We establish that the copper atom is coordinated by two active-site cysteine residues in a nearly linear geometry, supporting and extending prior biochemical and structural data. View details for DOI 10.1099/jmm.0.46983-0, View details for Web of Science ID 000245795600002. A., Kalscheuer, R., Bertozzi, C. R. Density Variant Glycan Microarray for Evaluating Cross-Linking of Mucin-like Glycoconjugates by Lectins, Direct observation of kinetic traps associated with structural transformations leading to multiple pathways of S-layer assembly. The surface-bound glycopolymers bind lectins in a ligand-specific manner. Screening of the library identified an inhibitor with a K(i) value of 11 microM. Clinical studies revealed that large glycoproteins are abundantly expressed on circulating tumour cells from patients with advanced disease. 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. Most identified proteins were involved in mechanisms of cellular metabolic functions, post-translational modifications, and some have been reported to be implicated in EOC etiology. She later refined the approach to improve its utility in cellular environments, facilitating research into interactions between biomolecules and into disease processes. The mammalian glycocalyx is a heavily glycosylated extramembrane compartment found on nearly every cell. LC-MS/MS mass spectrometry analysis was then performed and the processed data related to the identified glycoproteins show that several hundred proteins are differentially expressed between control and GALNT3 KD A2780s cells. However, the resulting C=N linkages are susceptible to hydrolysis under physiologically relevant conditions, which limits the utility of such conjugates in biological systems. Mutants with defects in sulfate assimilation indicate that the fate of sulfur in M. tb is a critical survival determinant for the bacteria during infection and suggest novel targets for tuberculosis drug therapy. We report that mycobacteria and other corynebacteria can be specifically detected with a fluorogenic trehalose analog. Bisphenol A (BPA) is a widely used plasticizer whose estrogenic properties may impact hormone-responsive disorders and fetal development. After subsequent injection with cyclooctyne reagents, glycoconjugate labeling was observed on isolated splenocytes and in a variety of tissues including the intestines, heart, and liver, with no apparent toxicity. Photoacoustic calorimetry is shown to be a simple, precise, and accurate method for the quantification of the photophysics of a fluorescence probe, e.g., dansylamide, in a variety of solvents. View details for DOI 10.1016/j.cbpa.2006.10.009, View details for Web of Science ID 000242919700018. Here we review common enrichment strategies used in modern mass spectrometry-based glycoproteomic experiments, including lectins and other affinity chromatographies, hydrophilic interaction chromatography and its derivatives, porous graphitic carbon, reversible and irreversible chemical coupling strategies, and chemical biology tools that often leverage bioorthogonal handles. Application of the IsoTaG platform to 15 cell lines metabolically labeled with Ac4GalNAz or Ac4ManNAz revealed 1375 N- and 2159 O-glycopeptides, variously modified with 74 discrete glycan structures. Antibodies are widely used biomarkers for the diagnosis of many diseases. View details for Web of Science ID A1995TD84500001. View details for Web of Science ID 000257257100003, View details for PubMedCentralID PMC2663890. View details for Web of Science ID 000227627800041. NodST catalyzes the sulfuryl group transfer from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to chitobiose, generating 3'-phosphoadenosine 5'-phosphate (PAP) and chitobiose-6-OSO(3)(-) as products. Mougous, J. D., Leavell, M. D., Senaratne, R. H., Leigh, C. D., Williams, S. J., Riley, L. W., Leary, J. Dube, D. H., Prescher, J. Kiick, K. L., Saxon, E., Tirrell, D. A., Bertozzi, C. R. An inhibitor of the human UDP-GlcNAc 4-epimerase identified from a uridine-based library: A strategy to inhibit O-linked glycosylation, Homogeneous glycopeptides and glycoproteins for biological investigation. One mechanism of proteasome inhibitor resistance may involve the transcription factor Nuclear Factor, Erythroid 2 Like 1 (NFE2L1, also referred to as Nrf1), which responds to proteasome insufficiency or pharmacological inhibition by upregulating proteasome subunit gene expression. 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. 