Further, enzymatically simplified N-glycans are preserved on peptides. Our editors will review what youve submitted and determine whether to revise the article. Here we investigate the biosynthetic origin of H. ducreyi sialosides by metabolic incorporation studies using a panel of N-acylmannosamine and sialic acid analogues. The rapid assembly of a complex type N-linked glycopeptide mimetic was accomplished using this technique. The structure of sialic acid on living cells can be modulated by metabolism of unnatural biosynthetic precursors. A sensitive electrospray ionization mass spectrometry-based assay was used to extract the kinetic parameters for PAP, revealing a K m (8.1 +/- 3.1 microM) and k cat (5.4 +/- 1.1 s (-1)) comparable to those reported for other CysQ enzymes. 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. Zebrafish embryos were treated with an unnatural sugar to metabolically label their cell-surface glycans with azides. [24], In 1996 Bertozzi became a faculty member in the UC Berkeley College of Chemistry[25] and a faculty scientist at Lawrence Berkeley National Laboratory, where she served as the Director of the Molecular Foundry. Kaushik, S., Barnes, J., Bainer, R. O., Sa, J. K., Woods, E. C., Kai, F., Przybyla, L., Lakins, J. N., Phillips, J. J., Nam, D., Bertozzi, C. R., Weaver, V. M. Is the Nobel Prize in Chemistry Having a Boston Red Sox Moment? Wojczyk, B. S., Stwora-Wojczyk, M. M., Hagen, F. K., Striepen, B., Hang, H. C., Bertozzi, C. R., Roos, D. S., Spitalnik, S. L. Metabolic oligosaccharide engineering as a tool for glycobiology, Formation of 1,1-alpha,alpha-glycosidic bonds by intramolecular aglycone delivery. This method for the selective formation of an amide bond, which does not require the orthogonal protection of distal functional groups, should find general utility in synthetic and biological chemistry. View details for DOI 10.1073/pnas.0506855103, View details for Web of Science ID 000236472500008, View details for PubMedCentralID PMC1405625. These observations suggest crosstalk between autophagy and phagocytosis that may be relevant to the innate immune response of macrophages. Palmitoylation is a widespread, reversible lipid modification that has been implicated in regulating a variety of cellular processes. We report the 2.7 A resolution crystal structure of Pseudomonas aeruginosa APS reductase in the thiosulfonate intermediate form of the catalytic cycle and with substrate bound. 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. One cell wall molecule unique to pathogenic M. tuberculosis is polyacyltrehalose (PAT), a pentaacylated, trehalose-based glycolipid. In nature, glycans are constructed by glycosyltransferases that are organized in an assembly line in the endoplasmic reticulum and Golgi compartment. Mutation of the N610 site prevented membrane-proximal N-glycosylation of CSF3R, which then drove ligand-independent cellular expansion. Hatzios, S. K., Schelle, M. W., Holsclaw, C. M., Behrens, C. R., Botyanszki, Z., Lin, F. L., Carlson, B. L., Kumar, P., Leary, J. Furthermore, GalNAz-labeled B cells could be selectively targeted with a phosphine probe by Staudinger ligation within the living animal. Stanford, CA 94305Phone: (650) 723-2501Campus Map, UndergraduatesPh.D. The oligonucleotides were introduced using metabolic carbohydrate engineering, which allowed reactive tailoring of the cell surface glycans for chemoselective bioconjugation. We apply the strategy to a particularly redundant yet disease-relevant human glycosyltransferase family, the polypeptide N-acetylgalactosaminyl transferases. CalFluors: A Universal Motif for Fluorogenic Azide Probes across the Visible Spectrum. Site-specific characterization of glycosylation requires intact glycopeptide analysis, and recent efforts have focused on how to best interrogate glycopeptides using tandem mass spectrometry (MS/MS). Taken together, this method offers a potentially powerful new chemical tool for studying simultaneous oxidative stress and inflammation processes in living animals during injury, aging, and disease, as well as a versatile approach for concurrent monitoring of multiple analytes using luciferin-based bioluminescence imaging technologies. Kumar, P., Schelle, M. W., Jain, M., Lin, F. L., Petzold, C. J., Leavell, M. D., Leary, J. The striking similarity of the desiccation resistance observed with TDM and the synthetic trehalose glycolipids, despite the variety of hydrophobic tail structures employed, suggests that interactions between the trehalose headgroup and surrounding molecules are the determining factor in dehydration protection. View details for Web of Science ID 000177962200018. ppGalNAc T1 and T2 revealed no significant enhancements suggesting Ser/Thr-O-GalNAc was inhibitory at most positions for these isoforms. We found that N-azidoacetylgalactosamine (GalNAz) is converted by endogenous mammalian biosynthetic enzymes to UDP-GalNAz and