Indeed, O-glycopeptides modified exclusively at the N-terminus would enable O-glycoproteomic methods to rely solely on collision-based fragmentation rather than electron-driven dissociation because glycan-retaining peptide fragments would not be required for localization. View details for DOI 10.1073/pnas.0807820106, View details for Web of Science ID 000263844100008, View details for PubMedCentralID PMC2651276. Harland, C. W., Botyanszki, Z., Rabuka, D., Bertozzi, C. R., Parthasarathy, R. Crosslinking Studies of Protein-Protein Interactions in Nonribosomal Peptide Biosynthesis. In an emerging strategy, glycans are imaged by metabolic labeling with chemical reporters and subsequent ligation to fluorescent probes. We specifically highlight studies in which chemically synthesized GPI anchors and analogues have been employed to study the roles of this unique posttranslational modification. These data unambiguously establish the configuration of the resting enzyme metal center and, importantly, reveal the formation of a three-coordinate tris(thiolate) trigonal planar complex upon substrate binding as furthermore supported by density functional theory (DFT) calculations. We also show that the integral membrane protein Sap and MmpL8 are both essential for sulfolipid transport. Chemical or genetic disruption of NGLY1 activity results in the accumulation of misprocessed Nrf1 that is largely excluded from the nucleus. Finally, the lipase inhibitor tetrahydrolipstatin disrupts Chp1 activity in M. tuberculosis, suggesting an avenue for perturbing SL-1 biosynthesis in vivo. To accomplish this goal, we took advantage of the bioorthogonal chemical reporter technique. Kehoe, J. W., Velappan, N., Walbolt, M., Rasmussen, J., King, D., Lou, J., Knopp, K., Pavlik, P., Marks, J. D., Bertozzi, C. R., Bradbury, A. R. Substrate recognition, protein dynamics, and iron-sulfur cluster in Pseudomonas aeruginosa adenosine 5 '-phosphosulfate reductase. To determine whether PapA3 participates in PAT assembly, we expressed the protein heterologously and evaluated its acyltransferase activity in vitro. Metastasis depends upon cancer cell growth and survival within the metastatic niche. Cell surface carbohydrates mediate interactions between the cell and its environment. Cyclodextrin complexation is therefore a promising approach for stabilizing compounds that possess the high intrinsic reactivities desired for Cu-free click chemistry. About that time, she also began mapping a specific glycana type of carbohydrate typically found on the surface of cellsthat specializes in attracting immune cells toward the lymph nodes. in these pages has relative advantages and disadvantages. Spreading of a mycobacterial cell surface lipid into host epithelial membranes promotes infectivity. Zhou, X., Rodriguez-Rivera, F. P., Lim, H., Bell, J. C., Bernhardt, T. G., Bertozzi, C. R., Theriot, J. View details for Web of Science ID 000246816400009. WebAn important step is to identify the key go/nogo experiments that would" - Carolyn Bertozzi (@CarolynBertozzi) - Prof @Stanford & Bioorthogonal Chemistry Pioneer Shoutout: @EnableBio, @Palleon_Pharma, @vennbio, @OliluxB, @gracescience, @LyciaTx, @NobelPrize! Formylglycine generating enzyme (FGE) performs a critical posttranslational modification of type I sulfatases, converting cysteine within the motif CxPxR to the aldehyde-bearing residue formylglycine (FGly). We exploited StcE's unique properties to improve sequence coverage, glycosite mapping, and glycoform analysis of recombinant human mucins by mass spectrometry. Her research group profiles changes in cell surface glycosylation associated with cancer, inflammation and bacterial infection, and uses this information to develop new diagnostic and therapeutic approaches, most recently in the area of immuno-oncology. Mycobacteria are endowed with a highly impermeable mycomembrane that confers intrinsic resistance to many antibiotics. 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. WebCarolyn Ruth Bertozzi (born October 10, 1966) is an American chemist. Click chemistry obviates the requirement of phosphines, but the Cu(I) catalyst is toxic to cells, thereby precluding in vivo applications. Additionally, we have utilized computational methods to understand the unique properties of these fully conjugated macrocycles. Here we performed a systematic analysis of the effects of strain and electronics on the reactivity of cyclooctynes with azides through both experimental measurements and computational studies using a density functional theory (DFT) distortion/interaction transition state model. Comparison of the photoacoustic signal for dansylamide