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TABLE 1.2. “Universal” principles of glycobiology - Essentials of Glycobiology - NCBI Bookshelf 4/29/12 1:18 PM TABLE 1.2 “Universal” principles of glycobiology Occurrence All cells in nature are covered with a dense and complex array of sugar chains (glycans). The cell walls of bacteria and archea are composed of several classes of glycans and glycoconjugates. Most secreted proteins of eukaryotes carry large amounts of covalently attached glycans. In eukaryotes, these cell-surface and secreted glycans are mostly assembled via the ER-Golgi pathway. The extracellular matrix of eukaryotes is also rich in such secreted glycans. Cytosolic and nuclear glycans are common in eukaryotes. For topological, evolutionary, and biophysical reasons, there is little similarity between cell-surface/secreted and nuclear/cytosolic glycans. Chemistry and structure Glycosidic linkages can be in !- or "-linkage forms, which are biologically recognized as completely distinct. Glycan chains can be linear or branched. Glycans can be modified by a variety of different substituents, such as acetylation and sulfation. Complete sequencing of glycans is feasible but usually requires combinatorial or iterative methods. Modern methods allow in vitro chemoenzymatic synthesis of both simple and complex glycans. Biosynthesis The final products of the genome are posttranslationally modified proteins, with glycosylation being the most common and versatile of these modifications. The primary units of glycans (monosaccharides) can be synthesized within a cell or salvaged from the environment. Monosaccharides are activated into nucleotide sugars or lipid-linked sugars before they are used as donors for glycan synthesis. Whereas lipid-linked sugar donors can be flipped across membranes, nucleotide sugars must be transported into the lumen of the ER-Golgi pathway. Each linkage unit of a glycan or glycoconjugate is assembled by one or more unique glycosyltransferases. Many glycosyltransferases are members of multigene families with related functions. Most glycosyltransferases recognize only the underlying glycan of their acceptor, but some are protein or lipid specific. Many biosynthetic enzymes (glycosyltransferases, glycosidases, sulfotransferases, etc.) are expressed in a tissue-specific, temporally regulated manner. Diversity Monosaccharides generate much greater combinatorial diversity than nucleotides or amino acids. Further diversity arises from covalent modifications of glycans. Glycosylation introduces a marked diversity in proteins. Only a limited subset of the potential diversity is found in a given organism or cell type. Intrinsic diversity (microheterogeniety) of glycoprotein glycans within a cell type or even a single glycosylation site. The total expressed glycan repertoire (glycome) of a given cell type or organism is thus much more complex than the genome or proteome. The glycome of a given cell type or organism is also dynamic, changing in response to intrinsic and extrinsic signals. Glycome differences in cell type, space, and time generate biological diversity and can help to explain why only a limited number of genes are expressed from the typical genome. Recognition Glycans are recognized by specific glycan-binding proteins that are intrinsic to an organism. Glycans are also recognized by many extrinsic glycan-binding proteins of pathogens and symbionts. Glycan-binding proteins fall in two general categories: those that can usually be grouped by shared evolutionary http://www.ncbi.nlm.nih.gov/books/NBK1931/table/ch1.t2/?report=objectonly Page 1 of 2 TABLE 1.2. “Universal” principles of glycobiology - Essentials of Glycobiology - NCBI Bookshelf 4/29/12 1:18 PM Glycan-binding proteins fall in two general categories: those that can usually be grouped by shared evolutionary origins and/or similarity in structural folds (lectins) and those that emerged by convergent evolution from different ancestors (e.g., GAG-binding proteins). Lectins often show a high degree of specificity for binding to specific glycan structures, but they typically have relatively low affinities for single-site binding. Thus, biologically relevant lectin recognition often requires multivalency of both the glycan and glycan-binding protein, to generate high avidity of binding. Genetics Naturally occurring genetic defects in glycans seem to be relatively rare in intact organisms. However, this