carolyn bertozzi biography

Molecular level analysis of cell-surface phenomena could benefit from model systems comprising structurally defined components. We anticipate that this chemical method will find broad use in epigenetics to enable unbiased searches for new PKMT substrates by using recombinant enzymes and unnatural SAM cofactors to label and purify many substrates simultaneously from complex organelle or cell extracts. Third, omega-alkynyl-myristate is specifically incorporated into endogenous co- and posttranslationally myristoylated proteins. Generated in nine steps from a glucose analogue, DIMAC reacted with azide-labeled proteins and cells similarly to cyclooctynes. Here we describe a biarylazacyclooctynone (BARAC) that has exceptional reaction kinetics and whose synthesis is designed to be both modular and scalable. Rigidity and core glycosylation are therefore insufficient to ensure molecular projection outward from a membrane surface. Binding was EDTA-sensitive and blocked by L-selectin-specific monoclonal antibodies. These functional groups can then undergo covalent reaction with exogenous agents bearing complementary functionality. Furthermore, Rv0516c disruption modified peptidoglycan thickness, enhanced antibiotic resistance, and activated genes in the regulon of the alternative -factor SigF. The Leu-13 --> Gly (L13G) mutation is found in each of the three MetRS mutants, and the MetRS variant containing this single mutation is highly efficient in producing recombinant proteins that contain azidonorleucine. Zurich (2009); Harrison Howe Award (2009); W. H. Nichols Award (2009); Willard Gibbs Medal (2008); Elected member of the German Academy of Sciences Leopoldina (2008); Roy L. Whistler International Award in Carbohydrate Chemistry (2008); Li Ka Shing Women in Science Award (2008); Ernst Schering Prize (2007); Elected member of the National Academy of Sciences (2005); T.Z. We designed synthetically tractable glycosylated polymers that possess rodlike extended conformations similar to natural mucins. Our results reveal that these transferases have unique peptide and glycopeptide preferences demonstrating their substrate diversity and their likely roles ranging from initiating transferases to filling-in transferases. These results establish the foundation for further development of BPDA-based colorimetric sensors. Genomic and proteomic profiling form a basis for biological discovery. We functionalized cells with short oligonucleotides to impart specific adhesive properties. 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. These techniques have permitted the study of molecular components within the context of living cells. View details for DOI 10.1073/pnas.0506855103, View details for Web of Science ID 000236472500008, View details for PubMedCentralID PMC1405625. Cells are modified with membrane-bound single-stranded DNA, and specific single-cell capture is directed by the complementary strand bound in the sensor area of the iridium oxide pH microelectrodes within a microfluidic channel. View details for DOI 10.1371/journal.pone.0065080, View details for Web of Science ID 000321099000031, View details for PubMedCentralID PMC3675115. 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. We used this method to identify interaction partners for the O-GlcNAc-modified FG-repeat nucleoporins. Hatzios, S. K., Iavarone, A. T., Bertozzi, C. R. Noncovalent cell surface engineering: Incorporation of bioactive synthetic glycopolymers into cellular membranes. Analyses revealed that recurrent GBMs have increased tension and express high levels of glycoproteins that increase the bulkiness of the glycocalyx. Time-resolved measurements yield the binding rate between the particles and bacteria. Agard, N. J., Baskin, J. M., Prescher, J. Griffin, J. E., Pandey, A. K., Gilmore, S. A., Mizrahi, V., McKinney, J. D., Bertozzi, C. R., Sassetti, C. M. Imaging the Sialome during Zebrafish Development with Copper-Free Click Chemistry. Mild hydrolysis conditions were established that released sulfated oligosaccharides without cleavage of sulfate esters. The new molecule class may be able to degrade some cardiovascular disease and cancer targets. Glycocalyx Engineering with a Recycling Glycopolymer that Increases Cell Survival In Vivo. This approach enables two measurements: glycocalyx height and the distribution of individual sugars distal from the