versus standard compounds (ferrocene, tetraphenylethylene, 8-anilinonaphthalene-1-sulfonate, and/or 5,5'-dithiobis(2-nitrobenzoic acid) in 12 different solvents gave fh values (fraction of each absorbed 337.1-nm photon returned as heat) from a low of 0.530 in 1,4-dioxane to a high of 0.973 in water. Previously, we developed isotope-targeted glycoproteomics (IsoTaG) as a mass-independent mass spectrometry method to characterize azide-labeled intact glycopeptides from complex proteomes. Site-selective protein modification based on covalent reactions of peptide tags and small molecules is a key capability for basic research as well as for the development of new therapeutic bioconjugates. These multivalent arrays are 4 orders of magnitude better than the monovalent carbohydrate. WebCarolyn R. Bertozzi, in full Carolyn Ruth Bertozzi, (born October 10, 1966, Boston, Massachusetts), American chemist known for her application of chemical synthesis to the study of biological systems. Stanford University biochemist Carolyn Bertozzi is a highly admired scientist, entrepreneur, and advocate for diversity, particularly for LGBTQ+ people. The inhibitory activity of 1-68A and a panel of synthetic analogues identified moieties necessary for inhibition. Direct visualization of proteins via the green fluorescent protein (GFP) and its congeners has revolutionized the field of protein dynamics. The GALNT3-dependent glycoproteins identified by this metabolic labeling approach support the oncogenic role of GALNT3 in EOC dissemination and may be pursued as novel EOC biomarkers and/or therapeutic targets.Knowledge of the O-glycoproteome has been relatively elusive, and the functions of the individual polypeptide GalNAc-Ts have been poorly characterized. The optimal configuration of sulfate esters on the N-acetyllactosamine (Galbeta1-->4GlcNAc) core of sulfosialyl-Le(X), however, remains unsettled. Polydiacetylene-based systems are attractive for sensing applications due to their colorimetric response to changes in the local environment. These discoveries at the forefront of biological research have motivated the design of synthetic glycoconjugates as tools for the fundamental study of glycobiology and as candidates for future generations of therapeutic and pharmaceutical reagents. GPI-anchored proteins are structurally and functionally diverse and play vital roles in numerous biological processes. 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. We also found that malignant breast cells possess higher levels of nuclear Gal-1 and 2,6-SA and lower levels of LacNAc than nonmalignant cells in culture and in vivo and that nuclear localization of Gal-1 promotes a transformed phenotype. They comprised glycopolypeptides bearing mono-, di-, and trisaccharides and were built through polymerization of glycosylated N-carboxyanhydrides. Here, we report the use of azido-modified unnatural sialic acid to identify those molecules that act as cell surface acceptors of the sialyl residue in the trans-sialidase-catalyzed reaction, which might then be involved in the immune alterations induced. Such activatable probes with near-infrared (NIR) emission would be ideal for in vivo imaging but have proven difficult to engineer. Interestingly, two sulfotransferase genes are highly similar to mammalian sulfotransferases, increasing the list of mycobacterial eukaryotic-like protein families. Using in situ atomic force microscopy to follow 2D assembly of S-layer proteins on supported lipid bilayers, we have obtained a molecular-scale picture of multistage protein crystallization that reveals the importance of conformational transformations in directing the pathway of assembly. This genetically encoded 'aldehyde tag' is no larger than a His(6) tag and can be exploited for numerous protein labeling applications. However, SL-1 per se is not required for establishing infection as pks2 mutants, which are defective in an earlier step in SL-1 biosynthesis, have no obvious growth defect. The polypeptide N-alpha-acetylgalactosaminyltransferases (ppGalNAcTs) play a key role in mucin-type O-linked glycan biosynthesis by installing the initial GalNAc residue on the protein scaffold. In this work, we apply an aluminum "lift off" lithography method to allow the efficient generation of complex patterns comprising different DNA sequences. The azide, being nonreactive within cells, was ideal for use in living systems. The results also mean that distinguishing stem cells from other mammalian cells may be facilitated by the major difference in the glycosylation of the cell membrane. Concomitantly, a subpopulation of neural progenitor cells (NPCs) acquired an immature