Glycoconjugate Research: Proceedings of the Interior Symposium on Glycoconjugates
By John Gregory
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Glycoconjugate Research - John Gregory
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BIOSYNTHESIS AND REGULATION
Outline
Chapter 1: The Control of Glycoprotein Synthesis
Chapter 2: Enzymic Modifications of Sialic Acids in the Course of Glycoconjugate Biosynthesis
Chapter 3: Role of Lipid-Saccharide Intermediates in Glycoprotein Biosynthesis
Chapter 4: Distinction and Partial Characterization of Two Galactosyl-transferase Activities in Normal Human Serum
Chapter 5: Characterization of Two Highly Purified Fucosyltransferases
Chapter 6: Purification by Affinity Chromatography and Properties of Microsomal Galactosyltransferase from Pig Thyroid
Chapter 7: Sheep Brain Glycoprotein Fucosyltransferase
Chapter 8: The Incorporation of [14C]Glucosamine into Glycosaminoglycans and the Influence of Corneal Epithelium on this Process
Chapter 9: Biosynthesis of Blood Group N- and M-Specific Haptenic Structures by Human Serum Glycosyltransferases
Chapter 10: Biosynthesis and Characterization of Lipid-Linked Sugars in Outer Membrane of Liver Mitochondria
Chapter 11: Incorporation of N-Acetylglucosamine and Mannose in Rat Liver Rough Microsomes: Stimulation by GTP after Treatment with Pyrophosphate
Chapter 12: Release of Complex Carbohydrates into Culture Medium by Cultured Hamster Cells
Chapter 13: On the Biosynthesis of Carboxypeptidase Y (CY)
Chapter 14: Metabolism of Free Sialic Acid, CMP-Sialic Acid, and Bound Sialic Acid in Rat Brain
Chapter 15: Effect of Bacitracin on the Biosynthesis of Dolichol Derivatives in Calf Pancreas Microsomes
Chapter 16: Biosynthesis of Dolichol Derivatives Containing D-Galactose in Calf Pancreas Microsomes
Chapter 17: Sulfogalactosyl Glycerides (SGG) from Rat Brain Myelin
Chapter 18: Complex Formation by Sequential Glycosyltransferases
Chapter 19: Biosynthesis of Heparin: Tritium Incorporation into Chemically Modified Heparin Catalyzed by C-5-Uronosylepimerase
Chapter 20: Serum Glycosyltransferase Enzymes in Normal and Leukemic Subjects: Experiences with Low-Molecular-Weight Acceptors
Chapter 21: Transfer of Glucose to Phenolic Steroids and Possible Physiological Role of the Glucosides
Chapter 22: Secretion of Proteoglycans by Chondrocytes. Influence of Colchicine, Cytochalasin B, and β-D-Xyloside
Chapter 23: Glycosyl Transfer to Bovine Rhodopsin
Chapter 24: Changes in Glycoproteins and Glycolipids of the Ghosh-Lai Rat Stomach Following Perfusions with Ethanol
Chapter 25: Heterogeneity of Arterial Proteoglycans
Chapter 26: Structural Changes of Sulfated Proteoglycans of the Growth Cartilage of Rats during Endochondral Calcification
Chapter 27: Composition and Biosynthesis of Rat Glomerular Basement Membrane in Sucrose-Fed Rats
Chapter 28: Biosynthesis of Elastin by Chondroblasts in Monolayer Cultures
Chapter 29: N-Glycosylation of Asparagine Residues in Subtilisin, Lysozyme, and Synthetic Peptides by Microsomal Transferases
Chapter 30: Glycolipid Intermediates Involved in the Transfer of N-Acetylglucosamine to Endogenous Proteins in Yeast
Chapter 31: Purification and Characterization of Two Sialyltransferase Activities from Porcine Submaxillary Glands
Chapter 32: Mannosyl Retinyl Phosphate: Its Role as a Donor of Mannose to Glycoconjugates in Rat Liver Membranes
Chapter 33: Isolation and Properties of Acylneuraminate Cytidylyltransferase from Frog Liver
Chapter 34: Sugar-Modified Lysozyme as N-Acetylneuraminic Acid Acceptor
Chapter 35: 2-Deoxy-D-glucose, 2-Deoxy-2-fluoro-D-glucose, and 2-Deoxy-2-fluoro-D-mannose as Inhibitors of Glycosylation
Chapter 36: Phosphorylation of Proteoglycans in Human Articular Cartilage
Chapter 37: Composition of the Chondroitin Sulfate Proteoglycan Produced by β-D-Xyloside-Treated Chondrocytes
Chapter 38: Properties of a Mannosyltransferase from Rabbit Liver
Chapter 39: A Structural Glycoprotein of Elastic Tissue: Its Synthesis by Cultured Fibroblasts
Chapter 40: Isolation and Characterization of Rat Stomach Glycoprotein
Chapter 41: Intracellular Site of Glycosyl- and Sulfate-Transferases in the Surface Mucous-Cells of the Rat Stomach
Chapter 42: Synthesis and Metabolic Effects of Halogenated L-Fucose and D-Galactose Analogs
Chapter 43: Studies on Immature Articular Cartilage
