[ { "id": "authors:3q1rg-vg693", "collection": "authors", "collection_id": "3q1rg-vg693", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20211215-182305837", "type": "conference_item", "title": "Synthesis of heparan sulfate glycosaminoglycan (HS GAG) libraries for unlocking the sulfation code and understanding GAG biology", "author": [ { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" } ], "abstract": "The complex sulfation patterns of heparan sulfate glycosaminoglycans (HS GAGs) are crit. for many important biol. processes such as viral invasion, growth factor signaling, blood coagulation and cancer. However, an understanding of their specific functions has been hampered by an inability to synthesize comprehensive libraries of HS oligosaccharides representing all of the diverse sulfation motifs. We will describe new methods to accelerate the synthesis of HS GAGs and enable generation of large collections of HS oligosaccharides. These mols. are invaluable for unlocking the \"sulfation code\" and understanding the roles of specific sulfation motifs in human physiol. and disease. Toward this end, we will also discuss the application of defined HS mols. and chem. tools to the discovery of a novel interaction between HS GAGs and an orphan receptor, Tie1. These studies provide insights into the mechanisms by which HS regulates cellular signaling pathways and plays a key role in the maturation and remodeling of the vasculature.", "publisher": "Caltech Library", "publication_date": "2021-08" }, { "id": "authors:wgghz-3n437", "collection": "authors", "collection_id": "wgghz-3n437", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200219-074158424", "type": "conference_item", "title": "Streamlined synthesis of heparan sulfate glycosaminoglycans and their roles in regulating vasculature development and homeostasis", "author": [ { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" } ], "abstract": "Heparan sulfate (HS) glycosaminoglycans (GAGs) are sulfated polysaccharides that mediate a wide range of important biol. processes, including growth factor signaling, blood coagulation, viral infection, neural development, and cancer. The diverse biol. functions of HS GAGs are thought to stem from their complex stereochem. and sulfation patterns. However, understanding the structure-activity relationships of HS has been hampered by a lack of methods to synthesize large collections of oligosaccharides with defined sulfation sequences. A major obstacle is the prepn. of suitably protected building blocks, whose synthesis typically requires 20-30 steps. We will describe a new approach to access all four of the core disaccharides required for HS assembly from natural heparin and heparosan polysaccharides. The use of disaccharides rather than monosaccharides as minimal synthons accelerates the synthesis of HS GAGs, providing strategically-protected building blocks and tetrasaccharides in about half the no. of steps. Rapid access to key building blocks is greatly facilitating the generation of libraries of HS oligosaccharides for systematic investigations into the 'sulfation code.' We will also describe the application of defined HS mols. to the discovery of a novel interaction between HS GAGs and the orphan receptor Tie1 and its implications for angiogenesis and vascular development and homeostasis.", "publisher": "Caltech Library", "publication_date": "2020-03" }, { "id": "authors:c8gb2-a6131", "collection": "authors", "collection_id": "c8gb2-a6131", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190812-140038054", "type": "conference_item", "title": "Streamlined synthesis of core disaccharide building blocks from natural polysaccharides for the generation of heparan sulfate libraries", "author": [ { "family_name": "Pawar", "given_name": "Nitin Jalindar", "orcid": "0000-0002-9755-0652", "clpid": "Pawar-N-J" }, { "family_name": "Wang", "given_name": "Lei", "clpid": "Wang-Lei" }, { "family_name": "Higo", "given_name": "Takuya", "clpid": "Higo-Takuya" }, { "family_name": "Bhattacharya", "given_name": "Chandrabali", "clpid": "Bhattacharya-C" }, { "family_name": "Kancharla", "given_name": "Pavan K.", "clpid": "Kancharla-P-K" }, { "family_name": "Zhang", "given_name": "Fuming", "clpid": "Zhang-Fuming" }, { "family_name": "Baryal", "given_name": "Kedar", "clpid": "Baryal-K" }, { "family_name": "Huo", "given_name": "Chang-Xin", "clpid": "Huo-Chang-Xin" }, { "family_name": "Liu", "given_name": "Jian", "orcid": "0000-0001-8552-1400", "clpid": "Liu-Jian" }, { "family_name": "Linhardt", "given_name": "Robert J.", "clpid": "Linhardt-R-J" }, { "family_name": "Huang", "given_name": "Xuefei", "clpid": "Huang-Xuefei" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" } ], "abstract": "Heparan sulfate (HS) glycosaminoglycans (GAGs) are linear, diversely sulfated polysaccharides that regulate a wide range of essential biol. processes, including growth factor signaling, blood coagulation, viral infection, neural development, and cancer. HS chains consist of repeating disaccharide units of glucosamine (GlcN) joined via a-1,4-linkages to either D-glucuronic acid (GlcA) or L-iduronic acid (IdoA). Sulfation at the 3-O-, 6-O-, and N-positions of GlcN and the 2-O-position of IdoA or GlcA creates many different sulfation sequences that are tightly regulated in vivo. The diverse biol. functions of