A., Bertozzi, C. R., Marahiel, M. A., Burkart, M. D. Uridine-Based Inhibitors as New Leads for Antibiotics Targeting Escherichia coli LpxC. Godula, K., Rabuka, D., Nam, K. T., Bertozzi, C. R. Metabolic Labeling of Sialic Acids in Living Animals with Alkynyl Sugars. They comprised glycopolypeptides bearing mono-, di-, and trisaccharides and were built through polymerization of glycosylated N-carboxyanhydrides. 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. View details for DOI 10.1074/jbc.M510520200, View details for Web of Science ID 000235426200035. The synthetic trehalose glycolipids protected supported monolayers of phospholipids against dehydration even as minority components of the overall membrane, down to as little as 20 mol % trehalose glycolipid as assessed by assays of membrane fluidity. View details for DOI 10.1016/j.carres.2007.05.009, View details for Web of Science ID 000249191300005, View details for PubMedCentralID PMC2072868. In previous studies, mannosamine analogues bearing simple N-acyl groups up to five carbon atoms in length were recognized as substrates by the biosynthetic machinery and transformed into cell surface sialoglycoconjugates [Keppler, O. T., et al. The assay was developed and validated in 7 distinct cohorts (n = 858) with the majority of the cohorts blinded prior to analysis. The cognate ligands for L-selectin possess the unusual sulfated tetrasaccharide epitope 6-sulfo sialyl Lewis x (Siaalpha2-->3Galbeta1-->4[Fucalpha1-->3][SO(3)-->6]GlcNAc). Fine-tuning of glycan biosynthetic pathways is further accomplished by specific associations among glycosyltransferases. 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. B., Shieh, P., Metruccio, M. E., Evans, D. J., Bertozzi, C. R., Fleiszig, S. J. The Staudinger ligation is highly selective and reliably forms its product in environs as demanding as live mice. A convergent synthesis of trehalose. This assay revealed that mycobacterial strains have distinct sulfatase fingerprints that can be used to judge both the species and lineage. Bertozzi received a bachelors degree in chemistry from Harvard University in 1988 and a doctorate in the same subject from the University of California, Berkeley in 1993. There is growing interest in extending this progress to O-glycoproteomics, which necessitates comparisons of method performance for the two classes of glycopeptides. Quantitation of metabolic intermediates suggested that cellular metabolism is limited by the phosphorylation of the N-acylmannosamines by ManNAc 6-kinase in the first step of the pathway. Hatzios, S. K., Baer, C. E., Rustad, T. R., Siegrist, M. S., Pang, J. M., Ortega, C., Alber, T., Grundner, C., Sherman, D. R., Bertozzi, C. R. Imaging the Glycosylation State of Cell Surface Glycoproteins by Two-Photon Fluorescence Lifetime Imaging Microscopy. We determined the crystal structure of the apo Rv3406 sulfatase at 2.5 . This review highlights the development of bioorthogonal chemical reporters and reactions and their application in living systems. Shin, S., Comolli, L. R., Tscheliessnig, R., Wang, C., Ki Tae Nam, K. T., Hexemer, A., Siegerist, C. E., De Yoreo, J. J., Bertozzi, C. R. D-Amino Acid Chemical Reporters Reveal Peptidoglycan Dynamics of an Intracellular Pathogen. Once released, HCBT and D-cysteine form firefly luciferin in situ, giving rise to a bioluminescent signal if and only if both chemical triggers proceed. Here we report that a truncated S-layer protein assembles into stable bilayers, which we characterized using cryogenic-electron microscopy, tomography, and X-ray spectroscopy. These findings suggest a dual role for trehalose as both a thermoprotectant and a precursor of critical cell wall metabolites. View details for DOI 10.1128/AAC.47.1.378-382.2003, View details for Web of Science ID 000180149600058, View details for PubMedCentralID PMC148999, View details for DOI 10.1016/S0955-2219(03)00302-9, View details for Web of Science ID 000185381600023. The lipooligosaccharides (LOS) of Haemophilus ducreyi are highly sialylated, a modification that has been implicated in resistance to host defense and in virulence. Molecular imaging with chemical reporters offers a new avenue for probing changes in the glycome that accompany development and disease. 