neuronal morphology and expressed early neuronal markers such as -III tubulin (TUJ1) and microtubule associated protein 2 (MAP2), phenotypes that took longer to manifest in the absence of OGT inhibition. From a panel of synthetic derivatives, we identified an azido GalNAc analog (N-azidoacetylgalactosamine, GalNAz) that is metabolized by numerous cell types and installed on mucin-type O-linked glycoproteins by the ppGalNAcTs. Author Correction: Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Collectively, these chemical approaches are contributing great insight into the myriad biological functions of oligosaccharides. She described the reaction between the modified sugar and the fluorescent molecule as bioorthogonal. Gilmore, S. A., Schelle, M. W., Holsclaw, C. M., Leigh, C. D., Jain, M., Cox, J. S., Leary, J. Higher order oligosaccharides were readily generated by alkylation of the corresponding 3-thioGalNAc with N-bromoacetamido sugars. Jasti, R., Bhattacharjee, J., Neaton, J. View details for DOI 10.1074/mcp.M600314-MCP200, View details for Web of Science ID 000242852000012. Mycobacterium tuberculosis possesses an unusual cell wall that is replete with virulence-enhancing lipids. This review highlights changes in glycosylation associated with cancer and chronic inflammation and new therapeutic and diagnostic strategies that are based on the underlying glycobiology. Shon, D. J., Malaker, S. A., Pedram, K. n., Yang, E. n., Krishnan, V. n., Dorigo, O. n., Bertozzi, C. R. A Pragmatic Guide to Enrichment Strategies for Mass Spectrometry-Based Glycoproteomics. 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. Therefore, shedding of TS occurs via microvesicles instead of as a fully soluble form. The quadricyclane (QC) ligation is a bioorthogonal reaction between a quadricyclane moiety and a nickel bis(dithiolene) derivative. Yet, our understanding of the invivo ligands and function for most lectins is still incomplete. Although the sulfated xenobiotics bind poorly to the ER, both stimulated the growth of receptor-positive breast tumor cells. 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. 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 Many identified proteins were not previously known to reside in the phagosome. A Pragmatic Guide to Enrichment Strategies for Mass Spectrometry-based Glycoproteomics. Glycopeptide-bound glycans observed by IsoTaG were found to be comparable to released N-glycans identified by permethylation analysis. We used the CalFluor probes to image various alkyne-labeled biomolecules (glycans, DNA, RNA, and proteins) in cells, developing zebrafish, and mouse brain tissue slices. We used this method to regulate production of sialyl Lewis x by alpha1,3-fucosyltransferase VII in living cells. Additionally, we demonstrate that in C. glutamicum, the peripheral peptidoglycan layer at the septal junction remains contiguous throughout septation, forming a diffusion barrier for the fluid mycomembrane. Shurer, C. R., Kuo, J., Roberts, L., Gandhi, J. G., Colville, M. J., Enoki, T. A., Pan, H., Su, J., Noble, J. M., Hollander, M. J., O'Donnell, J. P., Yin, R., Pedram, K., Mockl, L., Kourkoutis, L. F., Moerner, W. E., Bertozzi, C. R., Feigenson, G. W., Reesink, H. L., Paszek, M. J. Finally, we show that normal V snapping in C. glutamicum depends on complete assembly of the septal cell envelope. Despite recent progress, important mechanistic questions, such as the precise bacterial targets, the nature of any cooperation that occurs between peptides, and the purpose of multiple peptide isoforms, remain largely unanswered. We used this technique to image fucosylated glycans in the enveloping layer of zebrafish embryos during the first 5 days of development. Using ADAP, we detected anti-thyroglobulin autoantibodies from human patient plasma with a 1000-fold increased sensitivity over an FDA-approved radioimmunoassay. The response of the macrophage proteome to M. tuberculosis lipids reflects the cell's innate defense mechanisms as well as lipid-induced processes that may benefit the pathogen. The cysH mutant caused disease and death after 4-7 weeks of infection in four different groups of mice - Rag1(-/-), NOS2(-/-), gp91phox(-/-) NOS2(-/-) and gp91phox(-/-) mice given aminoguanidine [to suppress the effects of nitric oxide synthase 2 (NOS2)]- indicating minimal metabolic effect on the cysH mutant survival in these mice. Site-directed mutagenesis of any cysteine residue within the conserved motif led to a loss of cluster with a concomitant loss in catalytic activity, while secondary structure was preserved. In contrast, particles bound to L. monocytogenes are effectively