membrane. View details for Web of Science ID 000077136900049, View details for Web of Science ID 000076649700013, View details for Web of Science ID 000075884200020. Spiciarich, D. R., Nolley, R., Maund, S. L., Purcell, S. C., Herschel, J., Iavarone, A. T., Peehl, D. M., Bertozzi, C. R. Corneal surface glycosylation is modulated by IL-1R and Pseudomonas aeruginosa challenge but is insufficient for inhibiting bacterial binding. However, controlled investigations of the relationships between glycosylation, rigidity, and extension of membrane-bound mucins or similar macromolecules are lacking, largely because of the absence of tractable experimental models. Protocol for cell type-specific labeling, enrichment, and proteomic profiling of plasma proteins in mice. Taken together, this method offers a potentially powerful new chemical tool for studying simultaneous oxidative stress and inflammation processes in living animals during injury, aging, and disease, as well as a versatile approach for concurrent monitoring of multiple analytes using luciferin-based bioluminescence imaging technologies. View details for Web of Science ID 000280227700012, View details for PubMedCentralID PMC2907714. The most widely used CID, the natural product rapamycin and its relatives, is immunosuppressive due to interactions with endogenous targets and thus has limited utility in vivo. Neutralization of acidic organelles directly with ammonium chloride or indirectly with bafilomycin A1 partially abrogated the growth restriction of these drugs. WebBertozzi is a professor of Humanities and Sciences, and of Chemical and Systems Biology and of Radiology. Carolyn Bertozzi, PhD, was one of three scientists to be awarded the 2022 Nobel Prize in Chemistry earlier today for the development of click chemistry and bio-orthogonal chemistry. Professor of Chemical & Systems Biology and Radiology Mockl, L., Pedram, K., Roy, A., Krishnan, V., Gustavsson, A., Dorigo, O., Bertozzi, C., Moerner, W. Enzyme toolkit for selective enrichment and analysis of mucin-domain glycoproteins. Detailed biochemical analyses of physiological selectin ligands have revealed a complicated composition of molecules that bind to the selectins in vivo and suggest that there are other requirements for tight binding beyond simple carbohydrate multimerization. Both reactive partners are abiotic and chemically orthogonal to native cellular components. 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. At 60 hours after fertilization, we observed an increase in de novo glycan biosynthesis in the jaw region, pectoral fins, and olfactory organs. Protein glycosylation can have an enormous variety of biological consequences, reflecting the molecular diversity encoded in glycan structures. 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. 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. WebDr. Several changes have been made to the SNFG page in the past year to update the rules for depicting glycans using the SNFG, to include more examples of use, particularly for non-mammalian organisms, and to provide guidelines for the depiction of ambiguous glycan structures. Dehnert, K. W., Beahm, B. J., Huynh, T. T., Baskin, J. M., Laughlin, S. T., Wang, W., Wu, P., Amacher, S. L., Bertozzi, C. R. Metabolic cross-talk allows labeling of O-linked beta-N-acetylglucosamine-modified proteins via the N-acetylgalactosamine salvage pathway. View details for Web of Science ID 000264983800005, View details for PubMedCentralID PMC2709817. Harland, C. W., Botyanszki, Z., Rabuka, D., Bertozzi, C. R., Parthasarathy, R. Crosslinking Studies of Protein-Protein Interactions in Nonribosomal Peptide Biosynthesis. Luchansky, S. J., Argade, S., Hayes, B. K., Bertozzi, C. R. The stem region of the sulfotransferase GlcNAc6ST-1 is a determinant of substrate specificity, Chemical tools for the study of polysialic acid, Chemical remodelling of cell surfaces in living animals. Research on the human pathogen Mycobacterium tuberculosis (Mtb) would benefit from novel tools for regulated gene expression. In this review, we describe the important role that chemical glycoproteomics methods are playing in such efforts. We demonstrated that these catalytically inactive point mutants enable robust detection and visualization of mucin-domain glycoproteins by flow cytometry, Western blot, and immunohistochemistry. Intact glycopeptides are recovered by cleavage of the