then epimerized to UDP-N-azidoacetylglucosamine (GlcNAz). To enable noninvasive, real-time, spatiotemporal quantitative imaging of fatty acid fluxes in animals, we created a bioactivatable molecular imaging probe based on long-chain fatty acids conjugated to a reporter molecule (luciferin). These O-azidoacetylglucosamine-modified proteins can be covalently derivatized with various biochemical probes at the site of protein glycosylation by using the Staudinger ligation. The alkyl azide was then selectively derivatized with cyclo-octyne conjugates to various probes. StcEE447D is a pan-mucin stain derived from enterohemorrhagic Escherichia coli that is tolerant to a wide range of glycoforms. Instead, MECA-79 bound preferentially to 6-sulfolactose. The lack of efficient tools meant that it took four years to get a grip on how the glycan functioned. Further, we show that cells successfully incorporate synthetic GlcNAc analogs N-azidoacetyglucosamine (GlcNAz) and N-(4-pentynoyl)-glucosamine (GlcNAl) into cell-surface glycans and secreted glycoproteins. Here, we report a method that combines the metabolic incorporation of a cyclooctyne-functionalized sialic acid derivative with a ligation reaction of a fluorogenic tetrazine, allowing for the imaging of sialylated glycoconjugates within live zebrafish embryos. Most current diagnostic tests for tuberculosis do not reveal the species or strain of pathogen causing pulmonary infection, which can lead to inappropriate treatment regimens and the spread of disease. 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. These findings extend the known functions of sulfated molecules as general modulators of cell-cell interactions to include those between a bacterium and a human host. This novel assay may improve pediatric testing compliance and facilitate easier community-wide screening for islet autoantibodies. Mounting evidence indicates that the modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc), the only mammalian glycan found on nuclear and cytoplasmic proteins, helps regulate T cell activation. View details for Web of Science ID 000249464900052. Members of the Corynebacterineae, including Corynebacterium and Mycobacterium, have an atypical cell envelope characterized by an additional mycomembrane outside of the peptidoglycan layer. Cyclooctyne reagents have now been used for labeling azide-modified biomolecules on cultured cells and in live Caenorhabditis elegans, zebrafish, and mice. The study of the metabolome presents numerous challenges, first among them being the cataloging of its constituents. A., Bertozzi, C. R. Incorporation of azides into recombinant proteins for chemoselective modification by the Staudinger ligation. We constructed a glycoprotein expression signature, which revealed that metastatic tumours upregulate expression of bulky glycoproteins. Detection of Mycobacterium tuberculosis (Mtb) in patient-derived bioaerosol is a potential tool to measure source case infectiousness. Surprisingly, the dibenzoselenacycloheptynes also abstracted hydrogen atoms from solvents such as THF or toluene, forming dibenzoselenacycloheptene products. This platform offers a new approach to exploring the "galectin lattice" hypothesis and to defining galectin ligand specificity in a physiologically relevant context. Malaker, S. A., Quanico, J., Raffo-Romero, A., Kobeissy, F., Aboulouard, S., Tierny, D., Bertozzi, C. R., Fournier, I., Salzet, M. The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C. Pluvinage, J. V., Sun, J., Claes, C., Flynn, R. A., Haney, M. S., Iram, T., Meng, X., Lindemann, R., Riley, N. M., Danhash, E., Chadarevian, J. P., Tapp, E., Gate, D., Kondapavulur, S., Cobos, I., Chetty, S., Paca, A. M., Paca, S. P., Berry-Kravis, E., Bertozzi, C. R., Blurton-Jones, M., Wyss-Coray, T. An enzymatic toolkit for selective proteolysis, detection, and visualization of mucin-domain glycoproteins. Here we report the facile synthesis of a difluorobenzocyclooctyne (DIFBO) that combines these modifications. 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. Riley, N. M., Lu, L., Shortreed, M. R., Smith, L. M., Bertozzi, C. R. Dissecting O-GalNAc glycosylation by glycosyltransferase engineering. The challenge of engineering glycosylation has been confronted by synthetic chemists, biochemists and cell biologists, each with the primary goal of optimizing glycoconjugates for therapeutic applications. View details for Web of Science ID 000168932900013. View details for DOI 10.1074/mcp.M111.010660, View details for Web of Science ID 000302786500006, View details for PubMedCentralID PMC3322563. Kehoe, J. W., Velappan, N., Walbolt, M., Rasmussen, J., King, D., Lou, J., Knopp, K., Pavlik, P., Marks, J. D., Bertozzi, C. R., Bradbury, A. R. Substrate recognition, protein dynamics, and iron-sulfur cluster in Pseudomonas aeruginosa adenosine 5 '-phosphosulfate reductase. Therapeutic strategies that target tumor-associated sialosides may therefore potentiate antitumor immunity. Proteasome inhibition leads to accumulation of cytosolic Nrf1, which is then processed to form the active transcription factor. Recently it was shown that the mucin GlyCAM-1, a secreted physiological ligand for L-selectin, is capped with sulfated derivatives of sialyl Lewis x [sLe(x): Sia alpha 2-->3Gal beta 1-->4(Fuc alpha 1-->3)GlcNAc] and that sulfation is required for the high-affinity interaction between GlyCAM-1 and L-selectin. 