HS GAGs are thought to stem from their complex sulfation patterns. However, understanding their structure-activity relationships (SAR) has been hampered by a lack of methods to synthesize large collections of HS oligosaccharides with defined sulfation sequences. A major obstacle is the prepn. of differentially protected disaccharide building blocks, which typically require 20-30 chem. steps. Here, we report a new approach to access all four of the core disaccharides required for HS assembly from natural heparin and heparosan (K5) polysaccharides. The use of disaccharides rather than monosaccharides as minimal synthetic precursors greatly accelerates the synthesis of HS GAGs, providing easier access to core building blocks for the assembly of strategically protected HS tetrasaccharides in significantly fewer steps. Rapid access to such building blocks promises to significantly expand the scope of HS synthesis, enabling the future generation of large libraries of compds. for detailed investigations into the 'sulfation code' and its roles in biol.", "publisher": "Caltech Library", "publication_date": "2019-08" }, { "id": "authors:rr1b5-c5w61", "collection": "authors", "collection_id": "rr1b5-c5w61", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190812-135544133", "type": "conference_item", "title": "Chemical approaches toward a quantitative, systems-level understanding of protein O-GlcNAcylation signaling networks", "author": [ { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" } ], "abstract": "The dynamic posttranslational modification of proteins by O-linked-b-N-acetylglucosamine (O-GlcNAcylation) plays many diverse roles in cellular physiol. and disease. Here we will describe a quant., systems-level approach for studying the function, specificity, and dynamic regulation of O-GlcNAcylation. Elucidation of the signaling networks assocd. with the O-GlcNAc modification provides new insights into its central functions and may reveal new therapeutic approaches to enable its selective modulation.", "publisher": "Caltech Library", "publication_date": "2019-08" }, { "id": "authors:bhzjb-gtr88", "collection": "authors", "collection_id": "bhzjb-gtr88", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190325-092406743", "type": "conference_item", "title": "Streamlined methods for the synthesis of heparan sulfate oligosaccharide libraries", "author": [ { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" } ], "abstract": "Heparan sulfate (HS) glycosaminoglycans (GAGs) are sulfated polysaccharides that mediate a wide range of important biol. processes, including growth factor signaling, blood coagulation, viral infection, neural development, and cancer. The diverse biol. functions of HS GAGs are thought to stem from their complex stereochem. and sulfation patterns. However, understanding the structure-activity relationships of HS has been hampered by a lack of methods to synthesize large collections of oligosaccharides with defined sulfation sequences. A major obstacle is the prepn. of suitably protected building blocks, whose synthesis typically requires 20-30 steps. Here, we describe a new approach to access all four of the core disaccharides required for HS assembly from natural heparin and heparosan polysaccharides. The use of disaccharides rather than monosaccharides as minimal synthons accelerates the synthesis of HS GAGs, providing strategically-protected building blocks and tetrasaccharides in about half the no. of steps. Rapid access to key building blocks will greatly facilitate the generation of large, comprehensive libraries of HS oligosaccharides for detailed investigations into the 'sulfation code' and its roles in biol.", "publisher": "Caltech Library", "publication_date": "2019-04" }, { "id": "authors:phsck-72812", "collection": "authors", "collection_id": "phsck-72812", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180413-074121179", "type": "conference_item", "title": "O-GlcNAc glycosylation: From reductionism to systems biology", "author": [ { "family_name": "Hsieh-Wilson", "given_name": "Linda", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" } ], "abstract": "The dynamic posttranslational modification of proteins by O-linked-\u03b2-N-acetylglucosamine (O-GlcNAc glycosylation) plays\nmany important roles in physiol. and disease. Remarkably, only a single enzyme catalyzes the modification, raising the question of how this enzyme (O-GlcNAc transferase or OGT) selects from among its diverse substrates to regulate specific cellular processes. Here we will describe a new systems-level approach for studying the functions, specificity, and regulation of O-GlcNAc glycosylation. Elucidation of these dynamic O-glycosylation networks provides insights into the key functions of this modification and may reveal novel approaches for therapeutic intervention.", "publisher": "Caltech Library", "publication_date": "2018-03" }, { "id": "authors:4w5rz-bsd38", "collection": "authors", "collection_id": "4w5rz-bsd38", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160726-133936120", "type": "conference_item", "title": "Synthetic probes for understanding glycosaminoglycan recognition and signaling in the brain", "author": [ { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" } ], "abstract": "Glycosaminoglycans (GAGs) comprise a large family of sulfated