The availability of this new protocol greatly expands the applicability of the DNA-based attachment strategy for the generation of artificial tissues and the incorporation of living cells into device settings. Taken together these results suggest that: (a) the relative content of O-glycans and intragranular anionic groups is crucial for protein diffusion through the intragranular meshwork; (b) protein-protein, rather than carbohydrate-mediated, interactions are responsible for binding of SHGFP-MUC5AC/CK to the immobile fraction, although the degree of matrix O-glycosylation and sialylation affects such interactions; (c) intragranular organization does not depend on covalent multimerization of mucins or the presence of native disulfide bonds in the intragranular mucin/proteins, but rather on specific protein-mediated interactions that are important during the early stages of mucin matrix condensation; (d) alterations of the intragranular matrix precede granule discharge, which can be partial and, accordingly, does not necessarily involve the disappearance of the granule. In this work, we apply an aluminum "lift off" lithography method to allow the efficient generation of complex patterns comprising different DNA sequences. Grunwell, J. R., Rath, V. L., Rasmussen, J., Cabrilo, Z., Bertozzi, C. R. Discovery of sulfated metabolites in mycobacteria with a genetic and mass spectrometric approach. Expansion of this toolkit, an effort that is already well underway, is an important objective for chemists and biologists alike. Sulfated forms of sialyl-Le(X) containing Gal-6-SO(4) or GlcNAc-6-SO(4) have been implicated as potential recognition determinants on high endothelial venule ligands for L-selectin. The unnatural variant comprises approximately 90% of cell surface sialosides when exogenous substrates are added to the media at micromolar concentrations, despite the availability of natural sialic acid in the growth media. Previously, we described the biochemical activity of the sulfotransferase Stf0 that initiates SL-1 biosynthesis. Bifunctional, fluorinated cyclooctynes were used for the in situ "click" crosslinking of azide-terminated photodegradable star polymers, yielding photodegradable polymeric model networks with well-defined structures and tunable gelation times. Through rational design, we redirected a microbial lipoic acid ligase (LplA) to specifically attach an alkyl azide onto an engineered LplA acceptor peptide (LAP). Furthermore, we demonstrate that the metabolic diversity of nature enables the use of naturally occurring functional groups that display inherent biocompatibility alongside abiotic components for organism-specific applications. 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. Investigation of their function has been greatly assisted by sources of homogeneous material. One challenge for the development of such probes is the a priori identification of structures that will undergo a dramatic fluorescence enhancement by virtue of the chemical transformation. This data also suggested for a role of GALNT3 in aberrant EOC glycosylation, possibly implicated in disease progression. The machinery responsible for sulfatase activation is poorly understood in prokaryotes. View details for DOI 10.1016/S0076-6879(06)15015-6, View details for Web of Science ID 000242168500015. Please refer to the appropriate style manual or other sources if you have any questions. Numerous factors that influence cell-surface carbohydrate composition remain to be elucidated. The versatility of this technology was demonstrated by an example of selective drug delivery. Laureates [3] [ edit] Laureates per country [ edit] Although the early steps in SL-1 biosynthesis are known, the machinery underlying the final acylation reactions is not understood. Mucin-type O-linked glycoproteins are involved in a variety of biological interactions in higher eukaryotes. Generated in nine steps from a glucose analogue, DIMAC reacted with azide-labeled proteins and cells similarly to cyclooctynes. Shes been out since the late 1980s, when being a lesbian could have jeopardized her career. Together, localisation and association govern the assembly of complex glycans and thereby regulate interactions at the cell surface. Bioorthogonal chemical reactions, those that do not interact or interfere with biology, have allowed for exploration of numerous biological processes that were previously difficult to study. We further demonstrate that the efficacy of a clinically used compound, clofazimine, is augmented by pH-based partitioning in a macrophage infection model. Neutralization of acidic organelles directly with ammonium chloride or indirectly with bafilomycin A1 partially abrogated the growth restriction of these drugs. Our results suggest that 6-sulfo sLe(x) binds to L-selectin with higher affinity than does sLe(x) or 6'-sulfo sLe(x) and that sulfation of sLe(x) capping