Carbohydrate Metabolism

Question 1

What is the normal amount of glucose in the body?

Answer 1

5.0mM

Question 2

What is caused when glucose levels are low?

Answer 2

Hypoglycemia occurs and this is usually at critical levels at around 2.5mM. Symptoms include:

• muscle weakness
• loss of coordination
• mental confusion
• sweating
• hypoglycemic coma and death

Question 3

What is caused when glucose levels are high?

Answer 3

Hyperglycemia occurs and the symptoms include:

• non enzymatic modification of proteins
• cataracts
• lipoproteins important in atherosclerosis
• Hyperosmolar coma

Question 4

How does the body deal with excess blood glucose?

Answer 4

• glycogen synthesis
• pentose phosphate pathway
• fatty acid synthesis

Question 5

How does the body deal with lack of blood glucose?

Answer 5

• glycogen breakdown

- gluconeogenesis

Question 6

What does the liver do with excess glucose?

Answer 6

Liver cells first phosphorylate glucose by glucokinase (a branching enzyme) which turns it into glucose-6-phosphate- a key intermediate.
This intermediate can then be converted to either glycogen, ribose-5-phosphate or pyruvate.

Question 7

Why is glucose stored as glycogen and not glucose?

Answer 7

• Glycogen is a very branched molecule with 1-6 and 1-4 glycosidic bonds, and it is also very compact. Glucose is too osmotically active which mean it will cause an osmotic effect, resulting in water damages to the cell, so it is better to store glucose as glycogen.
• 400mM glucose is stored as 0.01mM glycogen.
• Fat can’t be mobilised as readily.
• Fat cannot be used as an energy source in the absence of oxygen.
• Fat cannot be converted in to glucose.

Question 8

What is required for glycogen to be formed from glucose-6-phosphate?

Answer 8

• glycogenin (a protein which glycogen is formed)

- glycogen synthase

Question 9

What happens in glycogen synthesis?

Answer 9

First glucose-6-phosphate is converted into glucose-1-phosphate via the enzyme phosphoglucomutase.
The glucose-1-phosphate will have to be activated by uridine triphosphate (UTP) and along with UDP-glucose-pyrophosphorylase , it will be converted into UDP-glucose.
This molecule will bind to glycogenin forming glycogen and glucokinase will form alpha 1-6 bonds at the 11th residue, gradually increasing the branching and therefore glycogen is formed.

Question 10

What are the two products formed when glycogen is broken down?

Answer 10

• glucose-1-phosphate (major product)

- glucose

Question 11

How is glycogen broken down?

Answer 11

The ends of the glycogen molecule are broken down untill you reach the branch by glycogen phosphorylase which breaks the 1-4 glycosidic bonds. Then a debranching enzyme called transferase breaks the branch and so generates glucose directly. Therefore more glucose-1-phosphate is produced than glucose as there are more residues.
LOOK AT NOTES FOR THE DIAGRAM.

Question 12

What are the key enzymes involved in the breakdown of glycogen?

Answer 12

• Glycogen Phosphorylase
• Transferase
• Debranching enzyme a 1-6/transferase
• Phosphoglucomutase

Question 13

What does glycogen phosphorylase do?

Answer 13

-Glycogen Phosphorylase breaks the a 1-4 links
*This is a key enzyme in glycogenolysis and its activity
forms glucose-1-phosphate
*Glycogen phosphorylase is a large, multi-subunit
enzyme.
*It is a an ‘allosteric’ enzymes has it has sites away
from the active site that control its activity by inducing
shape changes
*Many phosphorylase molecules are bound to each
glycogen particle so glycogenolysis can be switched
on very rapidly
*The glucose-6-phosphate ultimately formed provides
fuel for working muscles.
*In the liver, the glucose-6-phosphate is de-
phosphorylated (by glucose-6-phosphatase) and
secreted into the blood, maintaining the 5 mmol/l
blood sugar.

Question 14

What does transferase do?

Answer 14

-Transferase- debranching
*Debranching enzymes has two activities associated
with it
-Transferase activity moves the last glucose residues
to the non-reducing end of an existing chain
-Glucosidase that removes the 1-6 link releasing
glucose.

Question 15

What does debranching enzyme alpha 1-6/transferase do?

Answer 15

-Debranching enzyme a 1-6/transferase –> generates glucose as the branch point is being removed

Question 16

What does phosphoglucomutase do?

