GAGs and glycoproteins Flashcards
Other names for GAGs
Glycosaminoglycans, mucopolysaccharides, proteoglycans (I think that has a slightly more specific meaning but it doens’t matter for us so use it interchangably)
Basic properties of GAGs
repeating disaccharide units (amino sugar, acid sugar)
gel-like matrix, H2O binding, form ground substance, lubricating, stabilize and support cellular and fibrous components of tissue, maintain H2O and salt balance
stong negative charges, hydrated shell, compressible
Fxns of GAGs
cell shape maintenance, adhesion, migration, cell-cell communication, source of growth factors
Sugars in GAGs
Amino: D-glucosamine or D-Galactosamine
Acidic: D-glucuronic acid or L-iduronic acid
Keratan sulfate uses galactose
Major GAGs
Hyaluron (ic acid), Chondroitin sulfate, Keratan sulfate, Heparin, Heparan sulfate
Hyaluron
Hyaluronic acid, HA
No sulfates, not covalently linked to proteins
synovial fluid, vitreous humor, loose CT
large polymers, shock absorbing
D-glucuronic acid, N-Ac-D-glucosamine
Chondroitin sulfate
Most abundant GAG
cartilage, bone, heart valves
D-glucuronic acid, N-Acetyl-D-galactosamine (sulfated)
Keratan sulfate
aggregated with chondroitin sulfates
cornea, bone, cartilage
D-galactose, N-acetyl-D-glucosamine (sulfated)
Dermatan sulfate
Found in skin, blood vessels, heart valves
L-iduronic acid (sulfated), N-Ac-D-galactosamine (sulfated)
Heparin
component of intracellular granules in Mast cells lining arteries of lungs, liver and skin
More sulfated than heparan sulfates
D-Glucuronic or L-Iduronic acid (sulfated), N-Acetyl or N-sulfo-DGlucosamine
Anti-coagulent: Induces release of cell surface-associated TFPI (tissue factor pathyway inhibitor, anti-thrombin III)
Heparan sulfate
higher acetylated glucosamine than heparin
basement membranes, component of cell surfaces
D-Glucuronic or L-Iduronic acid (sulfated), N-Acetyl or N-sulfo-DGlucosamine
Strucutre of proteoglycans
attached to proteins (excpet HA) covallently attaced to protein to form proteoglycan monomers
≥100 monosaccharides
bottle brush
proteoglycan aggregates
chondroitin and keratin sulfates (i.e.: in cartilage) attached to protein core bound nonvovalently to HA (link proteins)
Linking sugars of proteoglycans
Gal-Gal-Xyl usually bound to Ser (Thr most likely alternative)
Steps of proteoglycan synthesis
synthesis of: amino sugars, acidic sugars, core protein, carbohydrate chain; addition of sulfate groups
Addition of sufate groups
ATP-sulfurase: ATP + SO42- –>Adenosine 5;-phosphosulfate (APS) + PPi
APS-kinase: APS + ATP –> 3’-phosphoadenoside 5’-phosphosulfate (PAPS) + ADP
Sulfotransferase: PAPS + sugar –> sulfated sugar + adenosine-5’, 3’-bisphosposphate
Locations for proteoglycan synthesis
protein: cytosol/rER
Linker sugars added: ER (UDP-xyl, then 2x UDP-Gal)
Everything else: Golgi
Warfarin
Vitamin K analog, anti-coagulent. Inhibits modification of several coagulation factors
slower acting than heparin, usually adminstered after
TFPI
tissue factor pathway inhibitor, anti-thrombin III
binds factor Xa and VIIa forming inactive quaternary complex
Applications of HA
used as lubricant to protect corneal endothelium in ocular surgery, god for patients with osteoarthritis (OA), anti-adhesive may be good for postsurgical wound healing
Functions of glycoproteins
membrane bound: 1. cell surface recognition; 2. cell surface antigenicity; 3. componets of ECM; 4. contribute to glycocalyx and cellular protection
secreted glycoproteins: part of ECM, lubricants
intracellular: lysosomal enzymes
Glycoprotein definition
protein with short oligosaccharide chain (2-10 residues), may or may not be branched or negatively charged
Glycoproteins and cellular infections
E. coli –> adhere to mannose residues on plasma membrane of human cheek cells
H. pylori –> interact with blood group antigen on gastric endothelium (ulcers)
Blood types
O-linked surgars (H substance) to protein (band 3?) or ceramide
Mucins
Large, negatively charged, NANA (N-acetyl neuraminic acid), trap H2O, protective barriers
N-Linked oligosaccharides
linked to amino group of Asn
Complex: N-acetylglucosamine (GlcNAc), L-Fucose (Fuc) and NANA
High mannose: mostly just mannose
O-linked oligosaccharides
linked to Ser or The (Hyl in collagen)
often GalNAc
collagen has glucose-galactose dimer
Synthesis of Glycoproteins: prep of sugars
Glucoseamine–>uses UDP-glucosamine
NANA–>uses CMP-NANA
Amine groups come from Gln
Synthesis of O-linked glycoproteins
protein synthesized in rER
glycosylation in golgi, use specific
glycosyltransferases, add sugars sequentially
begins with transfer of GlcNAc (from UDP-GlcNAc) to Ser or Thr
intracellular are free within golgi, for cell membrane become part of golgi membrane with carb on outside
Synthesis of N-linked glycoproteins
- protein synthesized in rER
2 & 3. ER: oligosaccharide constructed onto dolichol through pyrophosphate linkage (use membrane bound glycosyltransferases, 1)GlcNAc 2)Man 3)glu
- oligosaccharide transfered by protein-oligosaccharide tranferase in ER (to Asn)
- processed by removal of specific mannosyl and glucosyl resudues (ER)
6-7. Final processing in golgi: complex-add other sugars; final processing like O-linked
Degredation of GAGs and Glycoproteins
Occurs in lysosomes following endocytosis
Mucopolysaccaridosis
inability to degrade GAGs or glycoproteins
Shingolipidosis
inability to degrade sphingolipids
Enzyme transport to lysosomes
lysosomal enzymes tagged with N-linked mannose 6 phosphate
inability to tag leads to I-cell disease