groups on GlyCAM-1 at the 6-position is important for L-selectin recognition. View details for Web of Science ID 000177297600001. Loss of Stf3 expression, but not that of Cyp128, is correlated with elevated levels of menaquinone-9, an essential component in the electron-transport chain in M. tuberculosis. Developmental events can be monitored at the cellular and molecular levels by using noninvasive imaging techniques. However, the Staudinger ligation has some liabilities, such as the propensity of phosphine reagents to undergo air oxidation and the relatively slow kinetics of the reaction. However, little is known about how alterations in O-GlcNAc cycling affect human embryonic stem cell (hESC) neural differentiation. Discovery and functional interrogation of SARS-CoV-2 RNA-host protein interactions. In the measurement, we add 50-nm-diameter superparamagnetic magnetite particles, coated with antibodies, to an aqueous sample containing L. monocytogenes. [37], In 2008, Bertozzi founded a startup of her own: Redwood Bioscience also in Emeryville, California. A microtiter plate assay for UDP-galactopyranose mutase, an essential cell wall biosynthetic enzyme of Mycobacterium tuberculosis, was developed. 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. Schumann, B. n., Malaker, S. A., Wisnovsky, S. P., Debets, M. F., Agbay, A. J., Fernandez, D. n., Wagner, L. J., Lin, L. n., Li, Z. n., Choi, J. n., Fox, D. M., Peh, J. n., Gray, M. A., Pedram, K. n., Kohler, J. J., Mrksich, M. n., Bertozzi, C. R. An Acquired and Endogenous Glycocalyx Forms a Bidirectional "Don't Eat" and "Don't Eat Me" Barrier to Phagocytosis. To elucidate the important sites of sulfation on Le(x) with respect to L-selectin recognition, we have synthesized six sulfated Le(x) analogs and determined their abilities to block binding of a recombinant L-selectin-Ig chimera to immobilized GlyCAM-1. We developed a sulfatase-activated probe, 7-hydroxy-9H-(1,3-dichloro-9,9-dimethylacridin-2-one)-sulfate, that detects enzyme activity in native protein gels, allowing the rapid detection of sulfatases in mycobacterial lysates. Rabuka, D., Rush, J. S., dehart, G. W., Wu, P., Bertozzi, C. R. Cellular Microfabrication: Observing Intercellular Interactions Using Lithographically-Defined DNA Capture Sequences. 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. A chemical transformation that permits the selective formation of covalent adducts among richly functionalized biopolymers within a cellular context is presented. WebCarolyn Bertozzi (1966-ngin 10-ngiet 10-ngit ) he M-koet ke yit-chak fa-hok-k. Both significantly outperform EThcD methods, indicating that ETD-based methods are not required for routine N-glycoproteomics. The capability of the nanoinjector was demonstrated by injection of protein-coated quantum dots into live human cells. A broader theme that emerged was the urgent need to bring the glycosciences back into the mainstream of biology by integrating relevant education into the curricula of medical, graduate, and postgraduate training programs, thus generating a critical sustainable workforce that can advance the much-needed translation of glycosciences into a more complete understanding of biology and the enhanced practice of medicine. Herein, we sought to identify other palmitoylated proteins in mitochondria using a nonradioactive bio-orthogonal azido-palmitate analog that can be selectively derivatized with various tagged triarylphosphines. The mutant and wild-type Mtb replicated similarly during the acute phase of infection, but the mutant showed reduced viability during the persistent phase of the infection. Sulfotransferases have been linked with several disease states, prompting our investigation of specific sulfotransferase inhibitors. View details for Web of Science ID 000251457800039, View details for PubMedCentralID PMC2654346. The mammalian glycocalyx is a heavily glycosylated extramembrane compartment found on nearly every cell. [structure: see text] Divergent syntheses of sulfated sialyl Lewis X oligosaccharides corresponding to the core 1 and core 6 branches of the L-selectin ligand are reported. However, the diversity found in glycoproteins has undermined efforts to describe the intact glycoproteome via mass spectrometry (MS). Dube, D. H., Prescher, J. Cortez, F. d., Gebhart, D., Robinson, P. V., Seftel, D., Pourmandi, N., Owyoung, J., Bertozzi, C. R., Wilson, D. M., Maahs, D. M., Buckingham, B. Proteasome inhibition leads to accumulation of cytosolic Nrf1, which is then processed to form the active transcription factor. The azide, being nonreactive within cells, was ideal for use in living systems. We employed the recently introduced aldehyde tag method to obtain a recombinant protein with the aldehyde-bearing formylglycine residue at a specific site. Harland, C. W., Rabuka, D., Bertozzi, C. R., Parthasarathy, R. Rv2131c from Mycobacterium