Glycobiology I - Werlen 3/9/16 Flashcards Preview

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Flashcards in Glycobiology I - Werlen 3/9/16 Deck (28):

lysosomal storage diseases

can occur due to 

  • ER level : protein misfolding, transporter defects
  • ​Golgi level : defects in protein processing, transport preventing exit from Golgi; defective lysosomal targeting
  • ​lysosomal level : accumulation of unmetabolized substrates in lysosome


two types of proteins that might be implicated in LSDs

glycosaminoglycans (GAGs)


  • both glycosylated : proteins with sugar moieties
    • key diff: GAGs are mostly (90%) sugar moieties; glycoproteins are mostly proteins



heteropolysacch chains (repeating disacch units: one acidic sugar, one amino sugar) covalently associated with proteins

  • sugars tend to be long, unbranched, negatively charged
    • amino sugars usually acetylated → negative charge
    • slip/slide past each other (repulsion), giving slippery consistency of mucus/synovial fluid
  • can absorb significant quantities of water



oligosacchs covalently associated with proteins

  • mostly protein
  • don't contain repeating units
  • sugars are short, branched, not necessarily negatively charged

present in a lot of cell surface proteins: signalling, immune response 


GAG classification

6 major groups classified based on:

  • monomeric composition
  • types of glycosidic linkages
  • location of sulfate units

acidic sugars

1. glucuronic acid : GlcUA

2. iduronic acid : IdUA

3. galactose : Gal

N-acetylated amino sugar

4. N-acetylgalactosamine : GalNAC

5. N-acetylglucosamine : GlcNAC

6. glucosamine : GlcN


chondroitin 4-sulfate

chondroitin 6-sulfate

most abundant GAG in body

fx: cartilage (bind collagen), tendons, ligaments, aorta

deficiency causes osteoarthritis


acidic sugar: GlcUA

N-acetylated amino sugar: GalNAC

beta 1,3 glycosidic linkage


dermatan sulfate

fx: skin, blood vessels, heart valves

disease: Hunter/Hurler, Sanfilippo, Sly


acidic sugar: IdUA

N-acetylated amino sugar: GalNAC

beta 1,3 glycosidic linkage


keratan sulfate I

keratan sulfate II

most heterogeneous (contain addtl monosacchs)

fx: cornea (KS1), connective tissues (KSII)

disease: Morquio syndrome A, B


acidic sugar: Gal

N-acetylated amino sugar: GlcNAC

beta 1,4 glycosidic linkage




heparin sulfate



Hep: intracellularly in mast cells in arteries - esp liver, lungs, skin

HepS: membranes, cell surfaces

disease: Hunter/Hurler, Sanfilippo, Sly



acidic sugar: IdUA

N-acetylated amino sugar: GlcN

alpha 1,4 glycosidic linkage

heparin sulfate

acidic sugar: GlcUA

N-acetylated amino sugar: GlcNAC

alpha 1,4 glycosidic linkage


hyaluronic acid

no sulfate, doesn't form proteoglycan monomers; only GAG not ltd to animals

fx: lubricant, shock absorber, synovial fluid, vitreous humor, umb cord, loose CT, cartilate


acidic sugar: GlcUA

N-acetylated amino sugar: GlcNAC

beta 1,3 glycosidic linkage


GAG structure/fx

negative charges, extended conformation → high viscosity when solubilized

  • jt lubricating fluid

ability to bind lots of water, become gel-like → good ground substance for body

  • major component of ECM

hydrated GAGs can provide flexible support and molecular sieve fx

  • structural integrity for cells and passageways between cells


structure of proteoglycan monomers

all GAGs except hyaluronic acid attach to proteins through covalent bonds to form proteoglycans ("bottle brush" look)

  • side chains repel one another due to like charges

protein and GAG are linked by a trihexoside bond

GAG -- Gal-Gal-xylose -- Ser side chain on core protein


lysosome structure and fx

major digestive compartment of mammalian cells

  • resp for degrading internalized extracellular material and intracellular material through autophagocytosis

contain hydrolytic enzymes (pH optimum = 5)

  • optimum pH protects cytosolic components from degradation in case of leak (enzymes would be active, but not very active in cytosol pH7.2 environment)


