Glycobiology in Human Disease I

Question 1

Lysosomes contain digestive enzymes that are active at the acidic pH of this organelle, and most of these enzymes are soluble and localized in the

Answer 1

Lysosomal lumen

Question 2

The digestive enzymes in lysosomes are special because they are destined for

Answer 2

Intracellular organelles

Question 3

To do so, they require special processing within the

Answer 3

Golgi apparatus

Question 4

Similar to all other secretory proteins, lysosomal enzymes are synthesized in the

Answer 4

ER (then transported to golgi)

Question 5

Within the Golgi complex they undergo a variety of post-translational modifications, of which one is

Answer 5

Addition of terminal mannose-6P

Question 6

The attachment of terminal mannose-6-phosphate groups to some of the oligosaccharide side chains forms a

Answer 6

Glycoprotein

Question 7

The phosphorylated mannose residues serve as an “address label” that is recognized by specific receptors found on the inner surface of the

Answer 7

Golgi membrane

Question 8

Bind these receptors and are thereby segregated from the numerous other secretory proteins within the Golgi

Answer 8

Lysosomal Enzymes

Question 9

Subsequently, small transport vesicles containing the receptor-bound enzymes are pinched off from the Golgi and proceed to fuse with the

Answer 9

Lysosome

Question 10

Molecules are composed of a protein molecule linked to one or more carbohydrates

Answer 10

Glycoproteins

Question 11

Carbohydrates are O-linked, if they are linked to the protein via a

Answer 11

Serine or threonine amino acid

Question 12

Carbohydrates are N-linked if they are linked to the protein via an

Answer 12

Asparagine

Question 13

The mechanism of synthesis of O-linked glycoproteins is similar to that of

Answer 13

Glycosaminoglycans

Question 14

As the polypeptide is being synthesized, it is extruded into the lumen of the ER. The carbohydrate substrates are

Answer 14

UDP-derivates of sugars

Question 15

The mechanism of N-linked glycoprotein biosynthesis is distinct from that of O-linked biosynthesis. In this case, the carbohydrate substrates are not

Answer 15

UDP-derivatives

Question 16

In the N-linked glycoprotein synthesis, the carbohydrate substrates are not UDP-derivatives, but are instead

Answer 16

Dolichol pyrophosphate derivatives

Question 17

In N-linked glycoproteins, sugars are added individually directly to

Answer 17

Dolichol (not the protein)

Question 18

In N-linked glycoproteins, sugars are added individually directly to dolichol by

Answer 18

Glycosyltransferases

Question 19

The oligosaccharide is then transferred from dolichol to the

Answer 19

Asparagine side chain of the protein

Question 20

The N-linked oligosaccharide is then processed by removal of specific sugar residues – back to

Answer 20

Mannose residues

Question 21

Act as biological labels, including those specifying cell surface recognition and cell surface antigenicity

Answer 21

Glycoproteins

Question 22

Enhance protein solubility (due to polarity of the carbohydrate

Answer 22

Glycoproteins

Question 23

Glycoproteins are resistant to

Answer 23

Proteases

Question 24

The terminus of glycoproteins can also affect intracellular protein targeting. For example, terminal mannose-6-phosphate residues target enzymes for transport to the

Answer 24

Lysosome

Question 25

Mannose6-phosphate receptors on the internal Golgi surface bind mannose-6-phosphate and direct vesicle transport to the

Answer 25

Lysosome

Question 26

A rare but serious disease marked by skeletal abnormalities and psychomotor problems

Answer 26

I-cell disease

Question 27

In I-cell disease, how many acid hydrolases are missing from the lysosome?

Answer 27

8

Question 28

This abnormality, however, is a consequence of a single

Answer 28

Gene defect

Question 29

This abnormality, however, is a consequence of a single gene defect. It turns out that the gene encodes a

Answer 29

UMP transferase

Question 30

This UMP transferase catalyzes phosphate transfer to

Answer 30

Mannose-6-OH

Question 31

As a consequence, acid hydrolases that are normally targeted to the lysosome by mannose-6phosphate are misdirected, resulting in toxic accumulation of

Answer 31

Glycosaminoglycans and glycolipids

Question 32

I-Cell disease can be classified as a toxic accumulation of

Answer 32

Glycosaminoglycans and glycolipids

Question 33

Represent a large group of more than 50 clinically recognized conditions resulting from inborn errors of metabolism affecting the organelle known as the lysosome

Answer 33

Lysosomal Storage Disorders (LSDs)

