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Biochemistry 1 > Glycoaminoglycans > Flashcards

Glycoaminoglycans Flashcards

1
Q

What are GAG? proteoglycans? glycoproteins?

A
  • GAGs: Negatively charged heteropolysaccharides
  • Proteoglycans: Carbohydrates (GAGs; >95%) + Proteins
  • Glycoproteins: Carbohydrates(small amount) + Proteins
  • Long, unbranched polysaccharides containing a repeating disaccharide unit. [acidic sugar-amino sugar]n
  • Disaccharide units contain
  • Amino sugars
    - N-acetylglucosamine (GlcNAc) or
    - N-acetylgalactosamine (GalNAc)

** - Acidic sugar **

  • Uronic acids
    • Glucuronic acid
    • Iduronic acid
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2
Q

What are the features and functions of gag?

A
  • Negatively charged and bind to large amount of water (hydrated); extended in solution
  • Produce gel-like matrix- forms the basis of ground substance which along with fibrous structural proteins forms the extracellular matrix (ECM)
  • Hydrated GAGs provide flexible support to the ECM
  • Acts as a molecular sieve in ECM
  • “Slippery” consistency of mucous secretions & synovial fluid due to the due to the large number of negative charges on GAGs; they repel each other & slide past each other
  • When GAGs are compressed, water is ‘squeezed out’; when compression is released, GAGs spring back to their original hydrated volume
  • Contributes to the resilience of synovial fluid and the vitreous humor of the eye
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3
Q

What are the types of GAG ( mucopolysaccrides) and where are they located?

A
  • Located primarily
    - On the surface of cells
    - In the extra cellular matrix (ECM)
    - Mucus secretions
  • Types:
    - Hyaluronic acid
    - Dermatan sulfate
    - Chondroitin sulfate
    - Keratan sulfate
    - Heparan sulfate
    - Heparin
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4
Q

HYANDURONIC ACID

A

Composition: D-glucuronic acid + N-acetyl glucosamine

                                                      (GlcNAC)
  • Non sulfated & Not covalently linked to proteins
  • Location: Synovial fluid, vitreous humor, umbilical cord
               ECM of loose connective tissue

Functions: Lubricant and shock absorber, role in cell migration during embryogenesis

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5
Q

Dermatan sulfate

A

Composition: L-iduronic acid + N-acetyl galactosamine 4-S

                                                   (GalNAc)
  • Location: Skin, blood vessels, heart valves
  • Functions: Constituent of skin, role in wound healing
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6
Q

Chondroitin 4- and 6-sulfates

A

Composition: D-glucuronic acid + GalNAc-4- or 6- sulfate

  • Form proteoglycan aggregates with Hyaluronic acid
  • Most abundant GAG in the body
  • Location: Cartilage, tendons, ligaments, aorta, cornea
  • Function: In cartilage it binds to collagen and hold fibers in a tight strong network
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7
Q
  • Composition: D-glucuronate-2-sulfate (10%)
                         (or iduronate-2-sulfate (90%)

                                   \+

                    N-sulfo-D-glucosamine-6-sulfate

     - (heparans have less sulfate than heparins)

Ø Heparin: - Only intracellular GAG àmast cells lining arteries in liver, lungs and skin

- Anticoagulant: Heparin activates antithrombin III, which in turn inhibits thrombin & other clotting factors
A
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8
Q

Heparan sulfate

A

Ø: Basement membrane and cell surfaces

It binds specifically to lipoprotein lipase present in capillary walls

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9
Q

Karatin sulfate

A
  • Composition: Galactose + GlcNAc-6-sulfate
                               No Uronic acid
  • Most heterogeneous as may also contain L-Fucose,

N-acetyl neuraminic acid (NANA) & mannose

  • Location: Cornea, bone, cartilage aggregated with Chondroitin sulfates
  • Function: In cornea both Keratan sulfate & dermatan sulfate lie between collagen fibrils & facilitate corneal transparency.
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10
Q

Explain the structure of proteoglycans

A

The protein cores of proteoglycans are rich in Serine & threonine residues, which allows multiple GAG attachments
üMany such Proteoglycans monomers aggregate on a molecule of Hyaluronic acid to form proteoglycans aggregates through ionic interactions and stabilized by linker proteins

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11
Q

Explain how the the GAG is attached to the protein core

A

GAGs extend perpendicularly from the core in a bottle brush-like structure
Linkage of GAGs to protein core involves a specific trisaccharide, two galactose residues and a xylulose residue

(GAG—GalGalXyl-O-CH2-protein).

The trisaccharide linker is coupled to the protein core through an O-glycosidic bond to a Serine residue in the protein

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12
Q

Explain the synthesis of glucuronic acid for GAG formation

A
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13
Q

Where isthe synthesis of GAG, what are the amino and acidic sugars involved? Where does the synthesis of the core protein take place?

A
  • Synthesis of GAG: Golgi, glycosyltransferase
    • Amino sugars (amino group donated by glutamine)
      - N-acetyl glucosamine & N-acetyl galactosamine
      - Acidic sugars
      - D-Glucuronic acid & L-Iduronic acid
      - Glucuronic acid synthesized by uronic acid pathway
      - (3’phosphoadenosyl-5’-phosphosulfate) PAPS is the donor of sulfate group
  • Synthesis of core protein:
    • RER
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14
Q

What is the disease associated with the synthesis of GAG and proteoglycans?

