carolyn bertozzi biographycarolyn bertozzi biography
Current approaches offer a precision approaching that of genetic control. 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. Surprisingly, Gal-1's effects on mammary patterning were independent of its glycan-binding ability and instead required localization within the nuclei of mammary epithelia. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain. She is an elected member of the National Academy of Sciences, the American Academy of Arts and Sciences, and the German Academy of Sciences Leopoldina. The results were in excellent agreement with those obtained from previous assays, verifying the accuracy and reliability of the ESI-MS assay. View details for DOI 10.1074/mcp.M600314-MCP200, View details for Web of Science ID 000242852000012. We further developed a protein purification method that involves QC ligation of biotin to a protein of interest, capture on streptavidin resin, and finally release using only UV light. This review focuses on recent advances in chemical tools to study the specificity and dynamics of mammalian lectins in live cells. The foundation focuses on curing NGLY1 deficiency through developing therapeutics that are efficient and inexpensive. Our approach validates the use of the applied metabolic strategy to identify important functions of GalNAc-Ts in normal and pathological conditions. Progress in understanding the biology of protein fatty acylation has been impeded by the lack of rapid direct detection and identification methods. The absence of activity on the trisaccharide Gal beta 1-->6Gal alpha-R indicates a requirement for a substrate with a terminal GlcNAc residue, suggesting that sulfation precedes further biosynthetic assembly of L-selection ligands. The combination of novel biochemical and metabolism-based approaches with emerging genomic methods promises to accelerate efforts to understand glycosylation. Stanford chemist Carolyn Bertozzi was awarded the Nobel Prize in chemistry for her development of bioorthogonal reactions, which allow scientists to explore cells and track biological processes without disrupting the normal chemistry of the cell. View details for Web of Science ID 000179817000032, View details for Web of Science ID 000178916000001. By mutating catalytic residues of two such enzymes, we engineered mucin-selective binding agents with retained glycoform preferences. Intact glycopeptides are recovered by cleavage of the probe, analyzed with directed MS, and assigned by targeted mass-independent data analysis. View details for DOI 10.1016/j.bmc.2016.05.050, View details for Web of Science ID 000385905800005, View details for PubMedCentralID PMC5052108. The vast majority of H. ducreyi strains contain high levels of sialic acid (N-acetylneuraminic acid, NeuAc) in their LOS. Zhou, M. N., Delaveris, C. S., Kramer, J. R., Kenkel, J. Labeling cells with omega-alkynyl-palmitate does not affect membrane association of N-Ras. In this study we have examined how unnatural sialic acids can alter polysialic acid expression and influence the adhesive properties of the neural cell adhesion molecule (NCAM). Here we present a strain-promoted [3 + 2] cycloaddition between cyclooctynes and azides that proceeds under physiological conditions without the need for a catalyst. To establish this approach, we have developed Peroxy Caged Luciferin-2 (PCL-2), a H(2)O(2)-responsive boronic acid probe that releases 6-hydroxy-2-cyanobenzothiazole (HCBT) upon reacting with this reactive oxygen species, as well as a peptide-based probe, z-Ile-Glu-ThrAsp-D-Cys (IETDC), which releases D-cysteine in the presence of active caspase 8. There is growing interest in extending this progress to O-glycoproteomics, which necessitates comparisons of method performance for the two classes of glycopeptides. GRABOWSKI, J. J., Bertozzi, C. R., Jacobsen, J. R., Jain, A., Marzluff, E. M., Suh, A. Y. Together, glycomic and metabolic labeling techniques provide a comprehensive description of glycosylation as a foundation for hypothesis generation. The human pathogen Mycobacterium tuberculosis (M. tb) is thought to control the human immune response with diverse biomolecules, including a variety of exotic lipids. Hundreds of mammalian nuclear and cytoplasmic proteins are reversibly glycosylated by O-linked -N-acetylglucosamine (O-GlcNAc) to regulate their function, localization, and stability. Disruption of papA2 and papA1 in M. tuberculosis confirmed their essential role in SL-1 biosynthesis and their order of action. We show that both Rv1129c and the MCC enzymes are required for intracellular growth in macrophages and that the growth defect of MCC mutants is largely attributable to the degradation of host-derived cholesterol. In the mouse genome we have found a homologous ORF that predicts a novel murine GlcNAc 6-O-sulfotransferase with 88% identity to the human enzyme. This assay allows for direct product detection on the membrane, obviating excessive washing and elution steps endemic to other assays. Spreading of a mycobacterial cell surface lipid into host epithelial membranes promotes infectivity. 