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In general, what is a lysosomal storage disease?

1) The term lysosomal storage diseases is given to a variety of rare hereditary diseases in which there is a defect in a hydrolase enzyme resulting in the accumulation of the substrate in lysosomes
2) Many of these conditions involve a failure to hydrolyze a glycosidic bond


Describe the structure of glycoproteins vs. the structure of proteoglycans

1) Glycoproteins are proteins that have oligosaccharide chains covalently attached to their polypeptide chains (short chains of sugars attached to long polypeptide chain)
2) Proteoglycans have polysaccharide chains attached to proteins (similar to glycogen; long, linear polysaccharide chains [glycosaminoglycans] attached to few proteins)


What are 8 functions of glycoproteins and examples of each?

1) Structural molecule - Collagens
2) Lubricant - Mucins
3) Transport molecule - e.g. Transferrin, Ceruloplasmin
4) Immune system - Immunoglobulins, Histocompatibility antigens, Blood group determinants
5) Hormone - e.g. HCG, TSH
6) Enzymes - e.g. Alkaline phosphatase
7) Blood clotting - e.g. Fibrinogen
8) Cell surface recognition - Lectins


What are functions of proteoglycans?

1) Proteoglycans are usually structural components of the extracellular matrix
2) Some have a lubricant role
3) Heparin is normally intracellular and inhibits blood clotting


Describe the structure of glycoproteins in depth

1) There may be one or more carbohydrate chains covalently linked to a protein
2) The chains may be neutral or negatively charged
3) They are frequently branched
4) There are two types of glycosidic linkages:
O-glycosidic link & N-glycosidic link


What are examples of O-glycosidic links?

1) In collagen there is an O-glycosidic link between galactose or glucose and the hydroxyl group of hydroxylysine
2) Other O-linked glycoproteins have a glycosidic link between N-acetyl galactosamine and either serine or threonine (e.g. blood group substances and salivary mucins)


What are examples of N-glycosidic links?

N-glycosidic links exist between N-acetylglucosamine and asparagine. There are two types:
1) High mannose
2) Complex. For example, in addition to mannose they may contain N-acetylglucosamine, galactose, fucose and N-acetylneuraminic acid (sialic acid)


What causes I-cell (Inclusion cell/bodies) disease?

I-cell disease results from an enzyme deficiency so that lysosomal enzymes do not acquire the targeting signal, mannose 6-phosphate


What is a characteristic about fibroblasts in I-cell disease?

Fibroblasts in this disease have dense inclusion bodies (I-cells) and are deficient in many lysosomal enzymes


What is a characteristic about lysosomes in I-cell disease?

Lysosomes become engorged with indigestible substrates, leading to death in infancy


Describe the structure of proteoglycans in depth

1) Proteoglycans usually consist of a core protein covalently linked to a glycosaminoglycan
2) The glycosaminoglycan typically consists of a long polysaccharide chain with a repeating disaccharide motif
3) Glycosaminoglycans are polyanionic. The
negative charge comes from the presence of
carboxyl and/or sulfate groups. The carboxyl
group is on either D-glucuronic acid or its epimer L-iduronic acid (both have glucose with a carboxyl group on 6C, but differ in structure around 5C)
4) The repeating disaccharide is glycosidically
linked to a serine residue on the protein through a galactose-galactose-xylose- serine sequence


What are 6 examples of glycosaminoglycans?

1) Hyaluronic acid (Proteoglycan monomers typically are bound non-covalently to a hyaluronic acid molecule in association with linker proteins in a "bottle brush" arrangement)
2) Chondroitin sulfate
3) Dermatan sulfate
4) Heparan sulfate
5) Heparin
6) Keratan sulfate


What are 4 characteristic features of glycosaminoglycans (mucopolysaccharides)?

1) Polysaccharide chains
2) Repeating disaccharide motifs
3) Amino groups
4) Polyanionic character due to carboxyl and/or sulfate groups


What are two examples of differences between glycosaminoglycans?

1) The type of bonding between polysaccharides (alpha 1,3; beta 1,3; alpha 1,4; beta 1,4)
2) The degree of sulfation groups


What is the sulfate donor when something becomes sulfated in vivo?

PAPS (Phosphoadenosine phosphosulfate)


From what are the units in saccharide chains added to glycoproteins and proteoglycans?

1) Nucleoside diphosphate derivatives (UDP-glucuronic acid, UDP-N-acetylgalactosamine, & GDP-mannose)
2) Sialic acid in glycoproteins is added from CMP-NANA
3) These additions are catalyzed by specific glycosyltransferases


How can one characterize the synthesis of glycosaminoglycans and of O-linked glycoproteins?

The addition is direct


How can one characterize the synthesis of N-linked glycoproteins?

The chain is formed on dolichol pyrophosphate and then transferred to the protein


How are glycosaminoglycans & glycoproteins degraded?

1) Degradation of the saccharide chains is achieved by hydrolytic enzymes present in lysosomes
2) The enzymes act on the ends of the chains on a last-on-first-off basis


What are mucopolysaccharidoses (MPS)?

1) The mucopolysacharidoses are a series of hereditary diseases resulting from mutations in genes coding for degradative enzymes acting on glycosaminoglycans (mucopolysaccharides)
2) The enzymes are almost all hydrolases and deficiency leads to mental retardation and/or structural deformities
3) With the exception of the X-linked Hunter syndrome (MPS 2) they have an autosomal recessive inheritance


What is MPS I (Hurler syndrome)?

1) A deficiency of alpha L-iduronidase
2) Accumulation of dermatan sulfate & Heparan sulfate
3) Leads to clouding of cornea, mental retardation, dysostosis multiplex & structural changes due to accumulation


What is MPS II (Hunter syndrome)?

1) A deficiency of iduronate sulfatase
2) Accumulation of dermatan sulfate & Heparan sulfate
3) No clouding of cornea, milder course than in type 1, & X-linked disease


What is MPS IIIA (Sanfilippo Syndrome A)?

1) Deficiency in Heparan N-sulfamidase
2) Accumulation of Heparan sulfate
3) Mild somatic, but severe central nervous system effects (leads to severe mental retardation but little structural change)


What is MPS IV (Morquio Syndrome)?

1) Deficiency of a galactose-6-sulfatase or a beta-galactosidase (hexosamine 6-sulfatase)
2) Accumulation of Keratan sulfate
3) Normal intelligence but severe bone changes and cloudy cornea (severe deformity)


What is MPS IIIB (Sanfilippo Syndrome B)?

1) Deficiency in N-acetyl-alpha-D-glucosaminidase
2) Accumulation of Heparan sulfate
3) Mild somatic, but severe central nervous system effects (leads to severe mental retardation but little structural change)


What is MPS VI (Maroteaux-Lamy Syndrome)

1) Deficiency in Arylsulfatase B (N-acetylgalactosamine 4-sulfatase)
2) Accumulation of Dermatan sulfate
3) Severe bone, soft tissue & corneal change


What is MPS VII (Mucolipidosis)

1) Deficiency in Beta-glucuronidase
2) Accumulation of Dermatan sulfate & Heparan sulfate
3) Hepatosplenomegaly & dysostosis multiplex