polysaccharides that regulate diverse biol. events such as embryonic development, viral invasion, cancer metastasis, and spinal cord injury. Assembled from repeating disaccharide subunits, GAGs exhibit subtle variations in stereochem., chain length, and patterns of sulfation. This structural diversity is thought to enable the generation of a large no. of protein-binding motifs. We will describe the synergistic application of org. chem. and neurobiol. to understand how specific GAG structures interact with protein receptors in the brain. In addn., we will discuss recent work on GAG-based polymer mimetics, which have enabled the first explorations into the importance of macromol. structure on GAG function. These mimetics may also provide agents for modulating specific GAG-mediated processes in vivo. By combining synthetic org. chem., polymer chem., computational chem., and mol. and cellular neurobiol., our studies provide mechanistic insights into how GAGs regulate proteins and signaling events that underlie key processes such as neurite outgrowth, axon regeneration, and neural circuit formation.", "publisher": "Caltech Library", "publication_date": "2016-07" }, { "id": "authors:jdb7z-dmv16", "collection": "authors", "collection_id": "jdb7z-dmv16", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140424-104655243", "type": "conference_item", "title": "Harnessing chemistry to discover new roles for carbohydrates in neurobiology and cancer", "author": [ { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" } ], "abstract": "Carbohydrates comprise one of the largest and most diverse collections of biol. active mols., and they participate in nearly\nevery aspect of biol. However, relative to their macromol. peers (i.e., proteins and nucleic acids), carbohydrates remain\nrelatively unexplored, and their structure-function relationships are still poorly understood. Several of the fundamental\nchallenges inherent in studying carbohydrates include: (1) their chem. complexity; (2) the lack of efficient and sensitive anal.\nmethods for their detection and quantification; and (3) their complex chem. synthesis and biosynthesis. We will describe the\ndevelopment of chem. approaches to overcome these fundamental challenges and how the principles and tools of chem. can be\nused to uncover new functions for carbohydrates and their assocd. proteins in neurobiol. and cancer.", "publisher": "Caltech Library", "publication_date": "2014-03" }, { "id": "authors:j3t17-0a533", "collection": "authors", "collection_id": "j3t17-0a533", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140506-132538705", "type": "conference_item", "title": "Carbohydrate signaling in the brain", "author": [ { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" } ], "abstract": "Chem. neurobiol. is rapidly evolving and providing insights into the mols. and interactions involved in neuronal development,\nsensory perception and memory storage. We will describe the synergistic application of org. chem. and neurobiol. to understand\nhow specific carbohydrate mols. contribute to the wiring of the brain during development, as well as the ability of axons to\nregenerate after injury. Chondroitin sulfate polysaccharides have traditionally been viewed as passive, \"barrier\" mols. that\nimpede neuronal growth. By combining synthetic org. and polymer chem., computational chem. and in vivo biol., we now show\nthat these mols. actively participate in signaling processes that underlie the formation of neural circuits and neuroregeneration.", "publisher": "Caltech Library", "publication_date": "2014-03" }, { "id": "authors:n35dj-t1h07", "collection": "authors", "collection_id": "n35dj-t1h07", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130730-092228606", "type": "conference_item", "title": "Investigating the role of O-GlcNAc glycosylation in cancer and neurodegenerative disease", "author": [ { "family_name": "Wang", "given_name": "Andrew C.", "clpid": "Wang-Andrew-C" }, { "family_name": "Yi", "given_name": "Wen", "orcid": "0000-0002-4257-3355", "clpid": "Yi-Wen" }, { "family_name": "Jensen", "given_name": "Elizabeth H.", "clpid": "Jensen-E-H" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" } ], "abstract": "The addn. of a single O-linked N-Acetylglucosamine (O-GlcNAc) sugar onto proteins is a ubiquitous and dynamic posttranslational\nmodification that regulates many important biol. processes, including cell signaling, transcription, metab., and\nmemory storage. This intracellular modification has been identified on over a thousand proteins, including histones, RNA\npolymerase, enzymes involved in glycolysis, amyloid precursor protein, and tau. We are investigating the functional roles of this\nmodification in cancer and neurodegenerative diseases. Our studies have uncovered a unique role for the O-GlcNAc modification\nin regulating the metabolic state of cancer cells. Specifically, we show that glycosylation of phosphofruktokinase-1 (PFK1)\nenables cancer cells to acquire a selective growth and survival advantage by increasing metabolic flux through the pentose\nphosphate pathway. In the brain, the O-GlcNAc modification has been shown to reduce tau hyperphosphorylation, a major\nhallmark in several neurodegenerative diseases. To better understand the role of O-GlcNAc in the brain, we generated a\nconditional