immobilized and relax in about 1 s by rotation of the internal dipole moment. Furthermore, the membrane-bound glycopolymers were internalized into early endosomes similarly to endogenous membrane components and were capable of specific interactions with protein receptors. These results establish a platform for engineering S-layer assemblies with 3-D architecture. These data show that the normal distribution of surface glycosylation requires IL-1R, but not MyD88, and is not sufficient to prevent bacterial binding. The above reactions, as well as several newcomers with bioorthogonal attributes, have enabled the high-precision chemical modification of biomolecules in vitro, as well as real-time visualization of molecules and processes in cells and live organisms. 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. Swarts, B. M., Holsclaw, C. M., Jewett, J. C., Alber, M., Fox, D. M., Siegrist, M. S., Leary, J. Azides installed within cell surface glycoconjugates by metabolism of a synthetic azidosugar were reacted with a biotinylated triarylphosphine to produce stable cell-surface adducts. One leads directly to the final low-energy state and the other to the kinetic trap. The mobility of CD45 increased markedly upon engagement of Fc receptors. Oligosaccharides transact information exchange at the cell surface and modulate the activities and distribution of proteins within cells. The study of glycan function is a major frontier in biology that could benefit from small molecules capable of perturbing carbohydrate structures on cells. A. Sequential assembly of the septal cell envelope prior to V snapping in Corynebacterium glutamicum. Within this bilayered structure, registry between lattices in two layers was disclosed, whereas the intrinsic symmetry in each layer was altered. [43], In 2017, Bertozzi helped found InterVenn Biosciences, which uses mass spectrometry and artificial intelligence to enhance glycoproteomics for target and biomarker discovery, ovarian cancer diagnostics, and predicting the successes and failures of clinical trials. View details for Web of Science ID 000227308100055. Chemical inducers of dimerization (CIDs) are cell-permeable small molecules capable of dimerizing two protein targets. View details for DOI 10.1002/cbic.201000433, View details for Web of Science ID 000286433800014, View details for PubMedCentralID PMC3056122. Methods for directing the cell surface expression of novel protein-based and oligosaccharide-based epitopes are stimulating new directions in biotechnology and biomedical research. We designed phosphine-luciferin reagent 1 to activate bioluminescence in response to Staudinger ligation with azide-labeled glycans. Both the activity and specificity of the inducible enzymes were indistinguishable from their WT counterparts. This sensitive assay quantifies specific bacteria in a sample without the need to immobilize them or wash away unbound magnetic particles. The discovery of novel sulfated metabolites in M. tb and related mycobacteria strengthens this hypothesis. Finally, the Delta papA2 and Delta papA1 mutants were screened for virulence defects in a mouse model of infection. Cholesterol Catabolism by Mycobacterium tuberculosis Requires Transcriptional and Metabolic Adaptations. Sialic acids are a family of related sugars that play essential roles in many biological events intimately linked to cellular recognition in both health and disease. In this mechanism, PAPS and trehalose bind and their products are released in random fashion. Mtb capture was calculated per exhaled air volume sampled and bioaerosol volume for RASC-1 (n = 35) and for RASC-2 (n = 21). Kinetic analysis of the mutants identified residues that are essential for catalytic activity. View details for DOI 10.1096/fj.07-9198com, View details for Web of Science ID 000254143700018, View details for PubMedCentralID PMC2865240. We disabled key enzymes required for each of the three pathways in M. smegmatis by allelic replacement. WebCarolyn Bertozzi, PhD. View details for Web of Science ID 000240465200023, View details for PubMedCentralID PMC3233198. Although theoretical predictions suggest that proteins follow these pathways as a result of fluctuations that create unstable dense-liquid states, microscopic studies indicate these states are long-lived. Debets, M. F., Tastan, O. Y., Wisnovsky, S. P., Malaker, S. A., Angelis, N. n., Moeckl, L. K., Choi, J. n., Flynn, H. n., Wagner, L. J., Bineva-Todd, G. n., Antonopoulos, A. n., Cioce, A. n., Browne, W. M., Li, Z. n., Briggs, D. C., Douglas, H. L., Hess, G. T., Agbay, A. J., Roustan, C. n., Kjaer, S. n., Haslam, S. M., Snijders, A. P., Bassik, M. C., Moerner, W. E., Li, V. S., Bertozzi, C. R., Schumann, B. n. Delaveris, C. n., Wilk, A. n., Riley, N. n., Stark, J. n., Yang, S. n., Rogers, A. n., Ranganath, T. n., Nadeau, K. n., Blish, C. n., Bertozzi, C. n. Systematic