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. With their native proteinaceous backbones and natural glycosidic linkages, these agonists are attractive for translational applications. Phosphorylation of Rv0516c regulated the abundance of EspA, a virulence-associated substrate of the type VII ESX-1 secretion system. A., Mills, J. R., Roforth, M. M., Pittock, S. J., McKeon, A., Page, K., Wolf, W. A., Sanda, S., Speake, C., Greenbaum, C. J., Tsai, C. Bump-and-Hole Engineering Identifies Specific Substrates of Glycosyltransferases in Living Cells. Rodriguez, E. C., Winans, K. A., King, D. S., Bertozzi, C. R. Engineered cell surfaces: Fertile ground for molecular landscaping, Engineering chemical reactivity on cell surfaces through oligosaccharide biosynthesis. The Staudinger ligation is highly selective and reliably forms its product in environs as demanding as live mice. Our methodology should provide general access to biochemical and imaging studies of cell surface proteins, using small fluorophores introduced via a short peptide tag. The new molecule class may be able to degrade some cardiovascular disease and cancer targets. 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. View details for Web of Science ID 000296075300003. Furthermore, the same junctional peptidoglycan also serves as a mechanical link holding the daughter cells together and undergoes mechanical fracture during V snapping. 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. Scherman, M. S., Winans, K. A., Stern, R. J., Jones, V., Bertozzi, C. R., McNeil, M. R. Preparation of pHEMA-CP composites with high interfacial adhesion via template-driven mineralization, Characterization and mutagenesis of Gal/GlcNAc-6-O-sulfotransferases. We also note that >200 illustrations in the second edition have already been published using our nomenclature and are available for download at PubMed. CDG-Tre fluoresces upon activation by BlaC, the -lactamase uniquely expressed by Mtb, and the fluorescent product is subsequently incorporated within the bacterial cell wall via trehalose metabolic pathway. Kramer, J. R., Onoa, B., Bustamante, C., Bertozzi, C. R. Systemic Fluorescence Imaging of Zebrafish Glycans with Bioorthogonal Chemistry. The reaction features a large dynamic range of reactivity, showcasing second-order rate constants as high as 2.310(3) M(-1) s(-1) using diboron reaction partners. This approach enables two measurements: glycocalyx height and the distribution of individual sugars distal from the membrane. The protective efficacy of the current Mycobacterium bovis bacille Calmette-Gurin (BCG) vaccine is highly variable. View details for DOI 10.1371/journal.pone.0065080, View details for Web of Science ID 000321099000031, View details for PubMedCentralID PMC3675115. This field is now entering a stage of logarithmic growth, during which chemical innovations combined with mass spectrometry advances could make it possible to fully characterize the human glycoproteome. [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". Several anti-tuberculosis drugs target the biogenesis of this complex envelope, but their efficacy is declining due to resistance. Shin, S., Chung, S., Sanii, B., Comolli, L. R., Bertozzi, C. R., De Yoreo, J. J. Isotopic recoding is achieved via metabolic incorporation of a defined mixture of N-acetylglucosamine isotopologs into N-glycans. Glycoproteins are typically expressed as mixtures of glycoforms, their oligosaccharides being generated by a template-independent biosynthetic process. We specifically highlight studies in which chemically synthesized GPI anchors and analogues have been employed to study the roles of this unique posttranslational modification. This approach led to the identification of 2,219 intact O-linked glycopeptides across 1,045 glycoproteins. A., Bertozzi, C. R. Site-specific chemical protein conjugation using genetically encoded aldehyde tags. A ligation modeled after the Staudinger reaction forms an amide bond by coupling of an azide and a specifically engineered triarylphosphine. Lu, C., Jones, T., Pedram, K., Bertozzi, C., Paszek, M., Cui, B. In this mechanism, PAPS and trehalose bind and their products are released in random fashion. Here we demonstrate that information gained from the biochemical analysis of a physiological selectin ligand can provide new leads for small molecule design. This reaction has a second-order rate constant of 0.25 M(-1) s(-1), on par with fast bioorthogonal reactions of azides, and proceeds readily in aqueous environments. Rush, J. S., Beatty, K. E., Bertozzi, C. R. Self-catalyzed growth of S layers via an amorphous-to-crystalline transition limited by folding kinetics. A mineralization technique was developed that exposes carboxylate groups on the surface of cross-linked pHEMA, promoting high-affinity nucleation and growth of calcium phosphate on the surface, along with extensive calcification of the hydrogel interior. 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. Zebrafish embryos were treated with an unnatural sugar to metabolically label their cell-surface glycans with azides. View details for Web of Science ID 000304837800041. 