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. [19][39] Redwood Bioscience was acquired by Catalent Pharma Solutions in 2014. Here we present a strain-promoted [3 + 2] cycloaddition between cyclooctynes and azides that proceeds under physiological conditions without the need for a catalyst. This was confirmed by enzymatic assay of the partially purified enzyme with unnatural substrates. Cell surface trehalose mycolates are important modulators of mycobacterial pathogenesis and host immune response. The expanding integrin wave facilitates the zippering of Fc receptors onto the target and integrates the information from sparse receptor-ligand complexes, coordinating the progression and ultimate closure of the phagocytic cup. Mycobacteria, including persistent pathogens like Mycobacterium tuberculosis, have an unusual membrane structure in which, outside the plasma membrane, a nonfluid hydrophobic fatty acid layer supports a fluid monolayer rich in glycolipids such as trehalose 6,6'-dimycolate (TDM; cord factor). Barnes, J., Kaushik, S., Bainer, R. O., Sa, J. K., Woods, E. C., Kai, F., Przybyla, L., Lee, M., Lee, H., Tung, J. C., Maller, O., Barrett, A. S., Lu, K. V., Lakins, J. N., Hansen, K. C., Obernier, K., Alvarez-Buylla, A., Bergers, G., Phillips, J. J., Nam, D., Bertozzi, C. R., Weaver, V. M. Glycosyltransferase bump-hole engineering to dissect mucin-type O-glycosylation in the living cell. As this special issue testifies, the field of bioorthogonal chemistry is firmly established as a challenging frontier of reaction methodology and an important new instrument for biological discovery. Therefore, development of an effective new vaccine has gained momentum in recent years. Genome-scale knockout screens assigned putative functional relevance to the RNA-protein interactions observed by ChIRP-MS. Siegrist, M. S., Whiteside, S., Jewett, J. C., Aditham, A., Cava, F., Bertozzi, C. R. Strategy for Dual-Analyte Luciferin Imaging: In Vivo Bioluminescence Detection of Hydrogen Peroxide and Caspase Activity in a Murine Model of Acute Inflammation. Thus, subtle structural differences in PSA resulting from the incorporation of SiaProp residues do not alter the antiadhesive properties of polysialylated NCAM. Chemically tunable mucin chimeras assembled on living cells. N-butanoylmannosamine blocked polysialylation of NCAM and significantly reduced neurite outgrowth comparable with enzymatic removal of PSA by endoneuraminidases. At elevated temperatures, however, the mutant was unable to proliferate even in the presence of trehalose. The chemical reporter is then covalently modified in a highly selective fashion with an exogenously delivered probe. https://www.britannica.com/biography/Carolyn-R-Bertozzi. The compound was metabolized to the azidosialic acid and incorporated into cell surface and secreted sialoglycoproteins. Both sceHCD and EThcD have been used with success in large-scale glycoproteomic experiments, but they each incur some degree of compromise. We report a non-destructive biochemical technique, termed "Glyco-seek", for analysis of O-GlcNAcylated proteins. Chen, X., Wu, P., Rousseas, M., Okawa, D., Gartner, Z., Zettl, A., Bertozzi, C. R. DNA-barcode directed capture and electrochemical metabolic analysis of single mammalian cells on a microelectrode array. This system thus constitutes an AND-type molecular logic gate that reports on the simultaneous presence of H(2)O(2) and caspase 8 activity. Most cell membrane proteins are known or predicted to be glycosylated in eukaryotic organisms, where surface glycans are essential in many biological processes including cell development and differentiation. IsoTaG is therefore an effective platform for identification of intact glycopeptides labeled by alkynyl or azido sugars and will facilitate further studies of the glycoproteome. By contrast, most bacteria use trehalose solely as a general osmoprotectant or thermoprotectant. The combination of novel biochemical and metabolism-based approaches with emerging genomic methods promises to accelerate efforts to understand glycosylation. Irradiation of cells with UV light activated the crosslinker, resulting in formation of covalent bonds between O-GlcNAc-modified proteins and neighboring molecules, which could be identified by mass spectrometry. Multiple Ygp1 N-glycosylation sites bearing GlcNAc, isotopically labeled GlcNAc, or GlcNAz were identified; these modifications were dependent on the supplement added to the culture medium. We conclude that Rv3406 is an iron and -ketoglutarate-dependent sulfate ester dioxygenase that has unique substrate specificity that