Glycobiology in Human Disease I Flashcards
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
Lysosomal lumen
The digestive enzymes in lysosomes are special because they are destined for
Intracellular organelles
To do so, they require special processing within the
Golgi apparatus
Similar to all other secretory proteins, lysosomal enzymes are synthesized in the
ER (then transported to golgi)
Within the Golgi complex they undergo a variety of post-translational modifications, of which one is
Addition of terminal mannose-6P
The attachment of terminal mannose-6-phosphate groups to some of the oligosaccharide side chains forms a
Glycoprotein
The phosphorylated mannose residues serve as an “address label” that is recognized by specific receptors found on the inner surface of the
Golgi membrane
Bind these receptors and are thereby segregated from the numerous other secretory proteins within the Golgi
Lysosomal Enzymes
Subsequently, small transport vesicles containing the receptor-bound enzymes are pinched off from the Golgi and proceed to fuse with the
Lysosome
Molecules are composed of a protein molecule linked to one or more carbohydrates
Glycoproteins
Carbohydrates are O-linked, if they are linked to the protein via a
Serine or threonine amino acid
Carbohydrates are N-linked if they are linked to the protein via an
Asparagine
The mechanism of synthesis of O-linked glycoproteins is similar to that of
Glycosaminoglycans
As the polypeptide is being synthesized, it is extruded into the lumen of the ER. The carbohydrate substrates are
UDP-derivates of sugars
The mechanism of N-linked glycoprotein biosynthesis is distinct from that of O-linked biosynthesis. In this case, the carbohydrate substrates are not
UDP-derivatives
In the N-linked glycoprotein synthesis, the carbohydrate substrates are not UDP-derivatives, but are instead
Dolichol pyrophosphate derivatives
In N-linked glycoproteins, sugars are added individually directly to
Dolichol (not the protein)
In N-linked glycoproteins, sugars are added individually directly to dolichol by
Glycosyltransferases
The oligosaccharide is then transferred from dolichol to the
Asparagine side chain of the protein
The N-linked oligosaccharide is then processed by removal of specific sugar residues – back to
Mannose residues
Act as biological labels, including those specifying cell surface recognition and cell surface antigenicity
Glycoproteins
Enhance protein solubility (due to polarity of the carbohydrate
Glycoproteins
Glycoproteins are resistant to
Proteases
The terminus of glycoproteins can also affect intracellular protein targeting. For example, terminal mannose-6-phosphate residues target enzymes for transport to the
Lysosome
Mannose6-phosphate receptors on the internal Golgi surface bind mannose-6-phosphate and direct vesicle transport to the
Lysosome
A rare but serious disease marked by skeletal abnormalities and psychomotor problems
I-cell disease
In I-cell disease, how many acid hydrolases are missing from the lysosome?
8
This abnormality, however, is a consequence of a single
Gene defect
This abnormality, however, is a consequence of a single gene defect. It turns out that the gene encodes a
UMP transferase
This UMP transferase catalyzes phosphate transfer to
Mannose-6-OH
As a consequence, acid hydrolases that are normally targeted to the lysosome by mannose-6phosphate are misdirected, resulting in toxic accumulation of
Glycosaminoglycans and glycolipids
I-Cell disease can be classified as a toxic accumulation of
Glycosaminoglycans and glycolipids
Represent a large group of more than 50 clinically recognized conditions resulting from inborn errors of metabolism affecting the organelle known as the lysosome
Lysosomal Storage Disorders (LSDs)
An integral part of the larger endosomal/lysosomal system, and is closely allied with the ubiquitin-proteosomal and autophagosomal systems
Lysosome
Consist of the interruption of metabolic pathways involved in the recycling of degradation products of one or several types of macromolecules
LSDs
As a consequence of inefficient recycling, imperfectly degraded substances accumulate in cells with cascades of
Deleterious repercussions
The histological hallmark of LSDs is
Cell vacuolation
With time, cells in most severely affected tissues become progressively clogged with
Cytoplasmic inclusions
Over 50 LSDs are known and they have a collective incidence of approximately
1 - 7000/8000 births
LSDs are normally
Monogenic
LSDs are normally monogenic (i.e. they involve only a single gene), but, for most LSDs, numerous mutations have been described in the
Same gene
No obvious genotype–phenotype correlation has been found for most
LSDs
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
Glycogenoses, sphingolipidoses (lipidoses), mucopolysaccharidoses, and mucolipidoses
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
The brain
Defective hydrolysis of ganfliosides occurs in
GM1 and GM2 gangliosidoses
Defective degredation affects virtually every organ because they are widely distributed in the body
Mucopolysaccharides
Organs rich in phagocytic cells, such as the spleen and liver, are frequently enlarged in several forms of
LSDs
The most severe LSDs, infantile forms, present with acute
Brain involvement
These patients die within the
First years of life