Chapter 44: Effects of Tunicamycin on Procollagen Synthesis and Secretion
Chapter 45: Biochemical Studies of the Matrix of Cranio-vertebral Chordoma and a Metastasis
Chapter 46: Cell-Free Synthesis of Cartilage Specific Proteins
Chapter 47: Sialylation of Desialylated Ovine Submaxillary Mucin by Porcine Liver Sialyltransferase in Vitro
Chapter 48: Chemical Synthesis of α-N-Acetylhyalobiuronic Acid Phosphate Derivatives
Chapter 49: Role of Synthetic Phosphate Diesters in Study of Bacterial Cell Wall
Chapter 50: Incorporation of N-Acetylglucosamine and Mannose in Rat Liver Microsomes: Submicrosomal Localization and Effect of the Removal of Bound Ribosomes
Chapter 51: Alterations in Heparan Sulfate after SV40 Transformation
Chapter 52: The Effect of Hyaluronic Acid on the Synthesis of Proteoglycans by Chondrocytes
The Control of Glycoprotein Synthesis
Harry Schachter, Saroja Narasimhan and James R. Wilson
Publisher Summary
This chapter discusses some of the problems involved in the control of glycoprotein assembly. Most Asn–GlcNAc oligosaccharides have the core structure Man3GlcNAc2Asn. There are, however, two distinctly different types of oligosaccharide chains sharing this common core structure, namely, the N-acetyllactosamine type and the oligomannoside. Some N-acetyllactosamine-type oligosaccharides have a fucose residue attached to the asparagine-linked GlcNAc residue. Genetic information is fed into the system indirectly, and there is no template-mediated information transfer in the assembly of an oligosaccharide chain. Unlike the linkages between two amino acids in a polypeptide chain, linkages between two monosaccharide units can be very diverse (α or β, and between the anomeric carbon of one sugar and C-2,3,4 or 6of the other sugar). The endomembrane system must play a vital role in the control process. The substrate specificities of the glycosyltransferases have long been implicated in the control of oligosaccharide assembly. It has been suggested that multi-glycosyltransferase systems assemble oligosaccharide sequences; the product of one transferase becomes the substrate for the next transferase, and every linkage is forged by a separate and highly specific transferase. Dolichyl oligosaccharide pyrophosphate donates a large oligosaccharide to the polypeptide backbone in the rough endoplasmic reticulum. Fucose incorporation cannot occur until GlcNAc- transferase I has acted.
The purpose of this presentation will be to outline some of the problems involved in the control of glycoprotein assembly and to present some of the work of our own laboratory on this topic. The discussion will be limited to the asparagine-N-acetylglucosamine (Asn-GlcNAc)-linkage type oligosaccharides, although many of the points that will be raised are equally applicable to other types of oligosaccharide.
A study of the various structures that have been published recently raises some obvious questions of relevance to the control of glycoprotein biosynthesis:
(a) Most Asn-GlcNAc oligosaccharides have the core structure Man3GlcNAc2Asn shown in Scheme 1. There are, however, two distinctly different types of oligosaccharide chains sharing this common core structure, i.e., the N-acetyllactosamine (or complex
) type and the oligomannoside (or simple
) type (Scheme 1). The first question that can therefore be raised is what mechanisms serve to direct the biosynthetic pathway toward these two alternatives? It is interesting to note that some glycoproteins (e.g., calf thyroglobulin) contain both types of oligosaccharide on a single polypeptide chain (1); it is unlikely that both types of oligosaccharide can occur at the same amino acid position of the polypeptide chain, but this point requires further structural studies.
Scheme 1 Oligosaccharide structure of the Asn-GlcNAc-linkage type.
(b) Some N-acetyllactosamine-type oligosaccharides have a fucose residue attached to the asparagine-linked GlcNAc residue, [e.g., human immunoglobulins (2) and glycopeptide B from porcine thyroglobulin (3)], whereas other N-acetyllactosamine-type oligosaccharides do not, e.g., α1-acid glycoprotein, (Fournet et al., in this volume). Further, oligomannoside-type oligosaccharides never appear to carry fucosyl residues. What mechanisms control the incorporation of fucosyl residues into these oligosaccharide chains?