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. A., Qi, Y. n., Yasumoto, Y. n., Schmitz, C. O., Mumbach, M. R., Limaye, A. n., Wei, J. n., Alfajaro, M. M., Parker, K. R., Chang, H. Y., Horvath, T. L., Carette, J. E., Bertozzi, C. n., Wilen, C. B., Satpathy, A. T. Enhanced Bactericidal Effects of Pyrazinamide Toward Mycobacterium smegmatis and Mycobacterium tuberculosis upon Conjugation to a {Au(I)-triphenylphosphine}+ Moiety. Changes in glycosylation are often a hallmark of disease states. These data are the first to suggest the feasibility of a strategy that improves the efficiency of gene transfer by using the biosynthetic machinery of the cell to engineer novel sugars on the cell surface. Here, we present a panel of bacterial proteases that cleave mucin domains via distinct peptide- and glycan-based motifs, generating a diverse enzymatic toolkit for mucin-selective proteolysis. Riley, N. M., Malaker, S. A., Driessen, M. n., Bertozzi, C. R. An enzymatic toolkit for selective proteolysis, detection, and visualization of mucin-domain glycoproteins. 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. This represents over a million-fold signal amplification in comparison to using radioactive labeling methods. However, its superior polarity and water solubility reduced nonspecific binding, thereby improving the sensitivity of azide detection. Electron-based dissociation methods are necessary to capture the O-glycopeptide diversity present in OpeRATOR digestions. Lee, J. H., Baker, T. J., Mahal, L. K., Zabner, J., Bertozzi, C. R., WIEMER, D. F., Welsh, M. J. Exploiting differences in sialoside expression for selective targeting of MRI contrast reagents. Hur, G. H., Meier, J. L., Baskin, J., Codelli, J. The results from our study strongly suggest a rapid equilibrium random sequential Bi-Bi mechanism for Stf0 with formation of a ternary complex intermediate. Baranov, M. V., Bianchi, F., Schirmacher, A., van Aart, M. A., Maassen, S., Muntjewerff, E. M., Dingjan, I., Ter Beest, M., Verdoes, M., Keyser, S. G., Bertozzi, C. R., Diederichsen, U., van den Bogaart, G. Making Glycoproteomics via Mass Spectrometry More Accessible to the greater Scientific Community. We demonstrated the noninvasive imaging of glycans in live developing zebrafish, using a chemical reporter strategy. Hang, H. C., Yu, C., Pratt, M. R., Bertozzi, C. R. Detection of bacteria in suspension by using a superconducting quantum interference device. This story was updated on Wednesday, Oct. 6, at 1:23 p.m. PDT. Selectins are central in the inflammatory response; the discovery that they bind to carbohydrate ligands has galvanized carbohydrate chemists to search for inhibitors of the process. Metabolic labeling can identify recently synthesized glycans and thus directly track glycan dynamics. Additionally, we used a nonmetabolic approach to label sialylated glycans with an independent chemistry, enabling the simultaneous imaging of these two distinct classes of glycans. Surprisingly, 6', 6-disulfolactose was poorly recognized by MECA-79, a carbohydrate- and sulfate-dependent monoclonal antibody that binds competitively to L-selectin ligands. Modification of the terminal arabinan residues of this lipoglycan with mannose caps in M. tuberculosis or with phosphoinositol caps in Mycobacterium smegmatis results in distinct host immune responses. IsoStamp has the potential to enhance any proteomics platform that employs chemical labeling for targeted protein identification, including isotope coded affinity tagging, isobaric tagging for relative and absolute quantitation, and chemical tagging strategies for posttranslational modification. The molecular analysis of glycoconjugate function has benefited tremendously from new methods for their chemical synthesis, which provides homogeneous material not attainable from biosynthetic systems. A computational model predicted that these glycoproteins would influence transmembrane receptor spatial organization and function. 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. 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. Together with previous studies, these findings suggest that this redox cofactor may play a role in mycobacterial pathogenesis. Paulk, N. K., Rumachik, N., Malaker, S., Adams, C., Leib, R., Bertozzi, C. R., Kay, M. Award Address (Arthur C. Cope Award sponsored by the Arthur C. Cope Fund). 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. Oral fluid (OF) is a highly effective substrate for population-based HIV screening efforts, as it is noninfectious and significantly easier to collect than blood. Bertozzi, C. R., SINGER, M. S., ROSEN, S. D. L-selectin-carbohydrate interactions: Relevant modifications of the Lewis x trisaccharide. Higher order oligosaccharides were readily generated by alkylation of the corresponding 3-thioGalNAc with N-bromoacetamido sugars. Presented herein is the synthesis and evaluation of a bisubstrate analogue designed to inhibit estrogen sulfotransferase. 