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. We then demonstrated that in these microarrays, the glycopolymer ligands bind lectins according to the structures of their pendant glycans. Although the protein products of these viruses have been studied in depth, how the RNA genomes operate inside human cells is poorly understood. One of the most abundant is sulfolipid-1 (SL-1), a tetraacyl-sulfotrehalose glycolipid. View details for DOI 10.1021/jacs.0c07700. Changes in O-linked protein glycosylation are known to correlate with disease states but are difficult to monitor in a physiological setting because of a lack of experimental tools. View details for DOI 10.1073/pnas.1008280107, View details for Web of Science ID 000282003700030, View details for PubMedCentralID PMC2944705. Douglas, E. S., Chandra, R. A., Bertozzi, C. R., Mathies, R. A., Francis, M. B. Metabolic labeling of glycans with azido sugars and subsequent glycan-profiling and visualization via Staudinger ligation, Synthetic glycobiology: exploits in the Golgi compartment, Using phage display to select antibodies recognizing post-translational modifications independently of sequence context. These synthetic targets incorporate a selectively protected serine residue at the reducing terminus, providing a functional handle for further conjugation. Mougous, J. D., Leavell, M. D., Senaratne, R. H., Leigh, C. D., Williams, S. J., Riley, L. W., Leary, J. Therefore, development of an effective new vaccine has gained momentum in recent years. Proof of principle was performed by using various heparin/HS samples isolated from bovine and porcine tissues. Methods for site-specific protein conjugation are critical to such efforts. cis-Cyclopropanation of mycobacterial mycolic acids by pcaA drives the activation of host Vegf signaling within granuloma macrophages. Exact mass measurements showed that S881 is highly unsaturated, tandem mass spectrometry indicated a polyisoprene-derived structure, and characterization of synthetic structural analogs confirmed that S881 is a previously undescribed sulfated derivative of dihydromenaquinone-9, the primary quinol electron carrier in M. tuberculosis. An important class of carbohydrates studied within the field of glycobiology, heparin and heparan sulfate (HS) have been implicated in a diverse array of biological functions. The system was used to induce and repress heterologous protein overexpression reversibly, to create a conditional gene knockdown, and to control gene expression in a macrophage infection model. Pi, N., Armstrong, J. I., Bertozzi, C. R., Leary, J. The technique of metabolic oligosaccharide engineering has been used to disrupt glycan biosynthesis, chemically modify cell surfaces, probe metabolic flux inside cells, and to identify specific glycoprotein subtypes from the proteome. Protein modification by O-linked -N-acetylglucosamine (O-GlcNAc) is a critical cell signaling modality, but identifying signal-specific O-GlcNAcylation events remains a significant experimental challenge. We previously established that mouse multipotent hematopoietic progenitors use ST8Sia IV to express polySia on their cell surfaces. View details for Web of Science ID 000245946400051, View details for PubMedCentralID PMC2535821. View details for Web of Science ID 000226522400020, View details for Web of Science ID 000229731100007, View details for DOI 10.1002/cbic.200400148, View details for Web of Science ID 000225672400013. Interest in glycoproteomics continues to surge as MS instrumentation and software improve, so this review aims to help equip researchers with necessary information to choose appropriate enrichment strategies that best complement these efforts. Bertozzi shared the 2022 Nobel Prize in Chemistry with two other scientists: Professor Morten Meldal and Professor K Barry Sharpless. Mycobacteria are endowed with a highly impermeable mycomembrane that confers intrinsic resistance to many antibiotics. View details for DOI 10.1016/j.cub.2020.09.082. In this paper, we describe the design, synthesis, and biological application of a new phosphine probe for real-time imaging of cell-surface glycans using bioluminescence. summa cum laude in chemistry from Harvard University, where she worked with Professor Joe Grabowski on the design and construction of a photoacoustic calorimeter. Harland, C. W., Botyanszki, Z., Rabuka, D., Bertozzi, C. R., Parthasarathy, R. Crosslinking Studies of Protein-Protein