is likely distinct from other Mtb sulfatases. A detailed investigation of enzyme kinetics and specificities revealed the robustness of the approach to faithfully report on GalNAc-T activity and paves the way for studying substrate specificities in living systems. Thus the transient state exhibits the characteristics of a kinetic trap in a folding funnel. These findings functionally link mucinous proteins with tumor aggression, and offer a new view of the cancer glycocalyx as a major driver of disease progression. Rabuka, D., Rush, J. S., dehart, G. W., Wu, P., Bertozzi, C. R. Cellular Microfabrication: Observing Intercellular Interactions Using Lithographically-Defined DNA Capture Sequences. View details for DOI 10.1002/anie.200805756, View details for Web of Science ID 000267713800017, View details for PubMedCentralID PMC2735190. The machinery responsible for sulfatase activation is poorly understood in prokaryotes. Their diffusion properties mirrored those of many natural membrane-associated biomolecules. The staggering complexity of glycans renders their analysis extraordinarily difficult, particularly in living systems. Antigen presentation to Tcells in major histocompatibility complex class II (MHC class II) requires the conversion of early endo/phagosomes into lysosomes by a process called maturation. [31], Bertozzi studies the glycobiology of underlying diseases such as cancer, inflammatory disorders such as arthritis, and infectious diseases such as tuberculosis. 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. Ketones within the glycoconjugates on ManLev-treated cells were then reacted with synthetic aminooxy and hydrazide-functionalized carbohydrates. Wei, W., Riley, N. M., Yang, A. C., Kim, J. T., Terrell, S. M., Li, V. L., Garcia-Contreras, M., Bertozzi, C. R., Long, J. Oligosaccharides play a crucial role in many of the recognition, signaling, and adhesion events that take place at the surface of cells. The exquisite chemical selectivity required of this process is supplied by the Staudinger ligation of azides and phosphines, a reaction that has been performed on cultured cells without detriment to their physiology. During Bertozzi's third year of graduate school, Bednarski was diagnosed with colon cancer, which resulted in him taking a leave of absence and changing his career path by enrolling in medical school. Kostiuk, M. A., Corvi, M. M., Keller, B. O., Plummer, G., Prescher, J. Human and Baculovirus-Insect Manufacturing Platforms Generate Chemically and Functionally Distinct AAV Vectors with Sexually Dimorphic Liver Transduction. Our goal with this survey is to provide a foundation on which continued technological advancements can be made to promote further explorations of protein glycosylation. In addition, GalNAz efficiently labeled mucin-type O-linked glycoproteins expressed at endogenous levels. Characterizing their peptide and glycopeptide substrate specificity is critical for understanding the biological role and significance of each isoform. The glycosylation reaction afforded the desired isomer exclusively and in good yield. Together with determining their shedding and turnover rates, we also report that several membrane proteins, including TS and its substrates, both glycosylphosphatidylinositol-anchored proteins, are separately distributed on parasite surface and contained in different and highly stable membrane microdomains. Here we applied the bioorthogonal chemical reporter technique for the molecular imaging of mucin-type O-glycans in live C. elegans. Shieh, P., Hangauer, M. J., Bertozzi, C. R. Probing the Mycobacterial Trehalome with Bioorthogonal Chemistry. Luchansky, S. J., Goon, S., Bertozzi, C. R. Small molecule inhibitors of mucin-type O-linked glycosylation from a uridine-based library. View details for Web of Science ID 000171204900005. P. aeruginosa APS reductase contains an [4Fe-4S] cluster that is essential for catalysis. Professor Carolyn Bertozzi won the 2022 Nobel Prize in Chemistry for a technique she developed to look at tiny strands of sugar on the surface of our cells. Herein we analyzed the glycopeptide substrate preferences of several ppGalNAcT family members using a library screening approach. View details for DOI 10.1073/pnas.1608069113. Chemical biotinylation followed by enrichment and mass spectrometry led to the identification of glycoproteins that were found at elevated levels or uniquely in cancerous prostate tissue. The