(c) Some oligosaccharides have only a single GlcNAc residue attached to a core mannose residue, e.g., β-GlcNAc-(1+2)-Man in human immunoglobulins (2), whereas others are branched at this point and have two GlcNAc residues attached to a single mannose residue of the core, e.g., β-GlcNAc-(1→2)-[β-GlcNAc-(1→4)]-Man in α1-acid glycoprotein (Fournet et al., in this volume). What controls this branching?
(d) Some oligosaccharides are asymmetrical in that only a single N-acetyllactosamine arm is substituted with a sialic acid residue (Scheme 2), or in that one arm has a complete N-acetyllactosamine chain whereas the other arm has only a GlcNAc residue (Scheme 2) Why are such asymmetrical structures synthesized and what controls are operative?
Scheme 2 Some typical asymmetric oligosaccharides of the N-acetyllactosamine type. Glycopeptide A is present in human (2) immunoglobulin E and possibly in other immunoglobulin classes; glycopeptide B is present in bovine immunoglobulin G (4) and in human immunoglobulin G (5).
(e) Whereas the Man3GlcNAc2Asn core structure shown in Scheme 1 is found in many different glycoproteins (6), there are exceptions, e.g., the structure proposed by Kawasaki and Ashwell (7) for an oligosaccharide present in the asialoglycoprotein-binding receptor protein isolated from hepatic membranes; the core of this structure contains only two mannosyl residues. What is the significance of such variations in the core structure?
It is possible to list other structural features (e.g., variations in the linkages between sialic acid and galactose, or between galactose and N-acetylglucosamine, etc.) which require explanations at the level of biosynthetic control. The following discussion will unfortunately not answer all the queries raised. Rather, a general discussion of possible control sites in glycoprotein synthesis will be presented and some more specific aspects of the elongation process responsible for addition of N-acetyllactosamine-type arms (Scheme 1) will be outlined.
FACTORS THAT AFFECT THE CONTROL OF GLYCOPROTEIN BIOSYNTHESIS
The following factors must be considered in the control of glycoprotein assembly:
(a) Genetic information is fed into the system indirectlv. There is no template-mediated information transfer in the assembly of an oligosaccharide chain. Unlike the linkages between two amino acids in a polypeptide chain, linkages between two monosaccharide units can be very diverse (a or 3, and between the anomeric carbon of one sugar and C-2,3,4 or 6 of the other sugar); further, very complex branching may occur. A template mechanism would be difficult to envisage for the biosynthesis of oligosaccharides. Rather, information from the genome is transmitted to the assembly system in a diverse manner, i.e., by coding for the synthesis of the glycoprotein polypeptide backbone, the glycosyltransferases, the endomembrane system on which assembly occurs, and other unknown control factors.
(b) The endomembrane system must play a vital role in the control process and will be discussed further in the next section.
(c) The substrate specificities of the glycosyltransferases have long been implicated in the control of oligosaccharide assembly (8). It has been suggested that multiglycosyltransferase systems assemble oligosaccharide sequences (9); the product of one transferase becomes the substrate for the next transferase, and every linkage is forged by a separate and highly specific transferase (the one linkage-one transferase hypothesis). Several papers from Hill’s laboratory have recently verified earlier observations on the specificity of glycosyltransferases and have lent strong support to the one linkage-one transferase hypothesis (10–14; Sadler et al., in this volume; Beyer et al., in this volume). Further examples of glycosyltransferase specificity will be presented later, in the discussion on the elongation of N-acetyllactosamine-type oligosaccharides. It appears highly probable that glycosyltransferase specificity is the major controlling factor in the initiation, elongation, and termination of oligosaccharide chains. Initiation is a particularly important control point since the synthesis of the amino acid-sugar linkage predetermines the nature of the corresponding oligosaccharide. The initiation of Asn-GlcNAc-type oligosaccharides is believed to involve lipid (dolichol) intermediates, and this topic has been discussed by R. G. Spiro and others elsewhere in this book.
(d) Various other factors undoubtedly play a role in control of glycoprotein synthesis. Feedback control mechanisms are known to be involved in the synthesis of nucleotide-sugars and obviously the availability of nucleotide-sugars, dolichyl sugar phosphates and dolichyl oligosaccharide pyrophosphates is essential. The role of phosphatases and pyrophosphatases in regulating the levels of the latter compounds requires further investigation. Cations and various nucleotides are also known to affect glycosyltransferase activity.
