L19: PPP, structural CHOs, Glucuronation for Detox/CHO metabolism V

Question 1

Describe the structure and components of ECM. Where is ECM found, what synthesizes it?

Answer 1

• ECM is composed of fibrous proteins(collagen) and a gel-like component known as proteoglycans. Ground substance containining polysaccharides are also found in ECM. - Cells interact with the ECM via cell surface proteins which are glycosylated known as glycoproteins - ECM is adjacent to cells, unless epithelia, which have basal lamina first, then ECM. Fibroblasts synthesize ECM.

Question 2

Decribe structure of proteoglycans in ECM. Name the glycosaminoglycans and their distributions.

Answer 2

• Chains of disaccharide repeats (glucosamine or galactosamine are one of the saccharides connected to same or and exotic sugar) known as glycosaminoglycans, connected to core protein. The glycosaminoglycans have various degrees of sulfate groups added to them to make them negative. - Glycosaminoglycans are attached to linker proteins, which attach them to a hyaluronic acid (polysaccharide backbone) - Chondroitan sulfate: glucuronate and galactosamine – found in: cartilage, tendons, bones - Dermatan sulfate: iduronate and galactosamine – found in: skin, blood vessels, valves - Heparin: glucuronate and glucosamine – found in: liver - Heparan sulfate: glucuronate and glucosamine with more sulfations – found: cell surface - Hyaluronic acid: glucuronate and glucosamine – found in: joints, ocular fluids - Keratan sulfate: galactose and glucosamine – found in: cartilage and cornea

Question 3

Describe synthesis and sulfation of glycosaminoglycans.

Answer 3

• Core proteins are manufactured in ER - Transferred to Golgi where glycosyltransferases add disaccharides to them. - Sulfotransferases add sulfate groups to them (can be unpredictable) - Exported in membrane-bound vesicle, finds linker and attached to polysaccharide backbone

Question 4

Explain how sulfation of glycosaminoglycans contributes to the physical properties of ECM.

Answer 4

• ECM as a result of sulfations is negatively charged. - It becomes covered by a lot of water to prevent charge build up. - Water is difficult to remove and is trapped in ECM - Result is elasticity in mechanical tissue – think about cartilage

Question 5

What are mucopolysaccharidoses? What occurs?

Answer 5

• Problems with degradation of proteoglycans, resulting in undegraded glycosaminoglycans accumulation in lysosomes.

Question 6

Describe function of hyaluronic acid. What is it?

Answer 6

• Hyaluronic acid is a polysaccharide found in the ECM that contains linker proteins to which glucosaminoglycans are linked and form the proteoglycan structure in the ECM.

Question 7

List a few mucopolysaccharidoses. Describe defect and symptoms. Genetics?

Answer 7

• Hunter’s: defect in iduronate sulfatase, accumulation of dermatan sulfate and heparan sulfate. Symptoms = skeletal abnormalities, mental retardation. X-linked recessive. - Hurler-Scheie: defect in alpha-iduronase, accumulation of dermatan sulfate and heparan sulfate. Symptoms = skeletal abnormalities, mental retardation. Autosomal recessive. - Sanfilippo’s: defect of heparan sulfate degradation. Symptoms = mild physical defects, severe mental retardation. Autosomal recessive.

Question 8

Describe Hunter’s syndrome.

Answer 8

• Hunter’s: defect in iduronate sulfatase, accumulation of dermatan sulfate and heparan sulfate. Symptoms = skeletal abnormalities, mental retardation. X-linked recessive.

Question 9

Describe Hurler-Scheie syndrome.

Answer 9

• Hurler-Scheie: defect in alpha-iduronase, accumulation of dermatan sulfate and heparan sulfate. Symptoms = skeletal abnormalities, mental retardation. Autosomal recessive. - Enzyme replacement therapy is possible.

Question 10

Describe Sanfilippo’s syndrome.

Answer 10

• Sanfilippo’s: defect of heparan sulfate degradation. Symptoms = mild physical defects, severe mental retardation. Autosomal recessive.

Question 11

Protein glycosylations are abundant with sugars such as mannose, galactose and fucose. Describe how these are synthesized from glucose.

Answer 11

Question 12

What is the function of glycosylation? Importance.

Answer 12

• Increases water solubility. Used to facilitate excretion of poorly water soluble molecules via bile and urine.

Question 13

Explain how bilirubin is excreted. What occurs when there is a defect in this?

Answer 13

• Glucuronic acid is a prerequisite for bilirubin excretion. - UGT, which is an enzyme that catalyzes the conjugation of bilirubin with glucuronic acid leads to buildup of bilirubin and syndromes known as Crigler-Najjar/Gilbert.

Question 14

What is Crigler-Najjar/Gilbert syndrome? Symptoms.

Answer 14

• Glucuronic acid is a prerequisite for bilirubin excretion. - UGT, which is an enzyme that catalyzes the conjugation of bilirubin with glucuronic acid leads to buildup of bilirubin and syndromes known as Crigler-Najjar/Gilbert. - Jaundice

Question 15

Describe how xenobiotics are detoxified.

Answer 15

• Example: acetaminophen. - UGT catalyzes conjugation of UDP-glucuronate with acetaminophen, making it water soluble, allowing it to be excreted in urine

Question 16

What regulatory mechanisms allow for adapting to temporary fluctuations in glucose availability?

Answer 16

• Substrate availability - Allosteric regulation - Covalent modification - Translocation of transport proteins - Amount of protein

Question 17

Describe utilization of glucose by brain, RBCs, brain, liver, muscle and adipose.

Answer 17

• RBCs: glucose through glycolysis to produce lactate (used in liver), G6P into PPP - Brain: glucose through glycolysis to produce acetyl-CoA (oxphos), G6P into PPP. No production of lactate - Muscle/heart: glucose through glycolysis to produce both lactate (used in liver, ? produced in heart) and acetyl-CoA (oxphos), G6P into PPP, G1P as intermediate into glycogenolysis and glycogen synthesis - Adipose tissue: same as muscle/heart, except no lactate production AND acetyl-CoA used for FA synthesis in addition to oxphos. - Liver: glucose through glycolysis to produce pyruvate (to acetyl-CoA to oxphos or FA synthesis), pyruvate to OAA (to gluconeogenesis), G6P to PPP, G1P in glycogenolysis and glycogen synthesis. * no exit of glucose to serum unless from liver.