Extracellular Matrix and Glycosylation

Question 1

What are carbohydrates on the cell surface?

Answer 1

Glycoproteins - membrane proteins with short, branched oligosaccharides

Question 2

What are carbohydrates in ECM?

Answer 2

Proteoglycans - linear core proteins with long chains of repeating disaccharides

Amino-sugars alternating with uronic acids

Question 3

What is the fibrous content and ground substance of the ECM?

Answer 3

ECM has fibrous content which is collagen for tear resistance

Ground substance fills the space between fibers and glycosaminoglycans provide compression resistance and water retention

Question 4

What is the life of proteoglycan?

Answer 4

Starts at endoplasmic reticulum as a linear protein

Heavily glycosylated with glycosaminoglycans in Golgi

Glycosaminoglycans sulfated in Golgi and released into extracellular space via exocytosis

Assembled on hyaluronic acid in extracellular space using linker proteins

Taken up into cell via endocytosis

Protein backbone degraded in lysosome and glycosaminoglycan degraded in lysosome

Question 5

What is the importance of the metabolism of glycosaminoglycans?

Answer 5

Important for development

Affects skeleton, cardio, and at times CNS

Congenital disorder - diagnosis in first years of life

Question 6

What is the composition of proteoglycan?

Answer 6

Hyaluronic acid in center

Core protein linked non-covalently

Variable glycosaminoglycan linked to core proteins

Negative charges attract cations and their solvation cover

Question 7

What does it mean that Glycosylation of proteoglycans is O-linked?

Answer 7

Gycosaminoglycans are attached to core protein OH groups (serine and threonine)

Question 8

How is glycosaminoglycans degraded?

Answer 8

By lysosome! Requires specific hydrolases for different GAGs. Defects in hydrolases leads to accumulation of GAG

Question 9

Mucopolysaccharidosis

Answer 9

Inability to degrade dermatan and heparan sulfate

Patient presents with coarse facial features, thick skin, and enlarged spleen. Also show elevated urine glycosaminoglycan

Question 10

Hunter Syndrome

Answer 10

Mucopolysaccharidoses

X linked

Question 11

Hurler-Scheie Syndrome

Answer 11

Mucopolysaccharidoses

Enzyme affected is alpha-iduronidase

Urinary excretion of GAG

Question 12

Sanfillippo (A, B, C, D) Syndrome

Answer 12

Mucopolysaccharidoses

Mild physical defects

Severe intellectual disability

Question 13

What is the purpose of glucuronidation?

Answer 13

Increase solubility of waste products

Question 14

How do we excrete molecules like Bilirubin? What happens if bilirubin builds up?

Answer 14

BR is not very water soluble so needs additon of water soluble moiety

Inability to transfer glucuronic acid causes build up of unconjugated Bilirubin. Bilirubin-UGT defects cause non-hemolytic jaundice

Develop Gilbert Syndrome which is common or Crigler Najjar Syndrome which is a severe form

Question 15

How does glucuronidation function in drug metabolism? How does this relate to alcohol?

Answer 15

Liver UGT enzymes modify drugs for detoxification and excretion.

Glucuronidation of acetaminophen competes with oxidation by p450 enzymes

p450 enzymes product NAPQI if induced by ethanol

Question 16

What are the three sources for blood glucose?

Answer 16

1. Diet
2. Glycogen
3. Gluconeogenesis

Question 17

When are the three sources of blood glucose important throughout the day?

Answer 17

Dietary glucose fluctuates with each meal.

Glycogenolysis is important between meals and in the morning (starts falling)

Gluconeogenesis most important in the morning before breakfast.

Question 18

What do we adapt the metabolism to?

Answer 18

Nutritional state - glucagon/insulin

Redox potential - NAD/NADH and NADP/NADPH

Energy charge - ATP/ADP+AMP levels

Indicators of mitochondrial load - acetyl-CoA and citrate

External stressors - epinephrine and cortisol

Question 19

What are 5 regulatory mechanisms for carb metabolism?

Answer 19

1. Substrate Availability
2. Allosteric regulation
3. Colavent modification
4. Translocation of transport proteins
5. Amount of protein

Question 20

What are organ specific activities of glucose utilization?

Answer 20

Red blood cells lack mitochondria

Brain limited to glucose metabolism y permeability barrier

Muscles switch fuels (fat/carb) and patterns (anaroebic/aerobic)

Adipose tissue converts glucose to fat

Liver buffers blood glucose -hub for amino acid/fat/glucose conversion and detoxifies drugs/wastes

Question 21

What processes can red blood cells do?

Answer 21

Glycolysis and PPP

Question 22

What processes can brain do for carb metabolism?

Answer 22

No fat or glycogen

Glycolysis, PPP, and oxidative phosphorylation of acetyl-CoA

Question 23

What processes can the muscle do for carb metabolism?

Answer 23

Glycolysis, PPP, Oxidative phosphorylation, Glycogen metabolism

Question 24

What can adipose tissue do for carb metabolism?

Answer 24

Glycolysis, PPP, oxidative phosphorylation, Glycogen metabolism, and Fatty acid synthesis from acetyl-CoA

Question 25

What can the liver do to metabolize carbs?

Answer 25

Glycolysis, PPP, Oxidative Phosphorylation, Glycogen metabolism, Fatty acid synthesis, and gluconeogenesis.