Glycobiology - Xi Chen, University of California-Davis

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Chemoenzymatic Approaches for Chemical Glycobiology Xi Chen, Department of Chemistry, University of California-Davis The important roles of carbohydrates have been increasingly recognized. Among naturally existing carbohydrates, sialic acid-containing structures have attracted much attention. Sialic acids are common terminal monosaccharide residues presented on the carbohydrate moieties of glycoproteins and glycolipids on mammalian cell surface. As the outermost molecules, sialic acids are directly involved in many physiologically and pathologically important processes, including cellular recognition and communication, bacterial and viral infection, inflammation, and tumor metastasis, etc.[1] Compared to monosaccharides of five- or six- carbons, sialic acids are more complex and contain a 9-carbon backbone. Structural modifications on sialic acid residues further increase the complexity of sialic acid-containing structures. Currently, more than 50 sialic acid structures have been found in nature. In order to understand the glycobiology of sialic acid-containing structures and sialic acid modifications, my laboratory has developed highly efficient chemoenzymatic methods to obtain sialic acid-containing structures with naturally occurring sialic acid modifications which are difficult to be obtained either by isolation or by chemical synthesis. Their non-natural derivatives can also be obtained similarly.[2] These compounds have been used as invaluable probes for studying the important biological roles of sialic acid-recognizing proteins.[3] 1. (a) Angata T, Varki A. Chemical diversity in the sialic acids and related alpha-keto acids: an evolutionary perspective. Chem. Rev. 2002, 102, 439-469. (b) Schauer R. Achievements and challenges of sialic acid research. Glycoconj. J. 2000, 17, 485-499. 2. (a) Yu H, Chokhawala H, Karpel R, Yu H, Wu B, Zhang J, Zhang Y, Jia Q, Chen X. A multifunctional Pasteurella multocida sialyltransferase: a powerful tool for the synthesis of sialoside libraries. J. Am. Chem. Soc. 2005, 127, 17618–17619; (b) Yu H, Huang S, Chokhawala H, Sun M, Zheng H, Chen X. Highly efficient chemoenzymatic synthesis of naturally occurring and non-natural -2,6-linked sialosides: a P. damsela -2,6-sialyltransferase with extremely flexible donor substrate specificity. Angew. Chem. Int. Ed. 2006, 45, 3938–3944; (c) Yu H, Chokhawala H, Huang S, Chen X. One-pot three-enzyme chemoenzymatic approach to the synthesis of sialosides containing natural and non-natural functionalities. Nat. Protoc. 2006, 1, 2485–2492. 3. (a) Chokhawala H, Yu H, Chen X. High-throughput substrate specificity studies of sialidases using chemoenzymatically synthesized sialoside libraries. ChemBioChem 2007, 8, 194–201; (b) Ni L, Chokhawala HA, Cao H, Hening R, Ng L, Huang S, Yu H, Chen X, Fisher AJ. Crystal structures of a Pasteurella multocida sialyltransferase complexes with acceptor and donor analogs reveal substrate binding sites and catalytic mechanism. Biochemistry 2007, 46, 6288–6298; (c) Chokhawala HA, Huang S, Lau K, Yu H, Cheng J, Thon V, Hurtado-Ziola N, Guerrero J, Varki A, Chen X. Combinatorial chemoenzymatic synthesis and high-throughput screening of sialosides. ACS Chem. Biol. 2008, 3, 567–576; (d) Byres E, Paton AW, Paton JC, Smith DF, Lofling JC, Wilce MCJ, Chong DC, Talbot UM, Yu H, Huang S, Chen X., Varki NM, Varki A, Rossjohn J, Beddoe T. Incorporation of a non-human glycan mediates human susceptibility to a bacterial toxin. Nature 2008, 456, 648–652.

Glycobiology – Pascal Gagneux, University of California, San Diego

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Glycobiology – The Life Science of Glycans Pascal Gagneux, University of California, San Diego Cellular life forms spanning the three domains of Bacteria, Archaea, and Eukarya have cells covered with a glycocalyx, a “sugar shell”. These shells consist of a complex layer of glycans, oligosaccharide chains attached to glycoproteins, glycolipids or proteoglycans. Microorganisms and plants also produce long polysaccharides often combined with complex lipids to form capsules and/or cell walls. There are no „glycan genes” but 2% of the mammalian genome encodes genes whose products participate in glycan synthesis. These include genes coding for glycosyl-transferases, enzymes which assemble oligosaccharides co-and post-translationally in the endoplamatic reticulum and Golgi compartment of cells. The glycans attached to the nascent polypeptides strongly affect protein folding, cellular trafficking and function on the cell surface or upon secretion. Glycans can be branched and each monosaccharide unit can from multiple types of glycosidic bonds with other sugars. This explains why even with under a dozen commonly used monosaccharide units, the immense diversity of mammalian glycan structures remains to be fully characterized. Glycosylation has been proposed to serve as an “evolutionary capacitator”, providing a rich combinatorial system for generating complex and dynamic diversity on the interface of cells with their biotic and abiotic environment. Glycosylation plays crucial roles throughout the life cycle from reproduction, to development, immune function symbiosis and disease. The importance of cytoplasmic glycosylation, most commonly a modification with a monosaccharide (O-GlcNAc) has only recently become appreciated, as it modifies the function of many transcription factors in a manner similar to phosphorylation but often with opposite effects.