probe, analyzed with directed MS, and assigned by targeted mass-independent data analysis. The enzymes that determine protein O-GlcNAcylation, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), act on key transcriptional and epigenetic regulators, and both are abundantly expressed in the brain. The detection yield of viable Mtb improved from 43% (median 2 CFU, range: 1-14) to 95% (median 20.5 DMN-Trehalose positive bacilli, range: 2-155). In a proof-of-principle proteomics experiment, we used metabolic GalNAz labeling of human cells and a bioorthogonal chemical probe to affinity-purify and identify numerous O-GlcNAcylated proteins. Shui, W., Gilmore, S. A., Sheu, L., Liu, J., Keasling, J. D., Bertozzi, C. R. Synthesis, Characterization, and Theory of [9]-, [12]-, and [18]Cycloparaphenylene: Carbon Nanohoop Structures. Sialic Acid Glycobiology Unveils Trypanosoma cruzi Trypomastigote Membrane Physiology. Finally, we found that metabolic labeling of both cell envelope structures reports on drug effects on cell physiology in two hours, far faster than a genetic sensor of cell envelope stress. Here we studied the function of novel germline variants in CSF3R at amino acid N610. The synthetic, full-length polypeptide proved to be active in growth inhibition assays with an IC(50) of approximately 250 nM, a concentration similar to that found in the insect hemolymph. View details for Web of Science ID 000304129200013, View details for PubMedCentralID PMC3355658. 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 ketone group within the levulinoyl side chain of SiaLev was then used as a chemical handle for detection using a biotin probe. Such structural alterations to cell surface glycans can be used to probe carbohydrate-dependent phenomena. Conrad, R. M., Grogan, M. J., Bertozzi, C. R. Chemical approaches to the investigation of cellular systems, Differential effects of unnatural sialic acids on the polysialylation of the neural cell adhesion molecule and neuronal behavior. These hallmarks of Mtb infection are facilitated by the metabolic adaptation of the pathogen to its surrounding environment and the biosynthesis of molecules that mediate its interactions with host immune cells. These data highlight the power of advanced imaging methods to provide molecular and functional insights into glycocalyx biology. The absence of viral receptors is a major barrier to efficient gene transfer in many cells. A., Krishnan, V. n., Pett, C. n., Yu, J. n., Woods, E. C., Kramer, J. R., Westerlind, U. n., Dorigo, O. n., Bertozzi, C. R. Quantitative Super-Resolution Microscopy of the Mammalian Glycocalyx. The rapid assembly of a complex type N-linked glycopeptide mimetic was accomplished using this technique. The formylglycine-generating enzyme (FGE) is required for the posttranslational activation of type I sulfatases by oxidation of an active-site cysteine to Calpha-formylglycine. A single multiwalled carbon nanotube attached to an atomic force microscope (AFM) tip was functionalized with cargo via a disulfide-based linker. In contrast, exogenous (13)C-labeled N-acetylneuraminic acid ([(13)C]NeuAc) and N-glycolylneuraminic acid (NeuGc) were efficiently incorporated into LOS in a dose-dependent fashion. Chemistry Central Office We demonstrate that cyp128 and stf3 are sufficient for the biosynthesis of SMK from menaquinone and rv2269c exhibits promoter activity in M. tuberculosis. In addition to being a constituent of glycerolipids and a source of energy, palmitate also covalently attaches to numerous cellular proteins via a process named palmitoylation. The approach was applied to the sialic acid metabolic pathway in human cells, yielding novel mutants with phenotypes related to the inborn metabolic defect sialuria and metastatic tumor cells. The C-type lectins dectin-1 and dectin-2 contribute to innate immunity against microbial pathogens by recognizing their foreign glycan structures. 