quantitative changes in phagosomal proteins suggested a distinct role for mannose-capped LAM in modulating protein trafficking pathways that contribute to the arrest of phagosome maturation. The trend noted with solvent polarity is different and more revealing than that determined by the more classical approach of examining either the wavelength of the emission maximum or the fluorescence quantum yield. We engineered tumor cells to display glycocalyces of various thicknesses by coating them with synthetic mucin-mimetic glycopolymers. We demonstrate binding of all three selectins to GlyCAM-1 and demonstrate that the binding interactions satisfy a number of important criteria. View details for DOI 10.1016/j.cbpa.2003.08.006, View details for Web of Science ID 000186448100015. Surprisingly, corneas from MyD88-/- mice displayed similar GalNAz labeling to wild-type corneas, but labeling was reduced and patchy on IL-1 receptor (IL-1R)-knockout mouse corneas (P < 0.05, ANOVA). Alternatively, selective inhibition or activation of glycosyltransferases or glycosidases can define the biological roles of the corresponding glycans. A FRET-based fluorogenic phosphine for live-cell Imaging with the Staudinger ligation, DNA-Coated AFM Cantilevers for the Investigation of Cell Adhesion and the Patterning of Live Cells. 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. Polydiacetylene-based systems are attractive for sensing applications due to their colorimetric response to changes in the local environment. We were able to bypass the salvage pathway by using an azide-functionalized analogue of GDP-fucose. We find that monomers with an extended conformation first form a mobile adsorbed phase, from which they condense into amorphous clusters. 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. These tools have identified potential disease biomarkers and ways to monitor dynamic changes to the glycome in living organisms. We used this technique to image fucosylated glycans in the enveloping layer of zebrafish embryos during the first 5 days of development. We demonstrate, in vitro, that each enzyme in the hexosamine salvage pathway, and the enzymes that affect this dynamic modification (UDP-GlcNAc:polypeptidtyltransferase and O-GlcNAcase), tolerate analogues of their natural substrates in which the N-acyl side chain has been modified to bear a bio-orthogonal azide moiety. To overcome this barrier, we developed an artificial receptor based on expression of a novel sugar. View details for DOI 10.1074/jbc.M111.315473, View details for Web of Science ID 000301349400015. A., Bertozzi, C. R. Synthesis of mono- and dideoxygenated alpha,alpha-trehalose analogs. View details for Web of Science ID 000257629200046, View details for PubMedCentralID PMC2664610. 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. The ability to generate chemically defined analogues of GPI-anchored proteins is an important step toward elucidating the molecular functions of this interesting post-translational modification. The approach exploits the requirement of Golgi localization, a common feature of glycosyltransferase superfamily members. O-Linked -N-acetylgalactosamine (O-GalNAc) glycans constitute a major part of the human glycome. Pratt, M. R., Hang, H. C., Ten Hagen, K. G., Rarick, J., Gerken, T. A., Tabak, L. A., Bertozzi, C. R. Expanding the diversity of unnatural cell-surface sialic acids. The conjugation proceeds under mild conditions with excellent ligation efficiencies and in a stereoselective manner, providing glycopolymers with pendant glycans accommodated mostly in their cyclic beta-glycosidic form. A., Bertozzi, C. R. Cell type-selective secretome profiling in vivo. These values and the mathematical model confirm that chemoselective reactions on the cell surface can deliver to cells similar numbers of molecules as antibodies. View details for DOI 10.1073/pnas.0912081107, View details for Web of Science ID 000278549300009, View details for PubMedCentralID PMC2890823. Chemical tools have accelerated progress in glycoscience, reducing experimental barriers to studying protein glycosylation, the most widespread and complex form of posttranslational modification. The ketone group within the levulinoyl side chain of SiaLev was then used as a chemical handle for detection using a biotin probe. This system provides a unique framework with which to study the behavior of mucin-like macromolecules in a controlled, cell surface-mimetic environment. The objective of these methods is to make glycoconjugate synthesis accessible to a broader community, thereby accelerating progress in glycobiology. 