In adult forms, symptoms develop more slowly and disability often arises mainly from
Peripheral symptoms
Intermediate between infantile and adult forms of LSD
Juvenile forms of LSDs
Neurological symptoms of LSDs can include seizures, dementia and
Brainstem dysfunction
Among the peripheral symptoms of LSDs are enlargement of the spleen and liver (hepatosplenomegaly), heart and kidney injury, abnormal bone formation, muscle atrophy and
Ocular disease
Several diseases are characterized by prominent neurological involvement and minimal peripheral impairment, for example
Sanfilippo disease
Others have peripheral dysfunction with rare brain involvement, for example
Fabry Disease
All forms of Pompe disease (or glycogen-storage-disease type II) are characterized by
Myopathy
?Many of the sphingolipidoses are characterized by
Brain disease
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
Glycosaminoglycans
Made up of repeating disaccharide units, an amino sugar, and an acidic sugar
Glycosaminoglycans
N-acetylglucosamine and N-acetylgalactosamine are examples of
Amino sugars
Glucuronic acid and its C5 epimer iduronic acid are examples of
Acidic sugars
Synthesized by the sequential addition of alternating acidic and amino sugars
Glycosaminoglycans
The substrates for glycosaminoglycans are not the acidic and amino sugars per se, but are instead
UDP derivatives of each monosaccharide
In some glycosaminoglycans one or more of the hydroxyl groups of the amino sugar is esterified with
Sulfate
The combination of these sulfate groups and the carboxylate groups of glucuronic acid gives the glycosaminoglycans a very high density of
Negative charge
Consequently, glycosaminoglycans are long, thin, hydrated molecules with very high
Viscosity
Each of the glycosaminoglycans (except hyaluronate) is found covalently attached to extracellular proteins to form
Proteoglycan monomers
These are enormous aggregates in which the polysaccharide is the principal component, typically 95% or more of mass
Proteoglycans
The fundamental distinction between proteoglycans and glycoproteins is their
Sugar composition
The disaccharide repeating unit of proteoglycans, typically 20 – 60 dimers, is covalently attached to protein at a
Serine or threonine residue
This occurs via a trisaccharide linkage of
-xylose-galactose-galactose
The core protein of proteoglycans is synthesized in the cytosol and co-translationally translocated into the lumen of the
ER
Formation of the carbohydrate chain is initiated by transfer of xylose to either a
Serine or Threonine
This is followed by the addition of two
Galactose residues
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
Proteoglycan
Each of these additions is catalyzed by membrane-bound transferases while the nascent proteoglycan traverses the
ER
Occurs after monosaccharides have been incorporated into the growing carbohydrate chain
Sulfation of sugar residues
Proteoglycan monomers, in turn, are noncovalently linked to
Hyaluronate
Composed typically of approximately 50,000 disaccharide repeating units per chain, to form proteoglycan aggregates
Hyaluronate
One hundred or more proteoglycan monomers can bind a single, extended molecule of
Hyaluronate
Glycosaminoglycans and proteoglycans function as components of the extracellular matrix of
Cartilage and Tendons
Contribute tensile strength and elasticity to cartilage and tendons
Glycosaminoglycans and proteoglycans
Indeed, these structures can cushion compressive forces because glycosaminoglycans have highly hydrated
-spring back after being deformed
Polyanions
Extracellular proteoglycans are usually interwoven with fibrous proteins such as
Collagen and Elastin
The association between cells and the proteoglycan of extracellular matrix is mediated by a
- ) Membrane protein called
- ) Extracellular protein called
- ) Integrin
2. ) Fibronectin
Also comprise the synovial fluid of joints, mucous secretions, and the vitreous humor of the vertebrate eye
Proteoglycans
Unlike the other glycosaminoglycans, functions within the cell
Heparin
Heparin is a highly sulfated glycosaminoglycan that binds specifically to
Antithrombin
Accelerates the sequestration of
Antithrombin
Thus, Heparin functions as an
Anticoagulant
Lastly, the disaccharide repeating unit of glycosaminoglycans is also found as a component of the cell wall of certain
Gram-positive bacteria
Have the disaccharide repeating unit is N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc)
Gram-positive bacteria cell membranes
A component of human tears, kills bacteria by hydrolyzing the glycosidic bond between GlcNAc and MurNAc
Lysozyme
Several antibiotics exert their effects by targeting the peptidoglycan components of the wall. For example,
Penicillin
Targets peptidoglycan
Penicillin
Interferes with peptidoglycan biosynthesis by inhibiting a transpeptidase that catalyzes formation of the cross-linking polypeptide
Penicillin
Glycosaminoglycans are degraded in the
Lysosome
Glycosaminoglycans are broken down by an array of hydrolytic enzymes. Degradation is sequential, beginning with the last group added during
Biosynthesis
Hereditary disorders characterized by accumulation of glycosaminoglycans in various tissues
Mucopolysaccharidoses
Accumulation of glycosaminoglycans in various tissues is due to deficiency for specific lysosomal hydrolases in a
Mucopolysaccharidoses
