Differences between glycoproteins andproteoglycans
Functions and structures of glycoproteins andproteoglycans
Synthesis and degradation of glycoproteins andproteoglycans
Pathology related to glycoproteins andproteoglycans
Medical Biochemistry, third edition, edited byBaynes and Dominiczak.
Chapter 26, pages 351-366 on glycoproteins
Chapter 28, pages 384-388 on proteoglycans
Glycoproteins
Proteoglycans
Proteins conjugated to
saccharides lacking a
serial repeat unit
Proteins conjugated to
polysaccharides with
serial repeat units
Glycosaminoglycans
Mucopolysaccharides
Protein>>carbohydrate
Carbohydrate>>protein
Repeat unit
HexN and HexUA
These molecules function in the extracellular matrix (ECM)
Overview of glycoproteins:
--carbohydrate chain short
--no serial repeats
--often branched, not linear
--variable amounts of carbs
--wide range of functions
Some Functions of Glycoproteins
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Function Glycoprotein
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1. Structural moleculeCollagens
2. LubricantMucins
3. Transport moleculee.g. Transferrin,
Ceruloplasmin
4. Immune systemImmunoglobulins,
Histocompatibility antigens,
Blood group determinants
5. Hormonee.g. HCG, TSH
6. Enzymese.g. Alkaline phosphatase
7. Blood clottinge.g. Fibrinogen
8. Cell surface recognitionLectins
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STRUCTURE OF GLYCOPROTEINSSTRUCTURE OF GLYCOPROTEINS
One or more carbohydrate chains--covalently linked to a protein.
The chains may be neutral or negatively charged. They arefrequently branched.
There are two types of glycosidic links:
1. O-glycosidic link
O-glycosidic link between galactose or glucose and the hydroxylgroup of hydroxylysine (i.e. collagen).
Other O-linked glycoproteins have a glycosidic link between N-acetylgalactosamine and either serine or threonine (i.e. blood groupsubstances and salivary mucins).
2. N-glycosidic link
N-glycosidic links exist between N-acetylglucosamine andasparagine. There are two types:
A. High mannose
B. Complex. For example, in addition to mannose they may containN-acetylglucosamine, galactose, fucose and N-acetylneuraminic acid(sialic acid)
Lippincott
SYNTHESIS OF GLYCOPROTEINS
Synthesized on ribosomes attached to the RER, thentransported via vesicles to the Golgi for sorting
The units in the saccharide chains are added from
UDP-glucuronic acid, UDP-N-acetylgalactosamine and GDP-mannose.
Sialic acid in glycoproteins is added from CMP-NANA.
These additions are catalyzed by specificglycosyltransferases.
For synthesis of O-linked glycoproteins, addition is direct.
For N-linked glycoproteins, the chain is formed on dolicholpyrophosphate and then transferred to the protein.
DEGRADATION OF GLYCOPROTEINS
Degradation of the saccharide chains is achievedby hydrolytic enzymes present in lysosomes.
The enzymes act on the ends of the chains on alast-on-first-off basis.
Defects can lead to a number ofdiseases/disorders
I-cell disease results from an enzymedeficiency so that lysosomal enzymes do notaquire the targeting signal, mannose 6-phosphate.
Fibroblasts in this disease have denseinclusion bodies (I-cells) and are deficient inmany lysosomal enzymes.
The lysosomes become engorged withindigestible substrates, leading to death ininfancy.
Proteoglycans are usually structuralcomponents of the extracellular
matrix; some have a lubricant role.
--bind large amounts of water
--cell/cell signalling and adehsionroles
Heparin is normally intracellular andit inhibits blood clotting.
The proteoglycans include:Hyaluronic acidChondroitin sulfateDermatan sulfateHeparan sulfateHeparinKeratan sulfateProteoglycan monomers typically are bound non-covalently to a hyaluronic acid molecule inassociation with linker proteins in a “bottle brush”arrangement.The proteoglycans include:Hyaluronic acidChondroitin sulfateDermatan sulfateHeparan sulfateHeparinKeratan sulfateProteoglycan monomers typically are bound non-covalently to a hyaluronic acid molecule inassociation with linker proteins in a “bottle brush”arrangement.
STRUCTURE OF PROTEOGLYCANS (GAGs)Proteoglycans usually consist of a core protein covalentlylinked to a glycosaminoglycan. The glycosaminoglycantypically consists of a long polysaccharide chain with arepeating disaccharide motif.Proteoglycans are polyanionic. The negative charge comesfrom the presence of carboxyl and/or sulfate groups. Thecarboxyl group is on either D-glucuronic acid or its epimerL-iduronic acid.The repeating disaccharide is glycosidically linked to aserine residue on the protein through agalactose-galactose-xylose- serine sequence.STRUCTURE OF PROTEOGLYCANS (GAGs)Proteoglycans usually consist of a core protein covalentlylinked to a glycosaminoglycan. The glycosaminoglycantypically consists of a long polysaccharide chain with arepeating disaccharide motif.Proteoglycans are polyanionic. The negative charge comesfrom the presence of carboxyl and/or sulfate groups. Thecarboxyl group is on either D-glucuronic acid or its epimerL-iduronic acid.The repeating disaccharide is glycosidically linked to aserine residue on the protein through agalactose-galactose-xylose- serine sequence.
SYNTHESIS OF PROTEOGLYCANS
Synthesized in Golgi
The units in the saccharide chains are elongated inalternating acidic/amino sugars, donated from UDPderivatives. Last step is sulfation of some amino sugars.
For glycosaminoglycan synthesis and synthesis of O-linkedglycoproteins, the addition is direct.
For N-linked glycoproteins, the chain is formed on dolicholpyrophosphate and then transferred to the protein.
DEGRADATION OF PROTEOGLYCANS
Some proteoglycans must be phagocytosized first
Degradation of the saccharide chains is achievedby hydrolytic enzymes present in lysosomes.
The enzymes act on the ends of the chains on alast-on-first-off basis.
Defects can lead to a number ofdiseases/disorders
Rare inborn errors in the degradation of glycosaminoglycans result ina series of diseases called mucopolysaccharidoses;
characterized by mental retardation and/or structural defects.
MPS Type I
Hurler’s syndrome results from a deficiency of alpha-L-iduronidase.Heparan sulfate and dermatan sulfate accumulate. There is growthand mental retardation with characteristic facial changes.
MPS Type II
Hunters syndrome is similar to Hurler’s syndrome but the enzymedeficiency is for iduronate sulfatase and the inheritance is X-linked.
MPS Type III
Sanfilipo’s syndrome is caused by a deficiency of one of fourenzymes of which three are hydrolases and one is an N-acetyltransferase. There is severe mental retardation but only mildstructural features.
Other MPS Types are IV, VI and VII. There is no MPS Type V.
MPS I (HurlerSyndrome)
A deficiency of L-iduronidase leads tomental retardation andstructural changes dueto accumulation ofdermatan sulfate andheparan sulfate
MPS II (Hunter Syndrome)
X-linked disease due to adeficiency of iduronatesulfatase
MPS III (Sanfilippo Syndrome)
Deficiency in one of fourdegradative enzymes leads tosevere mental retardation butlittle structural change
MPS IV (Morquio Syndrome)
Deficiency of a galactose-6-sulfatase or a beta-galactosidase leads to accumulation of keratan sulfatewith normal intelligence but severe deformity
Summary
Glycoproteins and proteoglycans are distinct:
--functions/structures
--synthesis/degradation
--associated pathologies