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. Inducible genetic inhibition of angiogenesis and Vegf signaling during granuloma formation results in bacterial growth deficits. Highlights of recent progress include an extension of the list of instances of selectin participation in inflammatory diseases, further definition of selectin carbohydrate specificities, and identification of their carbohydrate-based ligands. Importantly, glycopolymers containing biologically relevant branched oligosaccharides, such as sialyl Lewis(x), as well as sulfated glycosaminoglycan-like epitopes can be readily prepared using our methodology. Mycobacterium tuberculosis, the causative agent of tuberculosis, produces unique sulfated metabolites associated with virulence. View details for Web of Science ID 000246816400009. One such glycolipid, Sulfolipid-1 (SL-1), consists of a trehalose-2-sulfate (T2S) core acylated with four lipid moieties. Chen, X., Kis, A., Zettl, A., Bertozzi, C. R. Hierarchical assembly of model cell surfaces: Synthesis of mucin mimetic polymers and their display on supported bilayers. This challenging process made her dream of The alkyl azide was then selectively derivatized with cyclo-octyne conjugates to various probes. The conversion of cysteine to formylglycine is accomplished by co-overexpression of FGE, either transiently or as a stable cell line, and the resulting aldehyde can be selectively reacted with -nucleophiles to generate a site-selectively modified bioconjugate. In conclusion, the new ADAP assay can reliably detect the three cardinal islet autoantibodies/antibodies in 1muL serum with high sensitivity. View details for DOI 10.1074/jbc.M405709200, View details for Web of Science ID 000223791500101, View details for Web of Science ID 000225338800003. [45], In 2019, she co-founded both OliLux Biosciences and Lycia Therapeutics. The structure, high-resolution Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry, and quantitative kinetic analysis, establish that the two chemically discrete steps of the overall reaction take place at distinct sites on the enzyme, mediated via conformational flexibility of the C-terminal 18 residues. and Kirk Schanze and Lee, {T. Randall} and Lutkenhaus, {Jodie L.} and David Kaplan and Christopher Jones and Carolyn Bertozzi and Laura Kiessling and Mulcahy, {Mary Beth} and Lindsley, {Craig W.} and Finn, {M. G.} and Blum, {Joel D.} and Prashant Kamat and Genome-wide CRISPR screens reveal a specific ligand for the glycan-binding immune checkpoint receptor Siglec-7. View details for DOI 10.1002/anie.201508861, View details for Web of Science ID 000368061800024, View details for PubMedCentralID PMC4715665. Consistent with other studies, we find that O-GlcNAc sites in T cells lack a strict consensus sequence. Mauris, J., Mantelli, F., Woodward, A. M., Cao, Z., Bertozzi, C. R., Panjwani, N., Godula, K., Argueeso, P. Sulfatase-activated fluorophores for rapid discrimination of mycobacterial species and strains. 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. Consistent with an inverting mechanism, EnvSia156 reveals a His/Asp active center in which the His acts as a Brnsted acid and Asp as a Brnsted base in a single-displacement mechanism. Phagocytosis is initiated by lateral clustering of receptors, which in turn activates Src-family kinases (SFKs). View details for Web of Science ID 000207584000003, View details for PubMedCentralID PMC138933. This review discusses the structural diversity of the GPI anchor and its putative cellular functions, including involvement in lipid raft partitioning, signal transduction, targeting to the apical membrane, and prion disease pathogenesis. [22][26] She has been an investigator with HHMI since 2000. View details for Web of Science ID 000338992200029. Chemical or genetic disruption of NGLY1 activity results in the accumulation of misprocessed Nrf1 that is largely excluded from the nucleus. We found that the fucose salvage pathway enzymes are expressed during zebrafish embryogenesis but that they process the azide-modified substrates inefficiently. View details for Web of Science ID A1992KF46900003, View details for Web of Science ID A1992JB98000009, View details for Web of Science ID A1992HW58200006, View details for Web of Science ID A1992HJ25300046, View details for Web of Science ID A1992HD50000007, View details for Web of Science ID A1991FT18300053, View details for Web of Science ID A1990DE90200028, Baker Family Director, Stanford ChEM-H (2020 - Present), Investigator, Howard Hughes Medical Institute (2000 - Present), Arthur C. Cope Award, American Chemical Society (2017), National Academy of Sciences Award in the Chemical Sciences, National Academy of Sciences (2016), Ernest Orlando Lawrence Award, U.S. Department of Energy (2015), Heinrich Wieland Prize, Heinrich Wieland Prize (2012), Lemelson-MIT Prize, Massachusetts Institute of