A

Chondrodystrophies:

        - Autosomal Recessive
        - Defect in the sulfation of GAG chain
        - Improper development and maintenance of the

          skeletal system
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15
Q

How are GAG’s degraded?

A

Degradation of GAG: Lysosomes, Acid Hydrolases

             Extra cellular GAG

                          ¯

                  phagocytosed

                          ¯

               fused with a lysosome

                          ¯

               endoglycosidases

                          ¯

            desulfated & deacetylated

                          ¯

       further action of acid hydrolases
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16
Q

What are mucopolysaccharidoses?

A
  • Hereditary disorders caused by the accumulation of GAG in various tissues due to the defect in the lysosomal hydrolases of GAG catabolism
  • Progressive disorders, cause skeletal & ECM deformities, intellectual disability
  • All of these disorders, except Hunter’s syndrome, are inherited in an autosomal recessive manner
  • Homozygous children apparently normal at birth, gradually deteriorate, may die in childhood
  • Incomplete GAG degradation results in excretion of oligosaccharides in urine, can be used for diagnosis
  • Diagnosis confirmed by assay of lysosomal hydrolase
  • Bone marrow, cord blood transplants, enzyme replacement therapy available
17
Q

Hurler’s disease

A

Autosomal recessive
Deficiency of a-L-Iduronidase
Degradation of dermatan & heparan sulfate are affected & they accumulate
Mental retardation & corneal clouding
Dwarfing, coarse (dysmorphic) facial features)
Upper airway obstruction, hearing loss
Deposition in coronary artery leading to ischemia and early death
Therapy: Bone marrow or cord blood transplantation and enzyme replacement

18
Q

Hunters disease, sanflippipo syndrome, Maroteaux-Lamy syndrome ,Morquio’s syndrome

Sly syndrome

A

Hunter’s syndrome

X-linked recessive
Deficiency of Iduronate sulfatase
degradation of dermatan & heparan sulfate affected
Clinical features similar to Hurler syndrome, but no corneal clouding
Therapy: Enzyme replacement

Sanfilippo syndrome (Types A to D)

Severe nervous system disorders due to defective degradation of heparan sulfate, developmental disability

Maroteaux-Lamy syndrome

Defective degradation of dermatan sulfate

Morquio’s syndrome

Defective degradation of keratin & chondroitin sulfate

Sly syndrome b-glucuronidase deficiency

19
Q

What are glycoprteins and what are their function?

A

•Proteins with covalently attached oligosaccharides
•Predominant sugars à glucose, galactose, mannose, Fucose, GalNAc, GlcNAc and NANA
•Functions
Structural molecule: Collagen
Lubricant & protective agent: Mucins
Transport: Transferrin, Ceruloplasmin
Protective: Immunoglobulins
Cell surface recognition by other cells, hormones, viruses
Hormones: hCG, TSH

Antigenicity (blood group antigens)
Enzyme: Alkaline phosphatase
Plasma proteins (except albumin)

20
Q

What are the linkages between the sugars and peptides?

A
21
Q

What is the differnce between proteoglycans and glycoproteins?

A

**proteoglycans: **
Contain long polysaccharide chains
Repeating disaccharide units in GAGs
Unbranched sugar chains
High carbohydrate content

Glycoproteins

short polysaccride chains

no repeating units, branched sugar units, and low carbohydrate content

22
Q

How are glycoproteins synthesized in the RER and in the golgi?

A
  1. protien sythesis begins and the polypeptide chain is extruded into the RER. 2. A branched oligosaccride is synthesized on dolichol pyrophosphate 3. the oligosaccride is transferred from the dolicol to amide N of an asparagine residue of growing polypeptide chain. 4. trimming of the carbohydrate chain begins as the protein moves through the RER. 5. the golgi further trims and adds monosarride units
23
Q

Exaplin in detail what occurs in the ER and the golgi

A

syntheis: protein part is snythesized in ribosomes, attached to RER. 1
1. N-linked- initially in the lumen of the ER and dolichol phosphate is required
2. Attachement of oligosaccrides
- O-Linked – In Golgi apparatus
- Incorporation of individual carbohydrate residues is catalyzed by specific glycosyl transferases
- UDP is the common nucleotide required for the incorporation of most of these carbohydrate residues
- Mannose & Fucose require GDP as carrier
- NANA (Sialic acid) is incorporated through CMP (as CMP-NANA)

24
Q

I-cell disease. What is it caused by? what does it lead to?

A
  • Defects in the proper targeting of enzymes to the lysosomes
  • Leads to the formation of dense inclusion bodies formation in the fibroblasts

Cause:

Deficiency in Phospho transferase to phosphorylate mannose residues in potential lysosomal enzymes

                                       ¯

Lack of mannose-6-phosphate tags in the enzymes, cannot reach the lysosomes

                                       ¯

Lysosomal enzymes secreted out of the cell, found in the plasma & urine

25
Q

How are glycoproteins degraded?

A
  • Degradation:
  • Within lysosomes à glycosidases
  • Exoglycosidases remove sugars sequentially from the non-reducing end
  • Defects in the genes encoding specific glycosidases, à incomplete degradation & subsequent accumulation of partially degraded glycoproteinsà glycoprotein storage diseases

Biochemistry 1 (15 decks)

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