apparent rarity may be due to a failure of detection, caused by unpredictable or pleiotropic phenotypes. Genetic defects in cell-surface/secreted glycans are easily obtained in cultured cells but have somewhat limited biological consequences. The same mutations typically have major phenotypic consequences in intact multicellular organisms. Thus, many of the major roles of glycans likely involve cell–cell or extracellular interactions. Nuclear/cytosolic glycans may have more cell-intrinsic roles, e.g., in signaling. Complete elimination of major glycan classes generally causes early developmental lethality. Organisms bearing tissue-specific alteration of glycans often survive, but they exhibit both cell-autonomous and distal biological effects. Biological roles Biological roles for glycans span the spectrum from nonessential activities to those that are crucial for the development, function, and survival of an organism. Many theories regarding the biological roles of glycans appear to be correct, but exceptions occur. Glycans can have different roles in different tissues or at different times in development. Terminal sequences, unusual glycans, and modifications are more likely to mediate specific biological roles. However, terminal sequences, unusual glycans, or modifications may also reflect evolutionary interactions with microorganisms and other noxious agents. Thus, a priori prediction of the functions of a specific glycan or its relative importance to the organism is difficult. Evolution Relatively little is known about glycan evolution. Interspecies and intraspecies variations in glycan structure are relatively common, suggesting rapid evolution. The dominant mechanism for such evolution is likely the ongoing selection pressure by pathogens that recognize glycans. However, glycan evolution must also preserve and/or elaborate critical intrinsic functions. Interplay between pathogen selection pressure and preservation of intrinsic roles could result in the formation of “junk” glycans. Such “junk” glycans could be the substrate from which new intrinsic functions arise during evolution. From: Chapter 1, Historical Background and Overview Essentials of Glycobiology. 2nd edition. Varki A, Cummings RD, Esko JD, et al., editors. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009. Copyright © 2009, The Consortium of Glycobiology Editors, La Jolla, California. NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health. http://www.ncbi.nlm.nih.gov/books/NBK1931/table/ch1.t2/?report=objectonly Page 2 of 2 TABLE 1.1. Important discoveries in the history of glycobiology - Essentials of Glycobiology - NCBI Bookshelf 4/29/12 1:19 PM TABLE 1.1 Important discoveries in the history of glycobiology Relevant chaptersa Year(s) Primary scientist(s) Discoveries 1876 J.L.W. Thudichum glycosphingolipids (cerebrosides), sphingomyelin and sphingosine 1888 H. Stillmark lectins as hemagglutinins 1891 H.E. Fischer stereoisomeric structure of glucose and other monosaccharides 1900 K. Landsteiner human ABO blood groups as transfusion barriers 1909 P.A. Levene structure of ribose in RNA 1 1916 J. MacLean isolation of heparin as an anticoagulant 16 1925 P.A. Levene characterization of chondroitin sulfate and “mucoitin sulfate” (later, hyaluronan) 1929 P.A. Levene structure of 2-deoxyribose in DNA 1 1929 W.N. Haworth pyranose and furanose ring structures of monosaccharides 2 1934 K. Meyer hyaluronan and hyaluronidase 15 1934– 1938 G. Blix, E. Klenk sialic acids 14 1936 C.F. Cori, G.T. Cori glucose-1-phosphate as an intermediate in glycogen biosynthesis 17 1942– 1946 G.K. Hirst, F.M. Burnet hemagglutination of influenza virus and “receptordestroying enzyme” 14 1942 E. Klenk, G. Blix gangliosides in brain 1946 Z. Dische colorimetric determination of deoxypentoses and other carbohydrates 2 1948– 1950 E. Jorpes, S. Gardell occurrence of N-sulfates in heparin and identification of heparan sulfate 16 1949 L.F. Leloir nucleotide sugars and their role in the biosynthesis of glycans 4 1950 Karl Schmid isolation of !1-acid glycoprotein (orosomucoid), a major serum glycoprotein 1952 W.T. Morgan, W.M. Watkins carbohydrate determinants of ABO blood group types 13 1952 E.A. Kabat relationship of ABO to Lewis blood groups and secretor vs. nonsecretor status 13 1952 A. Gottschalk sialic acid as the receptor for influenza virus 14 1952 T. Yamakawa globoside, the major glycosphingolipid of the erythrocyte membrane 10 1956– 1963 