Answer 16

-Phosphoglucomutase converts G1P to G6

Question 17

How is glycogen phosphorylase controlled?

Answer 17

Glycogen phosphorylase b (inactive) is converted to the active a form by a special enzyme – phosphorylase b kinase.
Phosphorylase b kinase transfers a phosphate from and ATP to one serine residue on each phosphorylase subunit.
LOOK AT NOTES FOR DIAGRAM.

Question 18

What is the other way that glycogen phosphorylase b can become activated in the muscles?

Answer 18

In muscle, glycogen phosphorylase b can also be activated without being phosphorylated. 5´-AMP (which forms when ATP is depleted) binds to another allosteric site, the nucleotide-binding site. ATP will bind to the same site, blocking the activation. Glucose-6-phosphate also blocks 5´-AMP activation.

Question 19

In the liver, how can phosphorylase be inhibited?

Answer 19

In the liver, glycogen breakdown by phosphorylase is inhibited by the presence of glucose, even after the enzyme has been activated to the a form by being phosphorylated.

Question 20

How is phosphorylase b Kinase activated by Ca2+ ions?

Answer 20

Ca2+ ions activate phosphorylase b kinase and so regulates the kinase. Ca2+ goes up when muscle contracts and so phosphorylase activation in enhanced and so glucose availability is increased. So Ca2+ mediates glycogenolysis during muscle contraction as glycogen is only broken down when glucose supply is limited.
You get max activity with Ca2+ and phosphorylation.
In liver α-adrenergic activation stimulates Ca2+ release

Question 21

How is phosphorylase kinase under dual regulation?

Answer 21

Phosphorylase kinase is under dual regulation via two different receptor types the most important is through the elevation of cAMP and the activation of PKA the other is calcium mediated through the alpha adrenergic/IP3 pathway.

Question 22

How is glycogen synthase regulated?

Answer 22

• activated in times of plenty
• activated by ATP and G6P
• inactivated by phosphorylation (by protein kinase A)
• activated by dephosphorylation (by protein phosphatase-1).

Question 23

How is glycogen phosphorylase regulate?

Answer 23

• activated when glucose is in short supply
• inactivated by ATP and G6P
• activated by phosphorylation (by protein kinase A)
• inactivated by dephosphorylation (by protein phosphatase-1).

Question 24

Explain the pentose phosphate pathway

Answer 24

This is activated when plenty of glucose is present. This is important for generating Ribose 5 phosphate – this is important precursor for the component of DNA and RNA and also important for coenzymes the body needs.
One thing that is important is that the pathway generates NADPH which is required for fatty acid synthesis. This synthesis only occurs when excess glucose is present.
The ribose 5 phosphate can be converted back to glucose 6 phosphate.
LOOK AT NOTES FOR THE DIAGRAM.

Question 25

What is gluconeogenesis?

Answer 25

This is when the body produced from non-carb sources when glucose level is low as the brain has a requirement for glucose.

Question 26

What are the steps involved in gluconeogenesis?

Answer 26

-The body maintains blood glucose because it is the preferred fuel for the brain and the only fuel for red blood cells
-Our daily requirement is 160g and the brain needs 120g and the total body reserves are 210g.
-In order to overcome low reserves there are mechanism where glucose can be formed from other sources à The gluconeogenic pathway converts pyruvate to glucose. The majority of the steps – all but three - are the reverse of glycolysis.
-This process takes place mostly in the liver and a little in the kidney but during starvation kidney productions rises to 40% –> majority of that glucose if for the function of kidney medulla not maintain the blood glucose levels.
-Three most important substrates for gluconeogenesis are the amino acid (alanine), lactate and glycerol
LOOK AT NOTES FOR THE PROCESS

Question 27

What inhibits gluconeogenesis?

Answer 27

Glucagon inhibits this process. The hormone that stimulates glycogen hormone inhibits glycolysis by inhibiting pyruvate kinase and phosphofructokinase. This prevents the two pathways occurring at the same time.

Question 28

Where are the places that gluconeogenesis takes place in?

Answer 28

• This process takes place in two different intracellular places – so they generation oxaloacetic acid from pyruvate takes place in the mitochondria whereas the cytosol is where the pyruvate is generated.
• The pyruvate is transported into the mitochondria. It is converted to oxaloacetate which cannot exit the mitochondria. So it has to be converted into malate.
• This is transported out into the cytosol and is converted back to oxaloacetate. This is then further converted,