler, M. E. Control of the Molecular Orientation of Membrane-Anchored Biomimetic Glycopolymers. Empty chamber samples were collected between patients as controls.The optimised RASC-2 protocol sampled a median of 258.4L (IQR: 226.9-273.6) of exhaled air per patient compared with 27.5L (IQR: 23.6-30.3) for RASC-1 (p<0.0001). In some cases, the functional significance of disease-associated changes in glycosylation has been revealed. A., Gray, M. A., Bertozzi, C. R., Rabuka, D., Bassik, M. C. Quantitative super-resolution microscopy of the mammalian glycocalyx. 1-68A and a 2-dehydroxy analogue, 1-68Aa, inhibit several purified LpxC orthologues. This technique has enabled visualization of glycans in living cells and in live organisms such as zebrafish. A revised, highly practical synthesis of the precursor N(alpha)-Fmoc-Thr(Ac(3)-alpha-D-GalNAc) allowed us to produce sufficient quantities of the glycopeptide for mechanistic assays. She has been recognized with many honors and awards for her research accomplishments. We have previously identified the polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) gene, a member of the GalNAc-transferases (GalNAc-Ts) gene family, as hypomethylated and overexpressed in high-grade serous EOC tumors, compared to low malignant potential EOC tumors and normal ovarian tissues. Trypsin ) for improved O-glycopeptide characterization with tandem mass spectrometry analysis to a of... Were screened for virulence defects in a mouse model of infection R., Chang, C..... '' is rapid and specific, with the aldehyde-bearing formylglycine residue at a specific ligand the! 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