M.R.J. Salton, J.M. Ghuysen, R.W. Jeanloz, N. Sharon, H.M. Flowers bacterial peptidoglycan backbone structure major structural polysaccharides in nature (chitin, cellulose, and peptidoglycan) are "1-4-linked throughout 20 1957 P.W. Robbins, F. Lipmann biosynthesis and characterization of PAPS, the donor for 4, 16 1957 H. Faillard, E. Klenk 1957– 1963 J. Strominger, J.T. Park, H.R. Perkins, H.J. Rogers mechanism of peptidoglycan biosynthesis and site of penicillin action 20 1958 H. Muir “mucopolysaccharides” are covalently attached to proteins via serine 16 glycan sulfation crystallization of N-acetylneuraminic acid as product of influenza virus receptor-destroying enzyme (RDE) (“neuraminidase”) http://www.ncbi.nlm.nih.gov/books/NBK1931/table/ch1.t1/?report=objectonly 10 26, 28 2 5, 13 15, 16 10, 14 14 Page 1 of 4 TABLE 1.1. Important discoveries in the history of glycobiology - Essentials of Glycobiology - NCBI Bookshelf 4/29/12 1:19 PM via serine 1960 D.C. Comb, S. Roseman structure and enzymatic synthesis of CMP-Nacetylneuraminic acid 1960– 1965 O. Westphal, O. Lüderitz, H. Nikaido, P.W. Robbins structure of lipopolysaccharides and endotoxin glycans 1960– 1970 R. Jeanloz, K. Meyer, A. Dorfman structural studies of glycosaminoglycans 15, 16 1961 S. Roseman, L. Warren biosynthesis of sialic acid 4, 14 1961– 1965 G.E. Palade ER-Golgi pathway for glycoprotein biosynthesis and secretion 3 1962 A. Neuberger, R. Marshall, I. Yamashina, L.W. Cunningham GlcNAc-Asn as the first defined carbohydrate-peptide linkage 8 1962 W.M. Watkins, W.Z. Hassid enzymatic synthesis of lactose from UDP-galactose and glucose 4 1962 J.A. Cifonelli, J. Ludowieg, A. Dorfman iduronic acid as a constituent of heparin 16 1962– 1966 L. Roden, U. Lindahl identification of tetrasaccharide linking glycosaminoglycans to protein core of proteoglycans 16 1962 E.H. Eylar, R.W. Jeanloz demonstration of the presence ofN-acetyllactosamine in !1-acid glycoprotein 13 1963 L. Svennerholm analysis and nomenclature of gangliosides 10 1963 D. Hamerman, J. Sandson covalent cross-linkage between hyaluronan and inter-!trypsin inhibitor 15 1963– 1964 B. Anderson, K. Meyer, V.P. Bhavanandan, A. Gottschalk "-elimination of Ser/Thr-O-linked glycans 9 1963– 1965 R. Kuhn, H. Wiegandt structure of GM1 and other brain gangliosides 10 1963– 1967 B.L. Horecker, P.W. Robbins, H. lipid-linked intermediates in bacterial lipopolysaccharide Nakaido, M.J. Osborn and peptidoglycan biosynthesis 20 1964 V. Ginsburg GDP-fucose and its biosynthesis from GDP-mannose 4 1964 B. Gesner, V. Ginsburg glycans control the migration of leukocytes to target organs 26 1965 L.W. Cunningham microheterogeneity of glycoprotein glycans 1965– 1966 R.O. Brady glucocerebrosidase is the enzyme deficient in Gaucher’s disease 41 1965– 1975 J.E. Silbert, U. Lindahl cell-free biosynthesis of heparin and chondroitin sulfate 16 1965– 1975 W. Pigman tandem repeat amino acid sequences with Ser or Thr as O-glycosylation sites in mucins 9 1966 M. Neutra, C. Leblond role of Golgi apparatus in protein glycosylation 3 1966– 1969 B. Lindberg, S. Hakomori refinement of methylation analysis for determination of glycan linkages 47 1966– 1976 R. Schauer multiple modifications of sialic acids in nature, their biosynthesis, and degradation 14 1967 L. Rodén, L.-Å. Fransson semonstration of a copolymeric structure for dermatan sulfate 16 1967 R.D. Marshall N-glycosylation occurs only at asparagine residues in the sequence motif Asn-X-Ser/Thr 8 1968 J.A. Cifonelli description of the domain structure of heparan sulfate 16 1968 R.L. Hill, K. Brew !-lactalbumin as a modifier of galactosyltransferase specificity 5 1969 L. Warren, M.C. Glick, P.W. Robbins increased size of N-glycans in malignantly transformed cells http://www.ncbi.nlm.nih.gov/books/NBK1931/table/ch1.t1/?report=objectonly 4, 14 20 2, 8, 9 8, 44 Page 2 of 4 TABLE 1.1. Important discoveries in the history of glycobiology - Essentials of Glycobiology - NCBI Bookshelf 4/29/12 1:19 PM 1969 R.J. Winzler structures of O-glycans from erythrocyte membranes 1969– 1974 V.C. Hascall, S.W. Sajdera, H. Muir, D. Heinegård, T. Hardingham hyaluronan-proteoglycan interactions in cartilage 1969 H. Tuppy, P. Meindl synthesis of 2-deoxy-2,3-didehydro-Neu5Ac as viral sialidase inhibitor 14 1968– 1970 E. Neufeld identification of lysosomal enzyme deficiencies in the mucopolysaccharidoses 41 1969 G. Ashwell, A. Morell glycans can control the lifetime of glycoproteins