GAGs and Proteoglycans Flashcards by Jerry Sojan

What are glycosaminoglycans (GAGs)?

Heteropolysaccharides made up up repeating disaccharide units

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What type of matrix do GAGs have?

Gel- like

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What causes GAGs to have a Gel- like matrix?

H20 binding properties

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What general part of the body do GAGs form?

Body’s ground substance

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What type of properties do GAGs have?

lubricating properties

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What do GAGs stabilize and support?

cellular and fibrous components of tissues

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What do GAGs help to maintain in the body?

Water and salt balance

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What causes GAG molecules to fan outwards and repel adjacent molecules?

Strong negative charges

-COO and -OSO3

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What type of shell surrounds each GAG molecule?

hydrated shell

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What are the functions of GAGs?

cell-shape maintenance
adhesion
migration
cell-cell communication
source of growth factors

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Where are GAGs found?

Extracellular (most)

except Heparin

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What property of GAGs accounts for the resilience of synovial fluid and vitreous humor of the eye?

Reverse compressibility

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GAGs are also named what?

mucopolysaccharides.

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What are proteoglycans?

Proteoglycans contain many GAGs linked to a protein chain

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Do proteoglycans mainly contain sugars or protein?

They contain mainly

sugars (95%) and a small amount of protein.

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What is the structure of a proteoglycan monomer?

Has a central core protein and via a trihexoside, many disaccharide units are linked.

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What is Hyaluronic acid synthesized by?

Integral membrane protein

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The integral membrane protein in hyaluronic acid synthesis does what?

elongates the GAG as it is released via ABC-transporters into the extracellular space

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What repeating disaccharide units make up GAGs?

[acidic sugar - amino sugar]

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What are the amino sugars that can make up GAGs?

D-glucosamine or

D-galactosamine

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What are the acidic sugars that make up GAGs?

D-glucuronic acid or C-5 empimer: L-iduronic acid exception is Keratin Sulfate)

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Why is Keratin Sulfate an exception when it comes to the acidic sugar unit?

Galactose instead of acidic sugar

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What makes up Hyaluronic acid?

D-glucuronic acid + N-acetyl-D-glucosamine

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Where is Hyaluronic acid found?

Synovial fluid
vitreous humor
ECM of loose connective tissue

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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

13. 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