GAG degradation

most have short half-lives (3-10 days)

exception: keratan sulfate (>120 days)


  • extracellular or cell surface molecules → phagocytosis
  • phagocytic vesicle fuses with a lysosome, hydrolytic enzymes do their thing
    • endoglycosidases cleave polysacchs → oligosacchs, followed by more degradation
    • "last on, first off" order of degradation


mucopolysaccharidoses (MPS)

  • autosomal recessive diseases (exception: Hunter syndrome, X linked)
  • progressive (normal at birth, progressively worse)

defective lysosomal hydrolases → defective degradation of heparan sulfate, dermatan sulfate

  • accumulation of GAGs → skeletal/ECM deformities, mental retardation, death
  • incomplete degradation of GAGs → presence in urine (used in diagnosis)



Hunter syndrome

enzyme: iduronate sulfatase deficiency

affects degradation of: dermatan sulfate, heparan sulfate


  • no corneal clouding
  • mild to severe physical deformity, mental retardation


Hurler syndrome

enzyme: alpha L iduronidase deficiency

affects degradation of: dermatan sulfate, heparan sulfate


  • corneal clouding
  • dysmorphic facial features
  • upper airway obst
  • hearing loss
  • deposition in coronary artery → ischemia/early death


Sanfilippo syndrome

enzyme: four enzymes

affects degradation of: heparan sulfate


  • severe system disorders
  • profound mental retardation


glycoprotein fx

  • cell surface recognition
  • cell surface antigenicity
  • ECM
  • mucins (protective lubricant)
  • acidic hydrolases in lysosomes


two types of glycoproteins

oligosacch attached to protein via N-glycosidic link or O-glycosidic link

glycoproteins can have N-link, O-link, both


Asn amide residue → high mannose or complex (add other sugars) conformations


Ser, Thr hydroxyl residue → variety of sugars arranged in linear, branched pattern


synthesis of O-linked glycoside

  • transfer of N-acetyl galactosamine from UDP-GalNAC → R group of Ser, Thr
  • extension of oligosacch via attachment of nt sugar residues [glucosyltransferase]



protein - ER

addition of sugar - posttrans in Golgi


RBC surface antigens

antigens are linked to O-linked glycoproteins


default antigen : H [type O]

addition of GalNAC via GalNAC transferase : antigen A [type A]

addition of Gal via Gal transferase : antigen B [type B]


individual makes antibodies against the MISSING antigens → Landsteiner's rule! (blood type compatibility)


synthesis of N-linked glycoside

in ER, branched oligosacch is synthesized on dolichol phosphate

oligosacch is transferred to Asn residue of polypeptide chain

as molecule moves through ER and Golgi, oligosacch is trimmed, monosacchs are added



protein - ER

addition of sugar - co- and posttrans in ER, Golgi


glycoprotein processing in Golgi

1. default : secreted from the cell : don't become associated with vesicular membrane

2. become associated with the portion of cell membrane that their vesicle becomes

3. sent to lysosomes


N-linked glycoprotein transport to lysosomes


defect in transport

acid hydrolases get targeted to lysosome by phosphorylation of the mannose residues of their N-linked oligosacch → mannose-6-phosphate [Golgi-bound phosphotransferase]

once in lysosome, they can do perform catabolic fx


defect in phosphotransferase leads to improper/absent targeting → improper secretion of all hydrolytic enzymes

  • substance buildup in lysosomes and inclusion cell phenotype (I Cell)


I-cell disease

  • skeletal abnormalities
  • restricted joint movement
  • coarse/dysmorphic facial features
  • severe psychomotor impairment


diagnosis: high conc of acid hydrolases in blood (usually only in lysosomes in cells)


lysosomal degradation of glycoproteins

similar to that of GAGs (last on, first off)

  • lysosomal acid hydrolases typically exoenzymes that are resp for removal of one glycoprotein component (reverse order)
  • one missing, degradation by others is stalled


glycoprotein storage disease


very rare, autosomal recessive caused by deficiency of any degradative enzyme → accumulation of partially degraded structures in lysosomes

ex. alpha mannosidosis type I

  • progressive, fatal deficiency of alpha mannosidase
  • presentation similar to Hurler
  • immune deficiency
  • mannose-rich oligos present in urine
  • diagnosis via enzyme assay