in blood circulation 26 1970 K.O. Lloyd, J. Porath, I.J. Goldstein use of lectins for affinity purification of glycoproteins 45 1971– 1973 L.F. Leloir dolichylphosphosugars are intermediates in protein N-glycosylation 4, 8 1971– 1975 P. Kraemer, J.E. Silbert heparan sulfate as a common constituent of vertebrate cell surfaces 16 1971– 1980 B. Toole hyaluronan in differentiation, morphogenesis, and development 15 1972– 1982 S. Hakomori lacto- and globo-series glycosphingolipids as developmentally regulated and tumor-associated antigens 10, 44 1972 J.F.G. Vliegenthart high-field proton NMR spectroscopy for structural analysis of glycans 2 1973 W.E. van Heyningen glycosphingolipids are receptors for bacterial toxins 39 1973 J. Montreuil, R.G. Spiro, R. Kornfeld a common pentasaccharide core structure of all N-glycans 8 1974 C.E. Ballou structure of yeast mannans and generation of yeast mannan mutants 1975 V.I. Teichberg the first galectin 1975 V.T. Marchesi primary structure of glycophorin, the first known transmembrane glycoprotein 3, 8, 9 1975– 1980 A. Kobata N- and O-glycan structural elucidation using multiple convergent techniques 2, 8, 9 1975– P. Stanley, S. Kornfeld, R.C. lectin-resistant cell lines with glycosylation defects 46 1980 1977 Hughes W.J. Lennarz Asn-X-Ser/Thr necessary and sufficient for lipid-mediated N-glycosylation 8 1977 I. Ofek, D. Mirelman, N. Sharon cell-surface glycans as attachment sites for infectious bacteria 39 1977– 1978 S. Kornfeld, P.W. Robbins biosynthesis and processing of intermediates of N-glycans in protein glycosylation 8 1977 R.L. Hill, R. Barker first purification of a glycosyltransferase involved in protein glycosylation 5, 8 1978 C. Svanborg glycosphingolipids as receptors for bacterial adhesion 1979– 1982 E. Neufeld, S. Kornfeld, K. Von Figura, W. Sly the mannose-6-phosphate pathway for lysosomal enzyme trafficking 1980– 1983 F.A. Troy, J. Finne, S. Inoue, Y. structure of polysialic acids in bacteria and vertebrates Inoue 14 1980 H. Schachter role of glycosyltransferases in N- and O-glycan branching 5, 8 1980– 1982 V.N. Reinhold, A. Dell, A.L. Burlingame mass spectrometry for structural analysis of glycans 47, 48 1980– 1985 S. Hakomori, Y. Nagai glycosphingolipids as modulators of transmembrane signaling 10 1981– M.J. Ferguson, I. Silman, M. structural definition of glycosylphosphatidylinositol (GPI) 11 http://www.ncbi.nlm.nih.gov/books/NBK1931/table/ch1.t1/?report=objectonly 9 16, 17 8, 46 33 10, 39 30 Page 3 of 4 TABLE 1.1. Important discoveries in the history of glycobiology - Essentials of Glycobiology - NCBI Bookshelf 4/29/12 1:19 PM 1985 Low anchors 1982 U. Lindahl, R.D. Rosenberg specific sulfated heparin pentasaccharide sequence recognized by antithrombin 16, 35 1982 C. Hirschberg, R. Fleischer transport of sugar nucleotides into the Golgi apparatus 3, 14 1984 G. Hart intracellular protein glycosylation by O-GlcNAc 18 1984 J. Jaeken description of “carbohydrate-deficient glycoprotein syndromes” 42 1985 M. Klagsbrun, D. Gospodarowicz discovery of heparin–FGF interactions 35 1986 W.J. Whelan glycogen is a glycoprotein synthesized on a glycogenin primer 17 1986 J.U. Baenziger structures of sulfated N-glycans of pituitary hormones 1986 Y. Inoue, S. Inoue discovery of 2-keto-3-deoxynononic acid (Kdn) in rainbow trout eggs 14 1986 P.K. Qasba, J. Shaper, N. Shaper cloning of first animal glycosyltransferase 5 1987 Y-C. Lee high-performance anion-exchange chromatography of oligosaccharides with pulsed amperometric detection (HPAEC-PAD) 47 13, 28 This time line of events is deliberately terminated about 20 years ago, on the assumption that it can take a long time to be certain that a particular discovery has had a major impact on the field. Historical details about several of these discoveries can be found in the “Classics” series of the Journal of Biological Chemistry (see http://www#.jbc.org/, click on “Classic Articles,” and search by author name). a Indicates main chapter(s) of this book in which the relevant topics are covered. From: Chapter 1, Historical Background and Overview Essentials of Glycobiology. 2nd edition. Varki A, Cummings RD, Esko JD, et al., editors. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009. Copyright © 2009, The Consortium of Glycobiology Editors, La Jolla, California. NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health. http://www.ncbi.nlm.nih.gov/books/NBK1931/table/ch1.t1/?report=objectonly Page 4 of 4