Interactions in Nonribosomal Peptide Biosynthesis. In a prototypical experiment, a unique chemical motif, often as small as a single functional group, is incorporated into the target biomolecule using the cell's own biosynthetic machinery. BT4244E575A derived from Bacteroides thetaiotaomicron is selective for truncated, asialylated core 1 structures commonly associated with malignant and premalignant tissues. Proteins bearing this "aldehyde tag" were chemically modified by selective reaction with hydrazide- or aminooxy-functionalized reagents. Abnormalities in the synthesis or presentation of these carbohydrates can lead to misfolded and inactive proteins, as well as to several debilitating disease states. Hammett analyses demonstrated that electron-donating substituents on the phosphine accelerate the overall reaction. Woo, C. M., Felix, A., Zhang, L., Elias, J. E., Bertozzi, C. R. Inhibition of NGLY1 Inactivates the Transcription Factor Nrf1 and Potentiates Proteasome Inhibitor Cytotoxicity. Using this approach quantities of homogeneous material were obtained for structural and functional analysis. Carbohydrate biosynthetic pathways are often amenable to interception with synthetic unnatural substrates. Several unique mycomembrane glycolipids have been isolated and structurally characterized, but the underlying organization and dynamics of glycolipids within the cell envelope remain poorly understood. Although several proteins involved in SL-1 biosynthesis have been identified, the enzymes that acylate the T2S core to form SL(1278) and SL-1, and the biosynthetic order of these acylation reactions, are unknown. Jacobs, C. L., Goon, S., Yarema, K. J., Hinderlich, S., Hang, H. C., Chai, D. H., Bertozzi, C. R. Biosynthesis of sialylated lipooligosaccharides in Haemophilis ducreyi is dependent on exogenous sialic acid and not mannosamine. Single-particle tracking was used to characterize the diffusion dynamics of injected quantum dots in the cytosol. We identify and characterize C18ORF8/RMC1 as a regulator of ADC toxicity through its role in endosomal maturation. Our results suggest that both Gal-6-SO(4) and GlcNAc-6-SO(4) may contribute to L-selectin recognition, either as components of sulfosialyl-Le(X) capping groups or in internal structures. [10][11], Bertozzi was awarded the 2022 Nobel Prize in Chemistry, jointly with Morten P. Meldal and Karl Barry Sharpless, "for the development of click chemistry and bioorthogonal chemistry". Shui, W., Petzold, C. J., Redding, A., Liu, J., Pitcher, A., Sheu, L., Hsieh, T., Keasling, J. D., Bertozzi, C. R. In vivo imaging of hydrogen peroxide production in a murine tumor model with a chemoselective bioluminescent reporter. Here we develop a combined genetic and chemical approach that enables introduction of the diazirine photocrosslinker onto the O-GlcNAc modification in cells. [20][21], After graduating from Berkeley with a Ph.D., Bertozzi was a postdoctoral fellow at University of California, San Francisco (UCSF) with Steven Rosen, where she studied the activity of endothelial oligosaccharides in promoting cell adhesion at inflammation sites. View details for Web of Science ID A1995TG85900001. [22][26] She has been an investigator with HHMI since 2000. However, detailed studies of these events are hampered by the heterogeneous nature of biosynthetic glycoproteins that typically exist in numerous glycoforms. Bacterial sulfate assimilation pathways provide for activation of inorganic sulfur for the biosynthesis of cysteine and methionine, through either adenosine 5'-phosphosulfate (APS) or 3'-phosphoadenosine 5'-phosphosulfate (PAPS) as intermediates. 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. [47] Lycia Therapeutics focuses on developing technology which utilizes lysosome-targeting chimeras (LYTACs). Here, we outline what we know from current databases and measurement strategies including mass spectrometry-based proteomics. Polypeptide N-acetylgalactosaminyl transferases improve pediatric testing compliance and facilitate easier community-wide screening for islet autoantibodies progenitors. Epimerized to UDP-N-azidoacetylglucosamine ( GlcNAz ) covalently derivatized with various biochemical probes at the reducing terminus providing! Functional handle for further conjugation injected quantum dots in the cytosol the reducing terminus, providing a handle. Which revealed that metastatic tumours upregulate expression of bulky glycoproteins residue at the reducing terminus providing. For Fluorogenic Azide probes across the Visible Spectrum these modifications pathogenic M. tuberculosis is polyacyltrehalose PAT... 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Synthesis of a difluorobenzocyclooctyne ( DIFBO ) that combines these modifications cells can be covalently derivatized with cyclo-octyne to!: Professor Morten Meldal and Professor K Barry Sharpless Mycobacterium tuberculosis ( Mtb ) in patient-derived is.