GAGs and Proteoglycans Flashcards
What are glycosaminoglycans (GAGs)?
Heteropolysaccharides made up up repeating disaccharide units
What type of matrix do GAGs have?
Gel- like
What causes GAGs to have a Gel- like matrix?
H20 binding properties
What general part of the body do GAGs form?
Body’s ground substance
What type of properties do GAGs have?
lubricating properties
What do GAGs stabilize and support?
cellular and fibrous components of tissues
What do GAGs help to maintain in the body?
Water and salt balance
What causes GAG molecules to fan outwards and repel adjacent molecules?
Strong negative charges
-COO and -OSO3
What type of shell surrounds each GAG molecule?
hydrated shell
What are the functions of GAGs?
cell-shape maintenance adhesion migration cell-cell communication source of growth factors
Where are GAGs found?
Extracellular (most)
except Heparin
What property of GAGs accounts for the resilience of synovial fluid and vitreous humor of the eye?
Reverse compressibility
GAGs are also named what?
mucopolysaccharides.
What are proteoglycans?
Proteoglycans contain many GAGs linked to a protein chain
Do proteoglycans mainly contain sugars or protein?
They contain mainly
sugars (95%) and a small amount of protein.
What is the structure of a proteoglycan monomer?
Has a central core protein and via a trihexoside, many disaccharide units are linked.
What is Hyaluronic acid synthesized by?
Integral membrane protein
The integral membrane protein in hyaluronic acid synthesis does what?
elongates the GAG as it is released via ABC-transporters into the extracellular space
What repeating disaccharide units make up GAGs?
[acidic sugar - amino sugar]
What are the amino sugars that can make up GAGs?
D-glucosamine or
D-galactosamine
What are the acidic sugars that make up GAGs?
D-glucuronic acid or C-5 empimer: L-iduronic acid exception is Keratin Sulfate)
Why is Keratin Sulfate an exception when it comes to the acidic sugar unit?
Galactose instead of acidic sugar
What makes up Hyaluronic acid?
D-glucuronic acid + N-acetyl-D-glucosamine
Where is Hyaluronic acid found?
Synovial fluid
vitreous humor
ECM of loose connective tissue
Is Hyaluronic acid sulfated?
No (only GAG without sulfate)
Is Hyaluronic acid covalently attached to proteins in proteoglycans?
No (only GAG not)
What makes up Chondroitin Sulfate?
D-glucuronic acid + N-acetyl-D-galactosamine
Where is chondroitin sulfate found?
Cartilage
Bone
heart valves
What is the most abundant GAG?
Chondrotin Sulfate
What makes up Keratin Sulfate?
D-Galactose + N-Acetyl-D-Glucosamine
Where is Keratin Sulfate found?
Cornea
Bone
Cartilage
Typically, Keratin Sulfate is found aggregated with what?
Chondroitin sulfates
What makes up Dermatan Sulfate?
L-iduronic acid + N-acetyl-D-galactosamine
Where is Dermatan Sulfate found?
Skin
Blood vessels
heart valves
Which GAGs are found in heart valves?
Dermatan Sulfate
Chondroitin Sulfate
What releases Hyluronic acid (during synthesis) into the extracellular space?
ABC transporters
What makes up Heparin and Heparan sulfate?
D-glucoronic/L-iduronic acid
+
N-acetyl/N-sulfo - D-glucosamine
Where is Heparin found?
Intracellular granules of mast cell lining the arteries of lungs;
Liver and skin
Which is more sulfated, Heparin or Heparan Sulfates?
Heparin
Where are Heparan Sulfates found?
- Basement membranes
- components of cell surfaces
Which contains more acetylated glucosamine, Heparin or Heparan Sulfates?
Heparan Sulfates
What makes up the tri-hexoside which links the GAG and protein?
Xylose-Galactose-Galactose
What links the linkage region of a GAG to the core protein?
Serine side chain
What makes up proteoglycans in cartilage?
Chondroitin Sulfate and Keratan Sulfate attached to a protein core
Where are GAGs synthesized?
ER and Golgi
What catalyzes elongation of GAGs in the Golgi?
glycosyl transferases
What are the steps in proteoglycan synthesis?
1) Synthesis of amino sugar
2) Synthesis of acidic sugar
3) Synthesis of core protein
4) Synthesis of carbohydrate chain
5) Addition of sulfate group
During proteoglycan synthesis, what is the sulfate donor?
PAPS
3-Phosphoadenosine 5-Phosphate
What enzyme is required for the addition of sulfates during proteogylcan synthesis?
Sulfotransferase
What is TFPI?
Tissue Factor Pathway Inhibitor
aka
Anti-thrombin III
What is the main source of TFPI?
Endothelial cells
When is TFPI activated?
When limited quantities of factor Xa are generated
How does TFPI exhibit its effect?
