3rd Unit / Ch 14 GAGS Glycosaminoglycans Flashcards
GAG Structure and Synthesis 14.1
What is an exception to the rule that GAGs are negatively charged heteropolysaccharide chains composed of a repeating disaccharide unit (acidic sugar–amino sugar), as shown?
In negatively charged keratan sulfate, the acidic sugar has been replaced by galactose and is thus an exception to the rule that GAGs are composed of a repeating unit (acidic sugar–amino sugar). [ Note: In GAGs, the amino sugar (glucosamine or galactosamine) frequently is acetylated on the NH2 group and sulfated (PAPS is the sulfate donor). The acidic (uronic) sugar (glucuronic acid or iduronic acid) is ionized at pH 7.4. The resulting net negative charge on
GAGs results in a high degree of hydration that contributes to cartilage and synovial fluid resilience.]
GAG Structure and Synthesis 14.1
What is produced when GAGs associate with small amounts of protein (core protein)?
- *ECM** and cell surface proteoglycans are produced when GAGs associate with a small amount of core protein.
- *GAGs** constitute -95% of a proteoglycan.
GAG Structure and Synthesis 14.1
Why might glucosamine or chondroitin sulfate supplementation benefit patients with osteoarthritis ( OA )?
OA is a degenerative joint disease characterized by loss of cartilage. Supplementation with an amino sugar or a GAG of proteoglycans delays the loss of cartilage, decreasing the symptoms of OA in some patients.
GAG Structure and Synthesis 14.2
Identify the lettered components of the proteoglycan aggregate shown. What characteristics of hyaluronic acid distinguish it from other GAGs?
A = link protein , B = proteoglycan monomer ( bottlebrush ), C = GAG, and D = core protein. Hyaluronic acid is distinguished from other GAGs because it is neither sulfated nor covalently attached to protein and is not limited to animal tissue.
GAG Structure and Synthesis 14.2
What bond joins the carbohydrate and protein components of a proteoglycan?
An O-glycosidic bond joins the OH of a Ser in the core protein to an OH of the xylose in the trisaccharide that connects the protein and the GAG (shown).
GAG Structure and Synthesis 14.2
Which GAG is used clinically as an anticoagulant?
Heparin is a GAG used as an injectable anticoagulant. It binds to and activates ATIII, which then inactivates the serine proteases of coagulation.
GAG Structure and Synthesis 14.3
What nucleotide is used in the activation of amino sugars for GAG synthesis?
UTP is used in the activation of amino sugars (to UDP-sugars) for GAG synthesis. [Note: Acidic NANA is the only example of a sugar utilized as a nucleoside monophosphate (CMP-NANA).]
GAG Structure and Synthesis 14.3
What is the structural relationship between the acidic sugars glucuronic and iduronic acids? What is the end product of glucuronic acid metabolism in humans? Which pathway uses it?
Glucuronic acid and iduronic acid are C-5 epimers. D-glucuronic acid is epimerized to L-iduronic acid after incorporation into GAGs. Xylulose is the end product of glucuronic acid metabolism in humans, and it is used in the PPP as xylulose 5-P.
GAG Structure and Synthesis 14.3
Why is glucuronic acid used in the transport, catabolism, and excretion of nonpolar endogenous substances (such as bilirubin and steroid hormones) and xenobiotics such as drugs?
Glucuronic acid is water soluble. It is transferred from UDP-glucuronic acid to nonpolar endogenous substances and xenobiotics ( glucuronidation ) to increase their solubility in aqueous solutions. Glucuronidation can occur after CYP -mediated hydroxylation as phase II of xenobiotic detoxification.
GAG Degradation 14.4
What specific GAG metabolism disorder is caused by iduronate sulfatase deficiency?
By a-L-iduronidase deficiency?
Iduronate sulfatase deficiency causes Hunter syndrome. a-L-Iduronidase deficiency causes Hurler syndrome. Both syndromes result in neurologic problems, but only Hurler syndrome causes corneal clouding. Treatment for both includes enzyme replacement therapy.
GAG Degradation 14.4
To what class of disorders do these enzymic deficiencies belong?
Both Hunter and Hurler syndromes are classified as mucopolysaccharidoses, lysosomal storage diseases caused by degradative lysosomal hydrolase deficiency.
[Note: Hunter syndrome is the only X-linked mucopolysaccharidosis. The others are AR disorders.]
GAG Degradation 14.4
Which is a disorder of degradation, sulfur-related chondrodystrophy or multiple
sulfatase deficiency?
Multiple sulfatase deficiency is a rare disorder of degradation in which all sulfatases (not just iduronate sulfatase ) are nonfunctional. Sulfur-related chondrodystrophies are defects in the ability to sulfate molecules such as GAGs during their synthesis. The
defect may be in sulfate uptake or the synthesis of PAPS, the sulfate donor.
Glycoproteins 14.5
Give an example in which glycoproteins play a role in cell-surface antigenicity, as shown.
ABO blood group antigens are glycoproteins that play a role in cell-surface antigenicity.
Glycoproteins contain relatively short hetero-oligosaccharide chains that may be branched but neither contain repeating
disaccharide units nor necessarily have a net negative charge. The chains are…
covalently attached to the protein at
selected Ser or Thr residues (and Hyl residues in collagen) through O-glycosidic bonds and/or to selected Asn residues through N-glycosidic bonds.
Glycoproteins 14.5
What processes use the UDP-glucose formed from glucose 1-P?
Glucose 1-P (formed from glucose 6-P by phosphoglucomutase ) is converted to UDP-glucose by _UDP-glucose
pyrophosphorylase_. The UDP-glucose can be used in glycogen synthesis, converted to UDP-galactose for lactose synthesis, and oxidized to UDP-glucuronate for GAG synthesis. [Note: UDP-glucuronate is also used in detoxifi cation reactions (e.g., glucuronidation of bilirubin.)]
Glycoproteins 14.6
To which organelle will the protein shown be targeted? What is the fate of such proteins if their targeting is defective?
The mannose 6-P signal, generated in the cis Golgi, is a unique marker that targets acid hydrolases to the lysosomes. If targeting is defective, the proteins are secreted from the cell
by default and appear in the blood and urine. Lack of the phosphotransferase needed to generate the signal causes I-cell disease, which is characterized by lysosomal inclusions of
undegraded material.
