View details for PubMedCentralID PMC5842139. The article will highlight recent approaches to thesynthesis of glycopeptide fragments bearing complex O-linkedglycans, as well as new strategies for the generation of full-lengthglycoproteins. We report the cloning, expression, and characterization of the first UDP-GalNAc:polypetide N-acetylgalactosaminyltransferase (ppGalNAc-T) from the human disease-causing parasite, Toxoplasma gondii. View details for DOI 10.1021/jacs.6b12541, View details for PubMedCentralID PMC5345120. Isotopic recoding is achieved via metabolic incorporation of a defined mixture of N-acetylglucosamine isotopologs into N-glycans. Penetration of cell membranes with this "nanoneedle" was controlled by the AFM. In addition, the general assay architecture should be readily applicable to high-throughput screens of other carbohydrate sulfotransferases. View details for DOI 10.1111/j.1365-2958.2006.05075.x, View details for Web of Science ID 000235842600009. Z. Multi-omics analysis of spatially distinct stromal cells reveals tumor-induced O-glycosylation of the CDK4-pRB axis in fibroblasts at the invasive tumor edge. Robinson, P. V., de Almeida-Escobedo, G., de Groot, A. E., McKechnie, J. L., Bertozzi, C. R. Chemical Lectinology: Tools for Probing the Ligands and Dynamics of Mammalian Lectins InVivo. 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). Immunization of mice with either BCG or DeltacysH followed by infection with the virulent M. tuberculosis Erdman strain demonstrated that DeltacysH can generate protection equivalent to that of the BCG vaccine. Laughlin, S. T., Agard, N. J., Baskin, J. M., Carrico, I. S., Chang, P. V., Ganguli, A. S., Hangauer, M. J., Lo, A., Prescher, J. Marschallinger, J., Iram, T., Zardeneta, M., Lee, S. E., Lehallier, B., Haney, M. S., Pluvinage, J. V., Mathur, V., Hahn, O., Morgens, D. W., Kim, J., Tevini, J., Felder, T. K., Wolinski, H., Bertozzi, C. R., Bassik, M. C., Aigner, L., Wyss-Coray, T. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Because the parameters which govern this effect are well understood and are amenable to chemical modification, this knowledge may enable the rational development of more effective antibiotics against tuberculosis. The efficacy of antimicrobial drugs against Mycobacterium tuberculosis, an intracellular bacterial pathogen, is generally first established by testing compounds against bacteria in axenic culture. We report here a study of mycomembrane dynamics that was enabled by trehalose-fluorophore conjugates capable of labeling trehalose glycolipids in live actinomycetes. Genome-scale knockout screens assigned putative functional relevance to the RNA-protein interactions observed by ChIRP-MS. Sequestration of peptides derived from an Escherichia coli proteome, pulse labeled with the bio-orthogonal amino acid azidohomoalanine as substitute for methionine, allows identification of numerous newly synthesized proteins. View details for Web of Science ID 000435537701267. Exhaled air and bioaerosol volumes were estimated using continuous CO2 monitoring and airborne particle counting, respectively. The sulfotransferases that generate specific carbohydrate 'sulfoforms' have recently been recognized as key modulators of these processes and therefore represent potential therapeutic targets. The Nobel Prize in Chemistry 2022. 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. These approaches have already identified several cancer biomarkers. Cell surface lipooligosaccharides (LOS) of H. ducreyi are thought to play important biological roles in host infection. A., Cheng, E. H., Bertozzi, C. R., Boyce, M. Modulation of Ocular Surface Glycocalyx Barrier Function by a Galectin-3 N-terminal Deletion Mutant and Membrane-Anchored Synthetic Glycopolymers. Mycobacterium tuberculosis ( Mtb) produces a number of sulfur-containing metabolites that contribute to its pathogenesis and ability to survive in the host. 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. Our results show that, like palmitate, incorporation of azido-palmitate occurred on mitochondrial proteins via thioester bonds at sites that could be competed out by palmitoyl-CoA. Similarly, the ability to perceive the spatial organization of glycans could transform our understanding of their role in development, infection, and disease progression. Remodeling the sialylation status of cancer cells affected the susceptibility to NK cell cytotoxicity via Siglec-7 engagement in a variety of tumor types. Despite proven disease relevance, correlating the activity of individual GalNAc-Ts with biological function remains challenging due to a lack of tools to probe their substrate