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. Rabuka, D., Hubbard, S. C., Laughlin, S. T., Argade, S. P., Bertozzi, C. R. Chemical technologies for probing glycans, A role for sulfation-desulfation in the uptake of bisphenol A into breast tumor cells. In 1961, Wittig and Krebs noted that the strained, cyclic alkyne cyclooctyne reacts violently when combined neat with phenyl azide, forming a triazole product by 1,3-dipolar cycloaddition. These results establish a platform for engineering S-layer assemblies with 3-D architecture. View details for DOI 10.1073/pnas.0506855103, View details for Web of Science ID 000236472500008, View details for PubMedCentralID PMC1405625. A., Bertozzi, C. R. Cell type-selective secretome profiling in vivo. Investigation of their function has been greatly assisted by sources of homogeneous material. Recent work has implicated tyrosine sulfate as a determinant of protein-protein interactions involved in leukocyte adhesion, hemostasis and chemokine signaling. Recent progress in identifying and analyzing physiological selectin counter-receptors suggests new approaches to the design of ligands that bind to specific selectins. In the past decade advances in genomics, proteomics and mass spectrometry have enabled the association of specific glycan structures with disease states. [reaction: see text] We report a new synthesis of trehalose analogs that involves the use of intramolecular aglycone delivery for stereoselective formation of the 1,1-alpha,alpha-glycosidic bond. Here, we show that Cu(I)-FGE is functional in O2 activation and reveal a high-resolution X-ray crystal structure of FGE in complex with its catalytic copper cofactor. Sulfation of GlcNAc within sialyl Lewis x is a crucial modification for L-selectin binding, and thus, the underlying sulfotransferase may be a key modulator of lymphocyte trafficking. Of the sequence motifs that are associated with 4Fe-4S centers, the cysteine dyad is atypical and has generated discussion with respect to coordination as well as the cluster's larger functional significance. While this method is highly effective for cultured mammalian cells, we report here a significant improvement of this technique that allows the direct modification of cell surfaces with NHS-DNA conjugates. cis-Cyclopropanation of mycobacterial mycolic acids by pcaA drives the activation of host Vegf signaling within granuloma macrophages. More broadly, well-defined synthetic glycopolymers enable the integration of glycoconjugate structural and spatial diversity in a single microarray screening platform. View details for DOI 10.1002/anie.201504249, View details for DOI 10.1021/jacs.5b04279, View details for Web of Science ID 000360321100003, View details for DOI 10.1021/acscentsci.5b00275, View details for PubMedCentralID PMC4827550. She described the reaction between the modified sugar and the fluorescent molecule as bioorthogonal. Carrico, I. S., Carlson, B. L., Bertozzi, C. R. A cell nanoinjector based on carbon nanotubes. Trypanosoma cruzi, the agent of the American trypanosomiasis or Chagas disease, bypasses its lack of de novo synthesis of sialic acids by expressing a surface-anchored trans-sialidase. Asparagine-linked glycosylation is a common post-translational modification of proteins; in addition to participating in key macromolecular interactions, N-glycans contribute to protein folding, trafficking, and stability. 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. View details for DOI 10.1074/jbc.M304928200, View details for Web of Science ID 000185713800121. This Nel relaxation process is detected by the superconducting quantum interference device. Herein we report a semisynthetic method of producing membrane-anchored proteins. A key tool we developed for this study is a cell-permeable, small molecule inhibitor of GlcNAc 2-epimerase designed based on mechanistic principles. View details for DOI 10.1038/NCHEMBIO.1388, View details for Web of Science ID 000328854900013. Pluvinage, J. V., Haney, M. S., Smith, B. There is urgent need for new therapeutic targets and a better understanding of EOC initiation and progression. This technique, which is described in detail, provides a direct measurement of the energy that is released nonradiatively following photostimulation, and can therefore be used to indirectly determine the amount of energy released via luminescent pathways. 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. Click chemistry and bio-orthogonal chemistry. Bertozzi, C. R., Chang, C. J., Davis, B. G., Olvera de la Cruz, M., Tirrell, D. A., Zhao, D. Integrins Form an Expanding Diffusional Barrier that Coordinates Phagocytosis. Nuclear repartitioning of galectin-1 by an extracellular glycan switch regulates mammary morphogenesis. Hang, H. C., Yu, C., Pratt, M. R., Bertozzi, C. R. Detection of bacteria in suspension by using a superconducting quantum interference device. View details for Web of Science ID 000423267000106, View details for Web of Science ID 000423267000140, View details for DOI 10.1021/acscentsci.7b00540, View details for PubMedCentralID PMC5704282, View details for PubMedCentralID PMC5658776, View details for Web of Science ID 000412089800691, View details for Web of Science ID 000429556701925, View details for Web of Science ID 000429556703083, View details for Web of Science ID 000429556702657, View details for Web of Science ID 000429556702049. The obtained data also uncover numerous novel glycoproteins; some of which could represent new potential EOC biomarkers and/or therapeutic targets. [6] Her lab's development of nanotechnologies which probe biological systems lead to the development of a fast point-of-care tuberculosis test in 2018. Hur, G. H., Meier, J. L., Baskin, J., Codelli, J. 