TFPI first binds to factor Xa, and then to tissue factor VIIa, thus forming an inactive quaternary complex.
What induces the release of cell surface associated TFPI?
Heparin
What does hyarluronic acid protect during ocular surgery?
Corneal endothelium
How is hyaluronic acid used to treat patients with Osteoarthritis?
Intra-articluar injects = pallative effect
How is hyaluronic acid useful postoperatively?
wound healing
anti-adhesive
What can a defect in sulfation of GAGs lead to?
Chondodystrophy
What is Chondodystrophy?
Disorder of the development and maintenance of the skeletal system
Which GAG permits cell migration in the ECM?
hyaluronic acid in the ECM
Describe glycoproteins
Mainly protein with some, often branched, sugars attached in O- or N-glycosylation. The amounts of carbohydrate is however very variable.
What do glycoproteins function as?
Cell surface receptors
Blood group determinants
Collagen, Fibronectin
Protective Barrier
- Are the sugars in blood group proteins linked in O-linkage or are they linked in N-linkage?
linked via O-linkage to proteins at their serine or threonine residues
Is albumin a glycoprotein?
No, it is the exception
most other plasma proteins are glycoproteins
What are mucins?
Large glycoproteins with negatively charged sialic acid
What are other names for Salic Acid?
N-acetyl neuraminic acid
NANA
What are the functions of mucins?
- Trap water
- Serve as protective barriers
What is the structure of mucins?
They have a long protein core and contain often negatively charged NANA
(N-acetylneuraminic acid or sialic acid) linked to single amino sugars
What is the structure of Glycoproteins?
Oligosaccharide part (mixture of D-hexoses, NANA) + L-fucose (6-deoxy-L-galactose) (C6 has a methyl group)
How are the oligosaccharides of glycoproteins attached to the protein?
N-glycosidic link
O-glycosidic link
What amino acid makes up N-glycosidic link?
Asparagine
What amino acids make up O-glycosidic link?
-OH group of Serine or Threonine
What is the concept of O-glycosylation?
O-glycosylation is performed in the RER/Golgi and includes step by step linkage of activated sugars in an individual way.
What is the concept of N-glycosylation?
N-glycosylation does not individually link sugars directly to the protein chain. Instead it uses a lipid bound in the ER membrane to form a precursor with several sugars that will be given in one step to proteins that are N-glycosylated
What are two broad classes of N-linked Oligosaccharides?
- Complex
- High Mannose
What makes up complex N-linked oligosaccharides?
Diverse group of additional sugars:
- N-acetylglucosamine (GlcNAc)
- L-frucose (Fuc)
- NANA
To what region of Asparagine (Asn) are N-linked oligosaccharides attached?
Amide Nitrogen
Glycosylation of O-linked glycoproteins occur where?
Golgi
What is the main difference between N-linked glycosylation and O-linked glycosylation of glycoprotein synthesis?
N-linked glycoside biosynthesis uses lipid (dolichol) and phosphorylated lipid (dolichol phosphate)
What’s special about the activated form of mannose in N-glycosylated glycoproteins?
Activated mannose is GDP-mannose, most other sugars are activated using UTP leading to UDP-sugars
Regarding the biosynthesis of N-linked glycosides, what is the first step?
Protein in synthesized int he rER and enters lumen
Regarding the biosynthesis of N-linked glycosides, what happens once the synthesized protein enters the lumen?
A lipid-linked oligosaccharide is constructed with dolichol
Regarding the biosynthesis of N-linked glycosides, how is dolichol attached?
Through pyrophosphate linkage to oligosaccharide with N-acetylglucosamine, mannose and glucose
Regarding the biosynthesis of N-linked glycosides, how are sugars added to dolichol?
By membrane bound glycosyltransferases
first N-acetylglucosamine, then mannose then glucose
Regarding the biosynthesis of N-linked glycosides, how is the oligosaccharide transferred to protein?
Protein-oligosaccharide transferase present in ER
Regarding the biosynthesis of N-linked glycosides, what happens after the N-linked Oligosaccharide is linked to the protein via Asn?
Processed by removal of specific mannosyl and glucosyl residues as glycoprotein moves through ER
Regarding the biosynthesis of N-linked glycosides, where are oligosaccharide chains completed?
Golgi
Regarding the biosynthesis of N-linked glycosides, how is it finally processed?
O-linked
N-linked glycoproteins targeted to lysosomes are typically what?
Hydrolytic enzymes such as: Proteases Lipases Glucosidases Nucleases
What is I-cell disease?
Rare syndrome in which hydrolytic enzymes normally found lysosomes are absent.
Individuals with I-cell disease lack what ability?
Enzymatic ability to phosphorylate mannose residues
Are the enzymes needed for lysosomes made in patients with I-cell disease?
Yes, enzymes made but translocation ability deficient
enzyme ends up in plasma