specificity in a complex biological environment. Our findings indicate that glycan valency can set thresholds for cross-linking by lectins. View details for DOI 10.1074/jbc.M212127200, View details for Web of Science ID 000181466800038, View details for Web of Science ID 000181517000014. The competitive inhibitors 2-bromopalmitate and 2-hydroxymyristate prevented incorporation of omega-alkynyl-palmitate and omega-alkynyl-myristate into palmitoylated and myristoylated proteins, respectively. A., Bertozzi, C. R. Site-specific chemical protein conjugation using genetically encoded aldehyde tags. Here, we show that increasing sialylated glycans on cancer cells inhibits human natural killer (NK) cell activation through the recruitment of sialic acid-binding immunoglobulin-like lectin 7 (Siglec-7). 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. Imbert, P. R., Saric, A. n., Pedram, K. n., Bertozzi, C. R., Grinstein, S. n., Freeman, S. A. Electron-Based Dissociation Is Needed for O-Glycopeptides Derived from OpeRATOR Proteolysis. We synthesized a 1338 member library of uridine analogs directed to the epimerase by virtue of substrate mimicry. View details for Web of Science ID 000249464900052. Tumors which remodel their glycocalyces, by overexpressing bulky glycoproteins like mucins, exhibit a higher predisposition to metastasize, but the role of mucins in oncogenesis remains poorly understood. View details for DOI 10.1073/pnas.1012864107, View details for Web of Science ID 000285521500020, View details for PubMedCentralID PMC3003011. WebCarolyn R. Bertozzi, in full Carolyn Ruth Bertozzi, (born October 10, 1966, Boston, Massachusetts), American chemist known for her application of chemical synthesis to the study of biological systems. View details for DOI 10.1073/pnas.0437851100, View details for Web of Science ID 000181675200023, View details for PubMedCentralID PMC152251. 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. Utilizing a biotin-terminated PAH scaffold prepared via RAFT polymerization, we quickly assembled a panel of glycopolymers that we microarrayed on streptavidin-coated glass. We tested this prediction by investigating whether bulky glycoproteins in the glycocalyx promote a tumour phenotype in human cells by increasing integrin adhesion and signalling. Ngo, J. T., Adams, S. R., Deerinck, T. J., Boassa, D., Rodriguez-Rivera, F., Palida, S. F., Bertozzi, C. R., Ellisman, M. H., Tsien, R. Y. Using azide-modified molecular precursors of sialic acids and copper-free click chemistry, we visualized the spatiotemporal dynamics of the sialome in live zebrafish embryos. Here we describe a strategy for exploiting trehalose metabolic pathways to label glycolipids in mycobacteria with azide-modified trehalose (TreAz) analogues. A combination of quantitative microscopy, mutational analysis, and interaction studies indicate that SteA and SteB form a complex that localizes to the cytokinetic ring to promote cell separation by RipC-FtsEX and may coordinate its PG remodeling activity with the biogenesis of other envelope layers during cell division. Similar FRAP profiles were observed in granules that remained in the cells after the addition of a mucin secretagogue. Though not directly subject to mutation, we can determine glycan structure-function relationships by synthesizing defined glycoconjugates or by altering natural glycosylation pathways. Van de Bittner, G. C., Dubikovskaya, E. A., Bertozzi, C. R., Chang, C. J. We investigated how the major phosphatase CD45 is excluded from contact sites, using single-molecule tracking. These studies yield insight into the biosynthesis and dynamics of glycans in the enveloping layer during embryogenesis and provide a platform for imaging other biomolecular targets by microinjection of appropriately functionalized biosynthetic precursors. The properties of therapeutic proteins can be enhanced by chemical modification. In this study, we developed a crosslinking assay, utilizing bioorthogonal probes compatible with carrier protein modification, for probing the protein interactions between COM domains of NRPS enzymes. In this work, we apply an aluminum "lift off" lithography method to allow the efficient generation of complex patterns comprising different DNA sequences. [85] Her father was of Italian descent. View details for Web of Science ID 000256043200016, View details for PubMedCentralID PMC2711008. However, the lack of chemical tools to study mucin-type O-linked glycosylation has hindered our molecular understanding of O-linked glycans in many biological contexts. Many cellular activities are controlled by post-translational modifications, the study of which is hampered by the lack of specific reagents due in large part to their ubiquitous and non-immunogenic nature. 