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. Therefore, shedding of TS occurs via microvesicles instead of as a fully soluble form. Tsai, C., Robinson, P. V., Cortez, F., Elma, M. B., Seftel, D., Pourmandi, N., Pandori, M. W., Bertozzi, C. R. Quantitative Super-Resolution Imaging Reveals Mammalian Glycocalyx Dynamics. A., Bertozzi, C. R. Global gene expression of cells attached to a tissue engineering scaffold, Directing flux in glycan biosynthetic pathways with a small molecule switch. Growth then proceeds by formation of new tetramers exclusively at cluster edges, implying tetramer formation is autocatalytic. Here we demonstrate that the Staudinger ligation can be executed in living animals, enabling the chemical modification of cells within their native environment. Since PSA is important in neural plasticity and development, this mechanism for modulating PSA structure might be useful for functional studies. Corrections? From a total of 1286 proteins identified, 463 were discovered by both isotope-labeling strategies at a high consistency, and the rest of proteins were detected by only one of the two approaches. View details for DOI 10.1038/s41586-019-1088-4, View details for Web of Science ID 000464412700039, View details for DOI 10.1073/pnas.1813020116, View details for Web of Science ID 000463936900024. Senaratne, R. H., De Silva, A. D., Williams, S. J., Mougous, J. D., Reader, J. R., Zhang, T. J., Chan, S., Sidders, B., Lee, D. H., Chan, J., Bertozzi, C. R., Riley, L. W. Mucin granule intraluminal organization in living mucous/goblet cells - Roles of protein post-translational modifications and secretion. Finally, the Delta papA2 and Delta papA1 mutants were screened for virulence defects in a mouse model of infection. 2023 Chuan He Hiroaki Suga Jeffery W. Kelly Isotopic recoding is achieved via metabolic incorporation of a defined mixture of N-acetylglucosamine isotopologs into N-glycans. IsoTaG is therefore positioned to enhance structural understanding of the glycoproteome. Furthermore, ADAP correctly identified 95% high-risk individuals with two or more autoantibodies by radioassay amongst 39 relatives of T1D patients tested. Current imaging techniques often detect only a single biochemical process, but, within whole organisms, multiple types of biochemical events contribute to physiological and pathological phenotypes. DMN-Tre labeling was detected within minutes and was inhibited by heat killing of mycobacteria. Despite their importance, few N-glycosites have been experimentally mapped in the Saccharomyces cerevisiae proteome. The structurally uniform alkyne-terminated mucin mimetic glycopolymers (see picture; TR = fluorophore) were printed on azide-functionalized chips by microcontact printing in the presence of a copper catalyst. This approach can highlight changes in physiology or environment and may be more informative than steady-state analyses. Hur, G. H., Meier, J. L., Baskin, J., Codelli, J. Diptericin increased the permeability of the outer and inner membranes of Escherichia coli D22 cells, suggesting possible mechanisms of action. 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. Pathogenic bacteria have developed numerous mechanisms to survive inside a hostile host environment. Here, we report that metabolic cross-talk between the N-acetylgalactosamine salvage and O-GlcNAcylation pathways can be exploited for the tagging and identification of O-GlcNAcylated proteins. Mass spectrometry revealed that the N610 residue is part of a consensus N-linked glycosylation motif in the receptor, usually linked to complex glycans. View details for Web of Science ID 000222930600016. This structure suggests a molecular mechanism by which conserved G domain architecture is used to energetically link GTP turnover to the production of an essential metabolite. Doi 10.1016/j.carres.2007.05.009, View details for PubMedCentralID PMC2735190 osmoprotectant or thermoprotectant, usually linked to complex glycans understand.! Bacteria have developed numerous mechanisms to survive inside a hostile host environment efficiently labeled mucin-type glycoproteins. Catalent Pharma Solutions in 2014 barrier, we developed an artificial receptor on! 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