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. 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. Glycans can be imaged by metabolic labeling with azidosugars followed by chemical reaction with imaging probes; however, tissue-specific labeling is difficult to achieve. Using a multicolor, time-resolved imaging strategy, we found that the distribution and dynamics of the glycans varied anatomically and with respect to developmental stage. The resulting trehalose biosynthesis mutant was unable to proliferate and enter stationary phase unless supplemented with trehalose. Beatty, K. E., Fisk, J. D., Smart, B. P., Lu, Y. Y., Szychowski, J., Hangauer, M. J., Baskin, J. M., Bertozzi, C. R., Tirrell, D. A. Bioluminescent Probes of Sulfatase Activity. 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. Such metabolic interference can block the expression of oligosaccharides or alter the structures of the sugars presented on cells. Nuclear translocation of Gal-1, in turn, was regulated by discrete cell-surface glycans restricted to the front of the mammary end buds. Interactions of mucin glycoproteins with cognate receptors are dictated by the structures and spatial organization of glycans that decorate the mucin polypeptide backbone. View details for DOI 10.1021/jacs.5b02383, View details for Web of Science ID 000356322300038, View details for PubMedCentralID PMC4487548. Key to these findings was the use of glycopolymers end-functionalized with phospholipids, which enable the introduction of synthetically defined glycans onto cancer cell surfaces. 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). This technology involves metabolic labeling of glycans with a specifically reactive, abiotic functional group, the azide. de Graffenried, C. L., Laughlin, S. T., Kohler, J. J., Bertozzi, C. R. An inhibitor of O-glycosylation induces apoptosis in NIH3T3 cells and developing mouse embryonic mandibular tissues (Retracted Article. K chhai 2022-ngin tet-to Nobel Fa-hok Ching . Our work provides a blueprint for a wide variety of future chemical approaches to identify, visualize, and characterize dynamic O-GlcNAc signaling. When evaluating mouse thymocytes and splenocytes as acceptors of the azido-sugar, a complex pattern of efficiently tagged glycoproteins was revealed. View details for DOI 10.1074/mcp.M111.015339, View details for Web of Science ID 000306408500017. To verify the quantitation and localization of glycans on the human embryonic stem cell membranes, flow cytometry and immunocytochemistry were performed. To address this shortcoming, we have developed a robust, high-throughput compatible, click chemistry-based approach to identify small molecules that interfere with the palmitoylation of Ras, a high value therapeutic target that is mutated in up to a third of human cancers. Using sequence alignments with other carbohydrate and cytosolic sulfotransferases, we selected residues within the putative binding regions for 3'-phosphoadenosine 5'-phosphosulfate (PAPS) and the carbohydrate substrate for mutagenesis. View details for DOI 10.1073/pnas.0403681101, View details for Web of Science ID 000225508400004, View details for PubMedCentralID PMC534710, View details for DOI 10.1074/jbc.M406397200, View details for Web of Science ID 000225229500103. A., Hangauer, M. J., Bertozzi, C. R. PapA1and PapA2 are acyltransferases essential for the biosynthesis of the Mycobacterium tuberculosis virulence factor Sulfolipid-1. Using a mass spectrometric approach to simultaneously monitor hundreds of lipids, we discovered that the size and abundance of two lipid virulence factors, phthiocerol dimycocerosate (PDIM) and sulfolipid-1 (SL-1), are controlled by the availability of a common precursor, methyl malonyl CoA (MMCoA). View details for DOI 10.1074/mcp.R120.002277. Several important human pathogens are represented in the Corynebacterineae suborder, including Mycobacterium tuberculosis and Corynebacterium diphtheriae. Putative Mtb bacilli were detected in collected fluid by fluorescence microscopy utilising DMN-Trehalose. Robinson, P. V., Tsai, C., de Groot, A. E., McKechnie, J. L., Bertozzi, C. R. Nuclear repartitioning of galectin-1 by an extracellular glycan switch regulates mammary morphogenesis. Carolyn 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 revised, highly practical synthesis of the precursor N(alpha)-Fmoc-Thr(Ac(3)-alpha-D-GalNAc) allowed us to produce sufficient quantities of the glycopeptide for mechanistic assays. View details for DOI 10.1016/S0076-6879(06)15015-6, View details for Web of Science ID 000242168500015. Here, we demonstrate that secreted protease of C1 esterase inhibitor (StcE), a bacterial protease from Escherichia coli, cleaves mucin domains by recognizing a discrete peptide- and