knockout mice lacking O-GlcNAc transferase (OGT), the single enzyme responsible for the modification. Our findings\nindicate that loss of OGT induces rapid neurodegeneration, suggesting that a redn. of O-GlcNAc glycosylation may contribute to\nthe pathol. of neurodegenerative diseases.", "publisher": "Caltech Library", "publication_date": "2013-04" }, { "id": "authors:w6ryh-xwe21", "collection": "authors", "collection_id": "w6ryh-xwe21", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130730-091750607", "type": "conference_item", "title": "Chemoenzymatic approaches to the imaging and detection of cancer relevant fucosylated glycoconjugates", "author": [ { "family_name": "Chaubard", "given_name": "Jean-Luc", "clpid": "Chaubard-J-L" }, { "family_name": "Krishnamurthy", "given_name": "Chithra", "clpid": "Krishnamurthy-Chithra" }, { "family_name": "Ban", "given_name": "Lan", "clpid": "Ban-Lan" }, { "family_name": "Yi", "given_name": "Wen", "orcid": "0000-0002-4257-3355", "clpid": "Yi-Wen" }, { "family_name": "Smith", "given_name": "David F.", "clpid": "Smith-D-F" }, { "family_name": "Wilson", "given_name": "Iain B.", "clpid": "Wilson-I-B" }, { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" } ], "abstract": "A major focus in the field of glycomics has been the development of new strategies for the detection and quantification of\nglycans and glycoconjugates. With alterations in glycoconjugate structure being a hallmark of various cancers, these strategies\ncan discover new cancer biomarkers and be developed into new clin. diagnostic tools. Here we report chemoenzymic strategies\nfor the rapid, sensitive detection of cancer-relevant fucosylated glycoconjugates. Our methods exploit non-mammalian\nglycosyltransferases that accept non-natural donor substrates. We then use \"Click\" chem. to append reporter tags for the\ndetection of these glycans. We have developed methods for the detection of glycans contg. fucose\u03b1(1-2)galactose (Fuc\u03b1(1-2)\nGal), a motif implicated cancer pathogenesis, as well as core fucosylated glycans, a carbohydrate modification that is upregulated\nin various cancer states and mediates cell signaling events. We demonstrate the specificity and utility of these methods for the\ndetection of cancerous compared to healthy cells and tissues.", "publisher": "Caltech Library", "publication_date": "2013-04" }, { "id": "authors:4jbfv-kys71", "collection": "authors", "collection_id": "4jbfv-kys71", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120823-103052826", "type": "conference_item", "title": "Sweet chemical signaling: Understanding the structure-function relationships of carbohydrates in neurobiology and cancer", "author": [ { "family_name": "Hsieh-Wilson", "given_name": "Linda C.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" } ], "abstract": "Carbohydrates comprise one of the largest and most diverse collections of biol. active mols., and it is increasingly clear that they participate in nearly every aspect of biol. However, relative to their macromol. peers (i.e., proteins and nucleic acids), carbohydrates remain relatively unexplored, and their structure-function relationships are still poorly understood. Several of the fundamental challenges inherent in studying carbohydrates include: (1) their chem. complexity; (2) the lack of efficient and sensitive anal. methods for their detection and quantification; and (3) their complex chem. synthesis and biosynthesis. We will describe the development of chem. approaches to overcome these fundamental challenges and how the principles and tools of chem. can be used to uncover new functions for carbohydrates and their assocd. proteins in neurobiol. and cancer.", "publisher": "Caltech Library", "publication_date": "2012-08" }, { "id": "authors:14r3a-way17", "collection": "authors", "collection_id": "14r3a-way17", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120816-131836909", "type": "conference_item", "title": "Chemical approaches to elucidating the neurobiology of carbohydrates", "author": [ { "family_name": "Hsieh-Wilson", "given_name": "L.", "orcid": "0000-0001-5661-1714", "clpid": "Hsieh-Wilson-L-C" } ], "abstract": "The field of chem. neurobiol. is rapidly evolving and providing insights into the mols. and interactions involved in brain\ndevelopment, neuronal communication and memory storage. We will describe the synergistic application of org. chem.\nand neurobiol. to understand how specific carbohydrate structures contribute to neuronal growth and regeneration.\nChondroitin sulfate proteoglycans (CSPGs) represent a major barrier to regenerating axons in the central nervous\nsystem (CNS), but the structural diversity of the polysaccharides has hampered efforts to understand their activity. By\ntaking advantage of our ability to chem. synthesize oligosaccharides, we demonstrate that a specific sugar epitope on\nCSPGs potently inhibits axonal growth. Blockage of the epitope reversed CSPG-mediated growth inhibition and\nstimulated axon regeneration in vivo, suggesting a novel therapeutic approach to CNS repair. More broadly, our studies\nsupport the notion that specific sulfation sequences within chondroitin sulfate polysaccharides direct the activity of\nproteins in vivo and coordinate key physiol. processes.", "publisher": "Caltech Library", "publication_date": "2010-12" } ]