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. Yang, A. C., Du Bois, H., Olsson, N., Gate, D., Lehallier, B., Berdnik, D., Brewer, K. D., Bertozzi, C. R., Elias, J. E., Wyss-Coray, T. IL-1R and MyD88 Contribute to the Absence of a Bacterial Microbiome on the Healthy Murine Cornea. We identified prominent localization of mucins in the pharynx of all four larval stages, in the adult hermaphrodite pharynx, vulva and anus, and in the tail of the adult male. View details for DOI 10.1016/j.chembiol.2015.07.009, View details for PubMedCentralID PMC4567249, View details for DOI 10.1021/acscentsci.5b00245, View details for PubMedCentralID PMC4827477. The cell surface contains a wealth of information that determines how cells interact with their environment. The implications of the binary and ternary complexes observed by gas-phase noncovalent interactions in the mechanism of APS reduction are discussed. In this work, we apply an aluminum "lift off" lithography method to allow the efficient generation of complex patterns comprising different DNA sequences. Laureates [3] [ edit] Laureates per country [ edit] In particular, Bertozzi has advanced the understanding of cell surface oligosaccharides involved in cell recognition and inter-cellular communication. We report here a strategy for the synthesis of N-linked glycopeptide analogues that replace the glycosidic linkages extending from the core pentasaccharide with thioethers amenable to construction by chemoselective ligation. Here, we compared these chemistries in the context of various biological applications, including labeling of biomolecules in complex lysates and on live cell surfaces. Several protein lysine methyltransferases (PKMTs) modify histones to regulate chromatin-dependent cellular processes, such as transcription, DNA replication and DNA damage repair. Cell surface sialosides constitute a central axis of immune modulation that is exploited by tumors to evade both innate and adaptive immune destruction. Chemistry Professor Carolyn Bertozzi has been named the Baker Family Director of Stanford ChEMH, an interdisciplinary research institute launched in 2013 to bridge chemistry, engineering and medicine to improve human health. Welch Award in Chemistry (2022); The Dickson Prize in Medicine, University of Pittsburgh (2022); Dr H.P. 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. Noncovalent complexes of the holoprotein with several ligands, including APS, thioredoxin, and AMP, were also investigated. Belardi, B., de la Zerda, A., Spiciarich, D. R., Maund, S. L., Peehl, D. M., Bertozzi, C. R. A Chemical Glycoproteomics Platform Reveals O-GlcNAcylation of Mitochondrial Voltage-Dependent Anion Channel 2. Herein, we designed and synthesized the first chemically defined ligands for dectin-1 and dectin-2. We identified fluorescein-trehalose analogues that are metabolically incorporated into the trehalose mycolates of representative Mycobacterium, Corynebacterium, Nocardia, and Rhodococcus species. (1994) Biochemistry 33, 4830-4835] evidence is presented that (SO4-6)Gal beta 1-->4GlcNAc forms the core of a sulfated sialyl Lewis x structure that may comprise a recognition determinant on GlyCAM-1. A. Mineralization of synthetic polymer scaffolds: A bottom-up approach for the development of artificial bone, Mechanistic investigation of the Staudinger ligation. Utilizing a series of random peptide and glycopeptide substrates, we have obtained the peptide and glycopeptide specificities of ppGalNAc T10 for comparison with ppGalNAc T1 and T2. Mycobacterial carbohydrate sulfotransferase Stf0 catalyzes the sulfuryl group transfer from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to trehalose. Tian, E., Ten Hagen, K. G., SHUM, L., Hang, H. C., Imbert, Y., Young, W. W., Bertozzi, C. R., Tabak, L. A. In this report, genetic complementation using Escherichia coli mutant strains deficient in APS kinase and PAPS reductase was used to define the M. tuberculosis and Mycobacterium smegmatis CysH enzymes as APS reductases. de Almeida, G., Sletten, E. M., Nakamura, H., Palaniappan, K. K., Bertozzi, C. R. Synthesis of Heterobifunctional Protein Fusions Using Copper-Free Click Chemistry and the Aldehyde Tag. Lantos, A. Wang, S., Gray, M. A., Xuan, S., Lin, Y., Byrnes, J., Nguyen, A. I., Todorova, N., Stevens, M. M., Bertozzi, C. R., Zuckermann, R. N., Gang, O. DNA-PKcs has KU-dependent function in rRNA processing and haematopoiesis. Finally, we showed in a mouse model of infection that the loss of cyp128 exhibits a hypervirulent phenotype similar to that in previous studies of the stf3 mutant. In addition, GalNAz efficiently labeled mucin-type O-linked glycoproteins expressed at endogenous levels. Thus, cell surface ketones are a potential vehicle for a metabolically controlled small-molecule drug delivery system. The preferred substrates and functions of the >20 isoforms in mammals are not well understood. Nevertheless, CD45 remained to be the main acceptor. 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. Here, we report an assay for mycobacterial strain assignment based on genetically conserved mycobacterial sulfatases. Furthermore, we show that these mimetics enhance the survival of nonmalignant cells in a zebrafish model of metastasis. Here we report two engineered aminoacyl-tRNA synthetases for mammalian bioorthogonal labeling: a tyrosyl ( ScTyrY43G) and a phenylalanyl ( MmPheT413G) tRNA synthetase that incorporate azide-bearing noncanonical amino acids specifically into the nascent proteomes of host cells.
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