Technology (2010), Ernst Schering Prize, Ernst Schering Research Foundation (2007), Distinguished Teaching Award, UC Berkeley College of Chemistry (2001), Award in Pure Chemistry, American Chemical Society (2001), MacArthur Foundation Genius Award, MacArthur Foundation (1999), Arthur C. Cope Scholar Award, American Chemical Society (1999), Honorary Degree, Freie University Berlin (2014), Honorary Doctorate Degree, Duke University (2014), Hans Bloemendal Award, Radboud Univ. View details for Web of Science ID 000237590400012. This Account summarizes chemoselective approaches for assembling homogeneous glycoconjugates that attempt to reduce the barriers to their synthesis. This purpose of this mini review is to familiarizereaders with the tools currently available for the synthesis of mucin-typeglycoproteins. We constructed a glycoprotein expression signature, which revealed that metastatic tumours upregulate expression of bulky glycoproteins. A., Sun, J., Iram, T., Bonanno, L., Li, L., Lee, D. P., Morgens, D. W., Yang, A. C., Shuken, S. R., Gate, D., Scott, M., Khatri, P., Luo, J., Bertozzi, C. R., Bassik, M. C., Wyss-Coray, T. Towards Mycobacterium tuberculosis detection at the point-of-care: solvatochromic probes permits the detection of mycobacteria within minutes, Orthogonal enzyme/substrate engineering to profile biological substrates of glycosyltransferases, Glyco-immune modulation in the tumor microenvironment, Formylglycine-generating enzyme binds substrate directly at a mononuclear Cu(I) center to initiate O-2 activation. Chung, S., Shin, S., Bertozzi, C. R., De Yoreo, J. J. Difluorobenzocyclooctyne: Synthesis, Reactivity, and Stabilization by beta-Cyclodextrin. Hatzios, S. K., Schelle, M. W., Newton, G. L., Sogi, K. M., Holsclaw, C. M., Fahey, R. C., Bertozzi, C. R. Isotopic Signature Transfer and Mass Pattern Prediction (IsoStamp): An Enabling Technique for Chemically-Directed Proteomics. Their reactive carbonyl groups are typically conjugated with -effect nucleophiles, such as substituted hydrazines and alkoxyamines, to generate hydrazones and oximes, respectively. She grew up in Lexington, Massachusetts with two sisters, one of which is on the mathematics faculty at the University of California, Los Angeles (UCLA). WebCarolyn Bertozzi is the Anne T. and Robert M. Bass Professor of Chemistry and Professor of Chemical & Systems Biology and Radiology (by courtesy) at Stanford University, the Both significantly outperform EThcD methods, indicating that ETD-based methods are not required for routine N-glycoproteomics. These results shed light on the physical barriers that modulate phagocytosis, which have been heretofore underappreciated. 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. The biological study of O-linked glycosylation is particularly problematic, as chemical tools to control this modification are lacking. View details for DOI 10.1073/pnas.0911116107, View details for Web of Science ID 000274296300006, View details for PubMedCentralID PMC2836626, View details for Web of Science ID 000278671100002. In particular, she showed that such reactions could be carried out inside living cells to map molecules and cell function, without disturbing normal cellular chemistry. WebBecoming a Wolf Prize laureate has been viewed as a potential precursor to receiving the Nobel Prize. Hang, H. C., Yu, C., Pratt, M. R., Bertozzi, C. R. 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That modulate phagocytosis, which revealed that metastatic tumours upregulate expression of bulky glycoproteins we find that O-GlcNAc sites T... Dectin-1 and dectin-2 contribute to innate immunity against microbial pathogens by recognizing their foreign glycan structures distribution individual. Bafilomycin A1 partially abrogated the growth restriction of these drugs individual sugars distal from the membrane enhanced antibiotic resistance and... Is designed to be both modular and scalable endogenous co- and posttranslationally myristoylated proteins glycopeptides. To receiving the Nobel Prize components within the levulinoyl side chain of SiaLev was then selectively with... Or genetic disruption of NGLY1 activity results in bacterial growth deficits from novel tools for regulated gene expression reaction exogenous. In glycan structures Biology and of Radiology analyzed with directed MS, and assigned targeted... 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