Question 34

An integral part of the larger endosomal/lysosomal system, and is closely allied with the ubiquitin-proteosomal and autophagosomal systems

Answer 34

Lysosome

Question 35

Consist of the interruption of metabolic pathways involved in the recycling of degradation products of one or several types of macromolecules

Answer 35

LSDs

Question 36

As a consequence of inefficient recycling, imperfectly degraded substances accumulate in cells with cascades of

Answer 36

Deleterious repercussions

Question 37

The histological hallmark of LSDs is

Answer 37

Cell vacuolation

Question 38

With time, cells in most severely affected tissues become progressively clogged with

Answer 38

Cytoplasmic inclusions

Question 39

Over 50 LSDs are known and they have a collective incidence of approximately

Answer 39

1 - 7000/8000 births

Question 40

LSDs are normally

Answer 40

Monogenic

Question 41

LSDs are normally monogenic (i.e. they involve only a single gene), but, for most LSDs, numerous mutations have been described in the

Answer 41

Same gene

Question 42

No obvious genotype–phenotype correlation has been found for most

Answer 42

LSDs

Question 43

The ever-expanding number of LSDs can be divided into rational categories based on the biochemical nature of the accumulated metabolite, thus creating such subgroups as the

Answer 43

Glycogenoses, sphingolipidoses (lipidoses), mucopolysaccharidoses, and mucolipidoses

Question 44

Rich in gangliosides, and hence defective hydrolysis of gangliosides, as occurs in GM1 and GM2 gangliosidoses, results primarily in accumulation within neurons and consequent neurologic symptoms

Answer 44

The brain

Question 45

Defective hydrolysis of ganfliosides occurs in

Answer 45

GM1 and GM2 gangliosidoses

Question 46

Defective degredation affects virtually every organ because they are widely distributed in the body

Answer 46

Mucopolysaccharides

Question 47

Organs rich in phagocytic cells, such as the spleen and liver, are frequently enlarged in several forms of

Answer 47

LSDs

Question 48

The most severe LSDs, infantile forms, present with acute

Answer 48

Brain involvement

Question 49

These patients die within the

Answer 49

First years of life

Question 50

In adult forms, symptoms develop more slowly and disability often arises mainly from

Answer 50

Peripheral symptoms

Question 51

Intermediate between infantile and adult forms of LSD

Answer 51

Juvenile forms of LSDs

Question 52

Neurological symptoms of LSDs can include seizures, dementia and

Answer 52

Brainstem dysfunction

Question 53

Among the peripheral symptoms of LSDs are enlargement of the spleen and liver (hepatosplenomegaly), heart and kidney injury, abnormal bone formation, muscle atrophy and

Answer 53

Ocular disease

Question 54

Several diseases are characterized by prominent neurological involvement and minimal peripheral impairment, for example

Answer 54

Sanfilippo disease

Question 55

Others have peripheral dysfunction with rare brain involvement, for example

Answer 55

Fabry Disease

Question 56

All forms of Pompe disease (or glycogen-storage-disease type II) are characterized by

Answer 56

Myopathy

Question 57

?Many of the sphingolipidoses are characterized by

Answer 57

Brain disease

Question 58

A family of linear polymers composed of repeating disaccharide subunits. The disaccharide repeating unit consists of an amino sugar for which the amino group is usually acetylated

Answer 58

Glycosaminoglycans

Question 59

Made up of repeating disaccharide units, an amino sugar, and an acidic sugar

Answer 59

Glycosaminoglycans

Question 60

N-acetylglucosamine and N-acetylgalactosamine are examples of

Answer 60

Amino sugars

Question 61

Glucuronic acid and its C5 epimer iduronic acid are examples of

Answer 61

Acidic sugars

Question 62

Synthesized by the sequential addition of alternating acidic and amino sugars

Answer 62

Glycosaminoglycans

Question 63

The substrates for glycosaminoglycans are not the acidic and amino sugars per se, but are instead

Answer 63

UDP derivatives of each monosaccharide

Question 64

In some glycosaminoglycans one or more of the hydroxyl groups of the amino sugar is esterified with

Answer 64

Sulfate

Question 65

The combination of these sulfate groups and the carboxylate groups of glucuronic acid gives the glycosaminoglycans a very high density of

Answer 65

Negative charge

Question 66

Consequently, glycosaminoglycans are long, thin, hydrated molecules with very high