tuberculosis is a CysQ 3 '-phosphoadenosine-5 '-phosphatase. Despite its broad functional significance, the dynamic and posttranslational nature of O-GlcNAc signaling makes it challenging to study using traditional molecular and cell biological techniques alone. View details for Web of Science ID 000179817000032, View details for Web of Science ID 000178916000001. Methods for introducing bioorthogonal functionalities into proteins have become central to protein engineering efforts. Proteasome inhibitors are used to treat blood cancers such as multiple myeloma (MM) and mantle cell lymphoma. Most bacteria possess only one trehalose biosynthesis pathway and do not elaborate the disaccharide into more complex metabolites, suggesting a distinct role for trehalose in mycobacteria. A novel and efficient enzyme kinetics assay using electrospray ionization mass spectrometry was developed and applied to the bacterial carbohydrate sulfotransferase (NodST). Here we explore an alternative bioorthogonal reaction, the 1,3-dipolar cycloaddition of azides and cyclooctynes, also known as "Cu-free click chemistry," for labeling biomolecules in live mice. 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. Biochemistry in the context of a living cell or organism is complicated by many variables such as supramolecular organization, cytoplasmic viscosity, and substrate heterogeneity. Methods for directing the cell surface expression of novel protein-based and oligosaccharide-based epitopes are stimulating new directions in biotechnology and biomedical research. Structural and mechanistic studies of this family of sulfotransferases have been hindered by the lack of a productive recombinant protein expression system. This technique has been exploited in fundamental studies of glycan-dependent cell-cell and virus-cell interactions and also provides an avenue for the chemical remodelling of living cells. Recognized for its roles in membrane tethering, cellular signaling, and protein trafficking, palmitoylation is also emerging as a potential regulator of metabolism. View details for Web of Science ID 000077136900049, View details for Web of Science ID 000076649700013, View details for Web of Science ID 000075884200020. O-GlcNAc transferase accepts UDP-GlcNAz as a nucleotide-sugar donor, appending an azidosugar onto its native substrates, which can then be detected by covalent labeling using azide-reactive chemical probes. Secretory products can both diffuse, although very slowly, through the meshwork pores and interact noncovalently with the matrix. Here we studied the function of novel germline variants in CSF3R at amino acid N610. Bacteria are able to adapt to dramatically different microenvironments, but in many organisms, the signaling pathways, transcriptional programs, and downstream physiological changes involved in adaptation are not well-understood. View details for Web of Science ID 000250428200015. Xiao, H., Woods, E. C., Vukojicic, P., Bertozzi, C. R. Proteomic dataset for altered glycoprotein expression upon GALNT3 knockdown in ovarian cancer cells. View details for Web of Science ID 000187945400003. A convergent synthesis of trehalose. Mesenchymal-like GBMs were highly contractile and expressed elevated levels of glycoproteins that expanded their glycocalyx, and they were surrounded by a stiff extracellular matrix that potentiated integrin mechanosignalling. Studies of 4Fe-4S cluster stability and cysteine reactivity in the presence and absence of substrates, and in the free enzyme versus the covalent enzyme-intermediate (E-Cys-S-SO(3)(-)), suggest a structural rearrangement that occurs during the catalytic cycle. The ability to access glycopeptides of this type through chemical synthesis will facilitate further mechanistic studies. 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). Using azide-derivatized analogues of fucose, we metabolically labeled cell-surface glycans and then detected the incorporated azides via copper-free click chemistry with a difluorinated cyclooctyne probe. 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. The participating functional groups must be inert to biological moieties, must selectively reactive with each other under biocompatible conditions, and, for in vivo applications, must be nontoxic to cells and organisms. Chung, S., Shin, S., Bertozzi, C. R., De Yoreo, J. J. Difluorobenzocyclooctyne: Synthesis, Reactivity, and Stabilization by beta-Cyclodextrin. Tsui, C. K., Barfield, R. M., Fischer, C. R., Morgens, D. W., Li, A., Smith, B. View details for DOI 10.1073/pnas.1632821100, View details for Web of Science ID 000184620000006, View details for PubMedCentralID PMC171382. We were able to bypass the salvage pathway by using an azide-functionalized analogue of GDP-fucose. View details for Web of Science ID 000088039800042. In the accompanying paper [Hemmerich, S., & Rosen, S.D. During the past two