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. View details for Web of Science ID A1994PH46500004. The rapid assembly of "core 1"and "core 3" O-linked glycopeptide mimetics was accomplished in this fashion. We also show that the integral membrane protein Sap and MmpL8 are both essential for sulfolipid transport. General overview of non-natural amino acid incorporation into a protein.a) Difference between normal translation (1), translation in the absence of nnAA (2) and when nnAA is supplied (3).b) The orthogonal tRNA can only work with the orthogonal aminoacyl-tRNA (aaRS) synthetase and the engineered tRNA with the engineered aaRS. We describe here a screening procedure for the identification of new aminoacyl-tRNA synthetase activity based on the cell surface display of noncanonical amino acids. Vocadlo, D. J., Hang, H. C., Kim, E. J., Hanover, J. Yap, M. C., Kostiuk, M. A., Martin, D. D., Perinpanayagam, M. A., Hak, P. G., Siddam, A., Majjigapu, J. R., Rajaiah, G., Keller, B. O., Prescher, J. 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. We demonstrated the method by constructing site-specifically glycosylated variants of the human growth hormone. Baskin, J. M., Dehnert, K. W., Laughlin, S. T., Amacher, S. L., Bertozzi, C. R. Rapid and selective detection of fatty acylated proteins using omega-alkynyl-fatty acids and click chemistry. View details for DOI 10.1038/nchembio0605-13, View details for Web of Science ID 000232621100006. One of the more remarkable lipids is a sulfated glycolipid, termed sulfolipid-1 (SL-1), which is thought to mediate specific host-pathogen interactions during infection. View details for Web of Science ID 000166039500060, View details for Web of Science ID 000165485300014. Thus, the protein-carbohydrate interactions, as well as other interactions contributing to ligand recognition, can be investigated. Delaveris, C. S., Chiu, S. H., Riley, N. M., Bertozzi, C. R. The clinical impact of glycobiology: targeting selectins, Siglecs and mammalian glycans. Finally, we engineered the Golgi-resident glycosyltransferase FucT7 for tunable control by Tmp-SLF in mammalian cells. The d-alanine analogues were specifically incorporated into nascent PG of the intracellular pathogen Listeria monocytogenes both in vitro and during macrophage infection. Malaker, S. A., Quanico, J., Romero, A. R., Pascal, Q., Kobeissy, F., Abou-louard, S., Tierny, D., Bertozzi, C. R., Fornier, I., Salzet, M. O-Pair Search with MetaMorpheus for O-glycopeptide Characterization. Cioce, A., Bineva-Todd, G., Agbay, A. J., Choi, J., Wood, T. M., Debets, M. F., Browne, W. M., Douglas, H. L., Roustan, C., Tastan, O. Y., Kjaer, S., Bush, J. T., Bertozzi, C. R., Schumann, B. LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. The assay proceeds by transfer of 35S-labeled sulfate from [35S]-3(')-phosphoadenosine-5(')-phosphosulfate (PAPS) to the free amino groups of de-N-sulfated heparin (NDST-1), or the 6-hydroxyl groups of N-acetylglucosamine residues linked to a polyacrylamide scaffold (HEC-GlcNAc-6-ST). WebCarolyn R. Bertozzi. The concise synthesis of a coumarin-conjugated cyclooctyne, coumBARAC, that undergoes a 10-fold enhancement in fluorescence quantum yield upon triazole formation with organic azides is reported. Our observations are the first reported instance of dehydration resistance provided by a membrane glycolipid. Jolly, A. L., Agarwal, P., Metruccio, M. M., Spiciarich, D. R., Evans, D. J., Bertozzi, C. R., Fleiszig, S. M. Visualization of mycobacterial membrane dynamics in live cells. Collectively, these results indicate that the stem region of GlcNAc6ST-1 influences substrate specificity, independent of its role in dimerization or Golgi retention. All three selectins recognize sulfated and sialylated derivatives of the Lewis x [Le(x):Gal beta 1-->4(Fuc alpha 1-->3)GlcNAc] and Lewis a [Le(a): Gal beta 1-->3(Fuc alpha 1-->4)GlcNAc] trisaccharide cores with affinities in the millimolar range, and it is believed that variants of these structures are the carbohydrate determinants of selectin recognition. Zhou, M. N., Delaveris, C. S., Kramer, J. R., Kenkel, J. Growth hormone chemical protein conjugation using genetically encoded aldehyde tags that contribute to pathogenesis. To study mucin-type O-linked glycosylation has hindered our molecular understanding of O-linked glycans in many contexts. In dimerization or Golgi retention competitive inhibitors 2-bromopalmitate and 2-hydroxymyristate prevented incorporation of defined! 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