Answer 66

Viscosity

Question 67

Each of the glycosaminoglycans (except hyaluronate) is found covalently attached to extracellular proteins to form

Answer 67

Proteoglycan monomers

Question 68

These are enormous aggregates in which the polysaccharide is the principal component, typically 95% or more of mass

Answer 68

Proteoglycans

Question 69

The fundamental distinction between proteoglycans and glycoproteins is their

Answer 69

Sugar composition

Question 70

The disaccharide repeating unit of proteoglycans, typically 20 – 60 dimers, is covalently attached to protein at a

Answer 70

Serine or threonine residue

Question 71

This occurs via a trisaccharide linkage of

Answer 71

-xylose-galactose-galactose

Question 72

The core protein of proteoglycans is synthesized in the cytosol and co-translationally translocated into the lumen of the

Answer 72

ER

Question 73

Formation of the carbohydrate chain is initiated by transfer of xylose to either a

Answer 73

Serine or Threonine

Question 74

This is followed by the addition of two

Answer 74

Galactose residues

Question 75

Alternating acidic and amino sugars are then added to the growing chain to reach of length of 20 – 60 disaccharide repeating units, depending upon the type of

Answer 75

Proteoglycan

Question 76

Each of these additions is catalyzed by membrane-bound transferases while the nascent proteoglycan traverses the

Answer 76

ER

Question 77

Occurs after monosaccharides have been incorporated into the growing carbohydrate chain

Answer 77

Sulfation of sugar residues

Question 78

Proteoglycan monomers, in turn, are noncovalently linked to

Answer 78

Hyaluronate

Question 79

Composed typically of approximately 50,000 disaccharide repeating units per chain, to form proteoglycan aggregates

Answer 79

Hyaluronate

Question 80

One hundred or more proteoglycan monomers can bind a single, extended molecule of

Answer 80

Hyaluronate

Question 81

Glycosaminoglycans and proteoglycans function as components of the extracellular matrix of

Answer 81

Cartilage and Tendons

Question 82

Contribute tensile strength and elasticity to cartilage and tendons

Answer 82

Glycosaminoglycans and proteoglycans

Question 83

Indeed, these structures can cushion compressive forces because glycosaminoglycans have highly hydrated -spring back after being deformed

Answer 83

Polyanions

Question 84

Extracellular proteoglycans are usually interwoven with fibrous proteins such as

Answer 84

Collagen and Elastin

Question 85

The association between cells and the proteoglycan of extracellular matrix is mediated by a 1. ) Membrane protein called 2. ) Extracellular protein called

Answer 85

1. ) Integrin | 2. ) Fibronectin

Question 86

Also comprise the synovial fluid of joints, mucous secretions, and the vitreous humor of the vertebrate eye

Answer 86

Proteoglycans

Question 87

Unlike the other glycosaminoglycans, functions within the cell

Answer 87

Heparin

Question 88

Heparin is a highly sulfated glycosaminoglycan that binds specifically to

Answer 88

Antithrombin

Question 89

Accelerates the sequestration of

Answer 89

Antithrombin

Question 90

Thus, Heparin functions as an

Answer 90

Anticoagulant

Question 91

Lastly, the disaccharide repeating unit of glycosaminoglycans is also found as a component of the cell wall of certain

Answer 91

Gram-positive bacteria

Question 92

Have the disaccharide repeating unit is N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc)

Answer 92

Gram-positive bacteria cell membranes

Question 93

A component of human tears, kills bacteria by hydrolyzing the glycosidic bond between GlcNAc and MurNAc

Answer 93

Lysozyme

Question 94

Several antibiotics exert their effects by targeting the peptidoglycan components of the wall. For example,

Answer 94

Penicillin

Question 95

Targets peptidoglycan

Answer 95

Penicillin

Question 96

Interferes with peptidoglycan biosynthesis by inhibiting a transpeptidase that catalyzes formation of the cross-linking polypeptide

Answer 96

Penicillin

Question 97

Glycosaminoglycans are degraded in the

Answer 97

Lysosome

Question 98

Glycosaminoglycans are broken down by an array of hydrolytic enzymes. Degradation is sequential, beginning with the last group added during

Answer 98

Biosynthesis

Question 99

Hereditary disorders characterized by accumulation of glycosaminoglycans in various tissues

Answer 99

Mucopolysaccharidoses

Question 100

Accumulation of glycosaminoglycans in various tissues is due to deficiency for specific lysosomal hydrolases in a

Answer 100

Mucopolysaccharidoses