years, significant progress has been made in the design and synthesis of carbohydrate-based inhibitors of selectins, receptors involved in the attachment of leukocytes to endothelial cells at sites of inflammation. In conjunction with techniques for site-specific introduction of aldehydes into proteins, the Pictet-Spengler ligation offers a means to generate stable bioconjugates for medical and materials applications. The building block was incorporated into a synthetic peptide derived from the active site of a Mycobacterium tuberculosis sulfatase. We have coexpressed a human GST-5 cDNA with a GlyCAM-1/IgG fusion protein in COS-7 cells and observed four-fold enhanced [(35)S]sulfate incorporation into this mucin acceptor. Despite being immunologically distinct, poly(SiaProp) can promote neurite outgrowth similarly to natural polysialic acid. This tutorial review will summarize the history of this emerging field, as well as recent progress in the development and application of bioorthogonal copper-free click cycloaddition reactions. We describe here a new ELISA that measures the binding between selectin-IgG chimeras and a physiological ligand for L-selectin and can be used to screen selectin inhibitors. View details for Web of Science ID 000237590400012. (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. View details for DOI 10.1371/journal.pone.0242049. She later refined the approach to improve its utility in cellular environments, facilitating research into interactions between biomolecules and into disease processes. The key building block, a pentasaccharide-Asn analogue containing two thiol residues, was incorporated into CD52 by 9-fluorenylmethoxycarbonyl (Fmoc)-based solid-phase peptide synthesis. Saad, O. M., Ebel, H., Uchimura, K., ROSEN, S. D., Bertozzi, C. R., Leary, J. 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. The ESI-MS assay presented herein requires no chromophoric substrate or product, and the analysis time is very short. Such metabolic interference can block the expression of oligosaccharides or alter the structures of the sugars presented on cells. The mycobacterial cell wall component lipoarabinomannan (LAM) has been described as one of the key virulence factors of Mycobacterium tuberculosis. Analysis of the growth kinetics leads to a quantitative model in which tetramer creation is rate limiting. A chimeric enzyme comprising the stem region of GlcNAc6ST-1 inserted between the catalytic and transmembrane domains of GlcNAc6ST-2 had the same substrate preference as native GlcNAc6ST-1. She coined the term bioorthogonal chemistry to describe the use of click reactionsquick, simple chemical reactionsto study living cells. This strategy uses a two-step labeling procedure in which an unnatural sugar analogue containing a functional handle is (1) incorporated into sugar-bearing proteins via the cell's own biosynthetic machinery and then (2) detected with an exogenously added probe. Here we present the first synthetic trehalose glycolipids capable of providing desiccation protection to membranes of which they are constituents. We synthesized a 1338 member library of uridine analogs directed to the epimerase by virtue of substrate mimicry. These results establish the foundation for further development of BPDA-based colorimetric sensors. Finally, using StcE, we discovered that sialic acid-binding Ig-type lectin-7 (Siglec-7), a glycoimmune checkpoint receptor, selectively binds sialomucins as biological ligands, whereas the related receptor Siglec-9 does not. 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. An N-azidoacetylmannosamine derivative caged with a peptide substrate for the prostate-specific antigen (PSA) protease was converted to cell-surface azido sialic acids in a PSA-dependent manner. Genome-scale knockout screens assigned putative functional relevance to the RNA-protein interactions observed by ChIRP-MS. 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). Polydiacetylene-based systems are attractive for sensing applications due to their colorimetric response to changes in the local environment. The glycan symbol nomenclature proposed by Harvey et al. View details for DOI 10.1016/j.jasms.2006.08.010, View details for Web of Science ID 000244109300001, View details for PubMedCentralID PMC2755055. Methods for site-specific protein conjugation are critical to such efforts. 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. Charter, N. W., Mahal, L. K., Koshland, D. E., Bertozzi, C. R. Tyrosylprotein sulfotransferase inhibitors generated by combinatorial target-guided ligand assembly. Enrichment of peptides derived from cytochrome c treated with the azide-containing cross-linker bis(succinimidyl)-3-azidomethyl glutarate (BAMG) shows several cross-link containing peptides. 