No attempt will be made to discuss all these topics. The remainder of this paper will deal with only two aspects, i.e., the endomembrane system and the elongation of N-acetyllactosamine-type oligosaccharides.
THE ENDOMEMBRANE SYSTEM
Fig. 1 shows the endomembrane system in the process of synthesizing a glycoprotein destined to become part of the plasma membrane; a similar scheme can be constructed for the synthesis of a secreted glycoprotein. There is considerable evidence that the peptide backbones of all glycoproteins are assembled on membrane-bound ribosomes (15,16); this has been most convincingly demonstrated by more recent work on enveloped viruses (such as vesicular stomatitis virus and Sindbis virus), which showed that messenger RNA coding for membrane glycoproteins was translated predominantly on membrane-bound ribosomes (17–19). In contrast, it has been suggested that nonglycosylated membrane proteins, destined for the cytoplasmic face of the endoplasmic reticulum or plasma membrane, are synthesized on free ribosomes and do not pass through the endomembrane assembly line; rather, these molecules possibly migrate through the cytosol (see 20 for a recent review).
Fig. 1 Schematic illustrations of the biosynthesis of a glycoprotein destined for insertion into the plasma membrane; a similar scheme can be drawn for secreted glycoproteins. The following stages are numbered on the figure: (1) Synthesis of polypeptide begins on free ribosomes. Some sort of signal
is believed to be synthesized near the amino-terminal end of the nascent peptide; this may be an extra hydrophobic sequence in the case of some secreted proteins (26–28), but the universality of such a sequence is not yet established.
The membrane glycoproteins of the endoplasmic reticulum present a special biosynthetic problem since glycosylation is completed in the Golgi complex and a mechanism is believed to exist for the transport of these molecules from the Golgi apparatus through the cytosol to the endoplasmic reticulum (21–24).
The signal
causes attachment of ribosome to endoplasmic reticulum membrane. (2) The ribosome becomes attached to endoplasmic reticulum membrane by binding to a special protein in the membrane; this protein may serve to form a channel for passage of nascent peptide through the membrane. (3) Translation of messenger RNA occurs and nascent peptide undergoes vectorial discharge
into the lumen of the rough endoplasmic reticulum. (4) Glycoproteins destined for secretion pass completely into the lumen and may remain only loosely bound to membrane; glycoproteins destined for the plasma membrane probably contain a hydrophobic region which keeps them bound tightly to membrane. Presumably when this hydrophobic region is translated, the ribosome lifts off the membrane and the remainder of the nascent peptide is released into the cytoplasmic side of the endoplasmic reticulum membrane. (5) The ribosome has lifted off the membrane and translation continues. Some proteins may undergo processing at this stage by a proteinase which removes the signal
sequence from the amino-terminal end (26). Also, as discussed in the text, some carbohydrate incorporation may occur while the peptide is still nascent on the ribosome. (6) Translation is completed and peptide detached from the ribosome. Incorporation of oligosaccharide into peptide from dolichyl oligosaccharide pyrophosphate probably occurs predominantly at this stage. The multiglycosyltransferase systems catalysing carbohydrate incorporation are directed towards the intravesicular space. (7) The glycoprotein migrates towards the Golgi apparatus where elongation of the core to N-acetyllactosamine-type oligosaccharide occurs. It is now believed that a second type of processing occurs either in the rough endoplasmic reticulum, smooth endoplasmic reticulum, or Golgi apparatus, such that a large protein-bound oligosaccharide is cleaved to a smaller unit; this small oligosaccharide serves as the starting point for elongation (see text). (8) Vesicles migrate from the Golgi apparatus to the plasma membrane where fusion occurs. (9) Secretory proteins are released from the cell; lateral migration causes insertion of membrane glycoprotein into the plasma membrane.
The mechanism for the segregation of messenger RNA between free and membrane-bound ribosomes has long been a topic of heated speculation. A signal hypothesis
has been proposed (25–27), which suggests that translation products destined for transfer across the endoplasmic reticulum membrane carry a signal
to initiate binding of ribosome to the endoplasmic reticulum (Fig. 1). The signal hypothesis
envisaged by Blobel and Dobberstein (26) applied to proteins destined for secretion from the cell and suggests that the signal is a sequence of hydrophobic amino acids near the amino-terminal end of the nascent polypeptide chain (Fig. 1); this signal sequence is not present in the final secreted product and is cleaved off within the endomembrane system by a specific protease. Presumably, proteins lacking such a signal sequence cannot initiate ribosome binding to membrane, are translated on free ribosomes, and do not enter the endomembrane assembly