glycan-based motif. [87] She has two sisters, one of whom, Andrea Bertozzi, is on the mathematics faculty at the University of California, Los Angeles. View details for DOI 10.1016/j.jprot.2016.04.009, View details for DOI 10.1021/acscentsci.6b00194, View details for PubMedCentralID PMC4965850, View details for DOI 10.1021/acscentsci.6b00167, View details for PubMedCentralID PMC4919776. Analysis of the growth kinetics leads to a quantitative model in which tetramer creation is rate limiting. View details for DOI 10.1099/jmm.0.46983-0, View details for Web of Science ID 000245795600002. The Gal/GalNAc/GlcNAc-6-O-sulfotransferases (GSTs) are a recently discovered family of carbohydrate sulfotransferases that share significant sequence homology at the amino acid level and mediate a number of different biological processes such as leukocyte adhesion at sites of chronic inflammation. The most potent examined, 1-68A, is a pH-dependent, two-step, covalent inhibitor of Escherichia coli LpxC that competes with UDP to bind the enzyme in the first step of inhibition. Specifically, three carbohydrate binding proteins termed selectins (E-, P-, and L-selectin) have been shown to be essential for leukocyte rolling along the vascular endothelium, the first step in the recruitment of leukocytes from the blood into inflammatory sites or into secondary lymphoid organs. Subsequently, the worms were reacted via copper-free click reaction with fluorophore-conjugated difluorinated cyclooctyne (DIFO) reagents. View details for DOI 10.1074/jbc.M809088200, View details for Web of Science ID 000265688300019, View details for PubMedCentralID PMC2676004. She also held an appointment as a professor of molecular and cellular pharmacology from 2000 to 2002 at the University of California, San Francisco. Jasti, R., Bhattacharjee, J., Neaton, J. Mycobacterium tuberculosis (M. tuberculosis) is an intracellular pathogen possessing a complex mixture of cell wall lipids that are thought to modulate the activities of host macrophages. [33][34] In 2017, due to her lab's discovery of linking the sugars on the surface of cancer cells and their ability to avoid the immune system defenses, she was invited to speak at Stanford's TED talk, giving a talk entitled "What the sugar coating on your cells is trying to tell you". We developed a series of ligand-inducible riboswitches that control gene expression in diverse species of Gram-negative and Gram-positive bacteria, including human pathogens that have few or no previously reported inducible expression systems. Here we highlight chemical tools that are beginning to address this need. ppGalNAc T1 and T2 revealed no significant enhancements suggesting Ser/Thr-O-GalNAc was inhibitory at most positions for these isoforms. A comparative study of bioorthogonal reactions with azides. 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. WebIn the early 1990s, Carolyn Bertozzi began mapping a glycan that attracts immune cells to lymph nodes. [reaction: see text] Nearly all known sulfatases share a common active site modification that is required for their activity: conversion of cysteine to alpha-formylglycine. The introduction of chemically unique groups into proteins by means of non-natural amino acids has numerous applications in protein engineering and functional studies. Only complex 1 with the {Au(PPh3)}+ moiety exhibits significant bactericidal activity against both strains. 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). 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 Web of Science ID 000294081900008. in these pages has relative advantages and disadvantages. The advantage of this ELISA over previous assays is that a macromolecular physiological ligand is employed, rather than a fortuitous or simplified carbohydrate ligand. Mycobacterium tuberculosis, the causative agent of tuberculosis, produces sulfated molecules that have eluded functional characterization for decades. 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. Metabolic labeling of recombinant interferon-beta and GlyCAM-Ig was achieved, demonstrating the utility of the method for functionalizing N-linked and O-linked glycoproteins of therapeutic interest. The sulfite generated in this reaction is utilized in bacteria and plants for the eventual production of essential biomolecules such as cysteine and coenzyme A. These reactions can be used to tag glycans with imaging probes or epitope tags, thus enabling the visualization or enrichment of glycoconjugates. The ketone undergoes highly selective condensation reactions with complementary nucleophiles such as aminooxy and hydrazide groups. Because M. tuberculosis catabolizes host lipids to grow during infection, we propose that growth of M. tuberculosis on fatty acids in vivo leads to increased flux of MMCoA through lipid biosynthetic pathways, resulting in increased virulence lipid synthesis. A key tool in this study is the Staudinger ligation, a highly selective reaction between modified triarylphosphines and azides that produces an amide-linked product. 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Different Types Of Asian Eyes By Country, Articles C
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