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. In addition, GalNAz efficiently labeled mucin-type O-linked glycoproteins expressed at endogenous levels. Mycobacterium tuberculosis (Mtb) has evolved into a highly successful human pathogen. This review highlights the development of bioorthogonal chemical reporters and reactions and their application in living systems. One of the most abundant is sulfolipid-1 (SL-1), a tetraacyl-sulfotrehalose glycolipid. Although global sulfatase activity was reduced in the mutant, a significant amount of residual sulfatase activity suggests the presence of FGE-independent sulfatases in this organism. The findings reported here provide a molecular basis to understand the abnormalities induced in the immune system by the trans-sialidase during T. cruzi infection. Many developmental processes depend on proper fucosylation, but this post-translational modification is difficult to monitor in vivo. Each enzyme preferred a terminal GlcNAc residue, and was impeded by the addition of a beta1,4-linked Gal residue (i.e., terminal LacNAc). Even though we have only demonstrated its use in visualizing glycans, it can be envisioned that this probe could also be used for bioluminescence imaging of any azide-containing biomolecule, such as proteins and lipids, since azides have been previously incorporated into these molecules. WebCarolyn R. Bertozzi Benjamin F. Cravatt United States United States United States: for their seminal contributions to understanding the chemistry of cellular communication and inventing chemical methodologies to study the role of carbohydrates, lipids, and proteins in such biological processes. This Glycoforum article summarizes these recent changes. View details for Web of Science ID 000168490400007, View details for Web of Science ID 000167717100191. Phosphatidylinositol-phospholipase-C activity is actually not present in trypomastigotes. Trypanosoma cruzi, the flagellate protozoan agent of Chagas disease or American trypanosomiasis, is unable to synthesize sialic acids de novo. Zhou, M. N., Delaveris, C. S., Kramer, J. R., Kenkel, J. First, we found that the W37I mutant of LplA catalyzes site-specific ligation of 10-azidodecanoic acid to LAP in cells, in nearly quantitative yield after 30 min. FGE has emerged as an enabling biotechnology tool due to the robust utility of the aldehyde product as a bioconjugation handle in recombinant proteins. We show that Glyco-seek detects attomoles of glycoproteins of interest from cell lysates, with sensitivity several orders of magnitude higher than that of current techniques. During maturation, phagosomes containing engulfed particles fuse with various endosomal compartments through the action of regulatory molecules on the phagosomal membrane. 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). She coined the This gene was mapped to mouse chromosome X at band XA3.1-3.2. These data show that the normal distribution of surface glycosylation requires IL-1R, but not MyD88, and is not sufficient to prevent bacterial binding. A., Bertozzi, C. R. A chemically synthesized version of the insect antibacterial glycopeptide, diptericin, disrupts bacterial membrane integrity. These alkenyl compounds arise from a hydrogen transfer reaction from solvent to the unisolable intermediate, and we postulate that the reaction proceeds via a radical mechanism originating from the strained alkynyl bond that has unusually high radical character. WebCarolyn Bertozzi (1966-ngin 10-ngiet 10-ngit ) he M-koet ke yit-chak fa-hok-k. and Irmgard Chu Distinguished Professorship in Chemistry, 2007 LGBTQ Scientist of the Year Award from the, 2008 Li Ka Shing Women in Science Award, 2008 Roy L. Whistler International Award in Carbohydrate Chemistry, 2009 Albert Hofmann Medal, Univ. These efforts epitomize the emerging field of 'synthetic glycobiology'. Bertozzis graduate research focused on carbohydrate analog synthesis, intended for biological applications. A. Glycans in cancer and inflammation. Dithiothreitol, glutathione and the C207A mutant of E. coli LpxC prevent the formation of a covalent complex by 1-68A, suggesting a role for Cys-207 in inhibition. The FGE recognition sequence, or aldehyde tag, can be inserted into heterologous recombinant proteins produced in either prokaryotic or eukaryotic expression systems. In addition, we have redefined the substrate specificity of the B. subtilis CysH, formerly designated a PAPS reductase, as an APS reductase, based on its ability to complement a mutant E. coli strain deficient in APS kinase. With the aid of density functional theory calculations reported previously by Nagano and co-workers, we identified azidofluorescein derivatives that were predicted to undergo an increase in fluorescence quantum yield upon Cu-catalyzed or Cu-free cycloaddition with linear or cyclic alkynes, respectively. ESI-FTICR MS was utilized to characterize a 4Fe-4S containing protein Mycobacterium tuberculosis APS reductase. 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