Synthesis of Glycoproteins

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Chapter: Biochemistry : Glycosaminoglycans, Proteoglycans, and Glycoproteins

Proteins destined to function in the cytoplasm are synthesized on free cytosolic ribosomes.


Proteins destined to function in the cytoplasm are synthesized on free cytosolic ribosomes. However, proteins, including glycoproteins, that are destined for cellular membranes, lysosomes, or to be exported from the cell, are synthesized on ribosomes attached to the RER. These proteins contain specific signal sequences that act as molecular “address labels,” targeting the proteins to their proper destinations. An N-terminal hydrophobic sequence initially directs these proteins to the RER, allowing the growing polypeptide to be extruded into the lumen. The proteins are then transported via secretory vesicles to the Golgi complex, which acts as a sorting center (Figure 14.15). In the Golgi, those glycoproteins that are to be secreted from the cell (or are targeted for lysosomes) are packaged into vesicles that fuse with the cell (or lysosomal) membrane and release their contents. Those that are destined to become components of the cell membrane are integrated into the Golgi membrane, which buds off, forming vesicles that add their membrane-bound glycoproteins to the cell membrane. [Note: The membrane glycoproteins are, thus, oriented with the carbohydrate portion on the outside of the cell (see Figure 14.15).]

Figure 14.15 Transport of glycoproteins through the Golgi apparatus and their subsequent release or incorporation into a lysosome or the cell membrane.


A. Carbohydrate components of glycoproteins

The precursors of the carbohydrate components of glycoproteins are nucleotide sugars, which include UDP-glucose, UDP-galactose, UDP-GlcNAc, and UDP-GalNAc. In addition, guanosine diphosphate (GDP)-mannose, GDP-L-fucose (which is synthesized from GDP-mannose), and CMP-NANA may donate sugars to the growing chain. [Note: When the acidic NANA is present, the oligosaccharide has a negative charge at physiologic pH.] The oligosaccharides are covalently attached to the R groups of specific amino acids in the protein, where the three-dimensional structure of the protein determines whether or not a specific amino acid is glycosylated.


B. Synthesis of O-linked glycosides

The synthesis of the O-linked glycosides is very similar to that of the GAGs. First, the protein to which the oligosaccharides are to be attached is synthesized on the RER and extruded into its lumen. Glycosylation begins with the transfer of GalNAc (from UDP-GalNAc) onto the R-group of a specific serine or threonine.


1. Role of glycosyltransferases: The glycosyltransferases responsible for the stepwise synthesis of the oligosaccharides are bound to the membranes of the Golgi apparatus. They act in a specific order, without using a template as is required for DNA, RNA, and protein synthesis (see Unit VI) but, rather by recognizing the actual structure of the growing oligosaccharide as the appropriate substrate.


C. Synthesis of the N-linked glycosides

The synthesis of N-linked glycosides occurs in the lumen of the RER and requires the participation of the phosphorylated form of dolichol (dolichol pyrophosphate), a lipid of the ER membrane (Figure 14.16). The initial product is processed in the ER and Golgi.

Figure 14.16 Synthesis of N-linked glycoproteins. o= N-acetylglucosamine; □= mannose; ●= glucose; ■ = N-acetylgalactosamine; ◄ or ◊  = terminal group (fucose or N-acetylneuraminic acid); mRNA = messenger RNA; Asn = asparagine.


1. Synthesis of dolichol-linked oligosaccharide: First, as with the O-linked glycosides, the protein is synthesized on the RER and enters its lumen. However, the protein does not become glycosylated with individual sugars. Instead, a lipid-linked oligosaccharide is first constructed. This consists of dolichol (an ER membrane lipid 80–100 carbons long) attached through a pyrophosphate linkage to an oligosaccharide containing N-GlcNAc, mannose, and glucose. The sugars to be added sequentially to the dolichol by the membrane-bound glycosyltransferases are first N-GlcNAc, followed by mannose and glucose (see Figure 14.16). The entire 14-sugar oligosaccharide is then transferred from the dolichol to the amide nitrogen (N) of an asparagine in the protein to be glycosylated by a protein-oligosaccharide transferase present in the ER. [Note: Tunicamycin inhibits N-linked glycosylation.]


Congenital disorders of glycosylation (CDGs) are syndromes caused primarily by defects in the N-linked glycosylation of proteins, either oligosaccharide assembly (Type I) or processing (Type II).


2. Final processing of N-linked oligosaccharides: After incorporation into the protein, the N-linked oligosaccharide is processed by the removal of specific mannosyl and glucosyl residues as the glycoprotein moves through the RER. Finally, the oligosaccharide chains are completed in the Golgi by addition of a variety of sugars (for example, N-GlcNAc, N-GalNAc, and additional mannoses, and then fucose or NANA as terminal groups) to produce a complex glycoprotein. Alternatively, they are not processed further, leaving branched, mannose-containing chains in a high-mannose glycoprotein (see Figure 14.16). The ultimate fate of N-linked glycoproteins is the same as that of the O-glycoproteins linked (for example, they can be released by the cell or become part of a cell membrane). In addition, N-linked glycoproteins can be targeted to the lysosomes. [Note: Nonenzymatic glycosylation of proteins is known as glycation.]


3. Enzymes destined for lysosomes: N-linked glycoproteins being processed through the Golgi can be phosphorylated on carbon 6 of one or more specific mannosyl residues. Mannose 6-phosphate receptors, located in the Golgi apparatus, bind the mannose 6-phosphate residues of these targeted enzymes, which are then packaged into vesicles and sent to the lysosomes. I-cell disease is a rare lysosomal storage disease in which the acid hydrolases normally found in lysosomes are absent, resulting in an accumulation of substrates normally degraded by these enzymes. [Note: I-cell disease is so-named because of the large inclusion bodies seen in cells of patients with this disease.] In addition, high amounts of lysosomal enzymes are found in the patient’s plasma and urine, indicating that the targeting process to lysosomes (rather than the synthetic pathway of these enzymes) is deficient. Individuals with I-cell disease are lacking the phosphotransferase needed to phosphorylate the mannose residues of potential lysosomal enzymes, causing the enzymes to be secreted (by default), rather than being targeted to lysosomal vesicles (Figure 14.17). I-cell disease is characterized by skeletal abnormalities, restricted joint movement, coarse (dysmorphic) facial features, and severe psychomotor impairment. [Note: Because I-cell disease has features in common with the mucopolysaccharidoses and sphingolipidoses, it is termed a mucolipidosis.] Currently, there is no cure, and death from cardiopulmonary complications usually occurs by age 10 years.

Figure 14.17 Mechanism for transport of N-linked glycoproteins to the lysosomes. Asn = asparagine; Man = mannose; P = phosphate; Pi = inorganic phosphate.

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