discovery and functional interrogation of SARS-CoV-2 viral RNA-host protein interactions during infection. Synthetically lipidated recombinant green fluorescent protein (GFP) was shown to be stably anchored to the membrane, and its lateral fluidity was quantitatively characterized by direct fluorescence imaging in supported membranes. Here we highlight chemical tools that are beginning to address this need. We describe the application of click-EM in imaging metabolically tagged DNA, RNA and lipids in cultured cells and neurons and highlight its use in tracking peptidoglycan synthesis in the Gram-positive bacterium Listeria monocytogenes. View details for Web of Science ID 000089664300011, View details for Web of Science ID 000089432300004. View details for DOI 10.1016/j.cbpa.2003.08.006, View details for Web of Science ID 000186448100015. 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. Riley, N. M., Bertozzi, C. R., Pitteri, S. J. 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). Using in situ Atomic Force Microscopy to investigate S-layer assembly on mica, we show this concept is equally valid during self-assembly of proteins into extended matrices. Winans, K. A., King, D. S., Rao, V. R., Bertozzi, C. R. Engineering novel cell surface receptors for virus-mediated gene transfer. Using this method, we identified 21 putative palmitoylated proteins in the rat liver mitochondrial matrix, a compartment not recognized for its content in palmitoylated proteins, and confirmed the palmitoylation of newly identified mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase. In the Several unique mycomembrane glycolipids have been isolated and structurally characterized, but the underlying organization and dynamics of glycolipids within the cell envelope remain poorly understood. These findings suggest a dual role for trehalose as both a thermoprotectant and a precursor of critical cell wall metabolites. This represents over a million-fold signal amplification in comparison to using radioactive labeling methods. However, inside infected macrophages, bacteria encounter an environment which differs substantially from broth culture and are subject to important host-dependent pharmacokinetic phenomena which modulate drug activity. Previous reports have shown that synthetic DNA strands can be attached to the plasma membrane of living cells to equip them with artificial adhesion "receptors" that bind to complementary strands extending from material surfaces. The system was used to induce and repress heterologous protein overexpression reversibly, to create a conditional gene knockdown, and to control gene expression in a macrophage infection model. The approach was validated by labeling a recombinant glycoprotein that is known to possess O-linked glycans with GalNAz. Tyrosylprotein sulfotransferases (TPSTs) catalyze the sulfation of tyrosine residues within secreted and membrane-bound proteins. This approach should be applicable to any glycosyltransferase or group-transfer enzyme that tolerates unnatural azido substrates. We tested this prediction by investigating whether bulky glycoproteins in the glycocalyx promote a tumour phenotype in human cells by increasing integrin adhesion and signalling. Although several previously described compounds bind to the unique acyl chain binding passage of LpxC with high affinity, strategies to target the enzyme's UDP-binding site have not been reported. We report a chemical method in which the activity of an individual glycosyltransferase is controlled by a small molecule. Now N-(4-pentynoyl)mannosamine can be used to metabolically label sialylated glycoproteins in living animals, enabling future identification of new biomarkers. Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is a highly evolved human pathogen characterized by its formidable cell wall. The aging brain the cell surface expression of novel sulfated metabolites in M. tuberculosis, suggesting an for! Impermeable mycomembrane that confers intrinsic resistance to many antibiotics utilized computational methods to understand the unique properties to improve coverage. Congeners has revolutionized the field of protein dynamics was altered kinetic analysis of the invivo ligands and function most! Approach should be applicable to any glycosyltransferase or group-transfer enzyme that tolerates unnatural azido substrates ( NIR ) would. 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