S2: Carbohydrate Metabolism

Question 1

What acts as a long term energy store and a short term energy store in our body?

Answer 1

Carbohydrates are stored as glycogen which acts as a short term energy store.
Fats are a more long term storage device.

Question 2

What is Hypoglycaemia?

List symptoms

Answer 2

Hypoglycaemia is low blood sugar.

• Muscle weakness
• Loss of coordination
• Mental confusion
• Sweating
• Hypoglycaemic coma
• Death

Question 3

What is Hyperglycaemia?

Why is it dangerous?

Answer 3

Hyperglycaemia is high blood sugar.

It is very dangerous as glucose is very reactive and at high concentrations, it starts to modify proteins (non-enzymatically), causing them to not function properly.
This may lead to cataracts or modify lipoproteins important in atherosclerosis. It can also lead to a hyperosmolar coma.

Question 4

Why is glucose regulated more strictly than fats?

Answer 4

Our body is good at maintaining blood glucose over a range of activities e.g. rest, exercise, blood glucose stays relatively same level.
This is because brain cells use glucose and RBC’s only use glucose.
Fats are regulated more loosely so may vary much more.

Question 5

What happens when there is excess blood glucose?

Answer 5

Glycogen synthesis
Pentose phosphate pathway
Fatty acid synthesis

Question 6

What happens when there is lack of blood glucose?

Answer 6

Glycogen breakdown (glycogenlysis)
Gluconeogenesis

Question 7

Why is G6P important?

Answer 7

It is an key intermediate molecule for:

• pyruvate (need for energy or to synthesise fatty acids)
• glycogen
• ribose 5-phosphate (pentose phosphate pathway)

Question 8

Describe the structure of glycogen

Answer 8

• Glycogen is a highly branched polymer of D-glucose
• Majority is alpha 1,4-linked
• Branches off which are alpha 1,6-linked

Protein glycogenin acts as a primer allowing the initiation of synthesis of glycogen.
It also uses enzymes glycogen synthase and branching enzyme.

Glycogen acts a a store of glucose and is readily formed and rapidly broken

Question 9

Describe glycogen synthesis

Answer 9

1. G6P is converted to glucose 1 phosphate catalysed by phosphoglucomutase enzyme.
2. Glucose 1 phosphate reacts with UTP which activates the glucose molecule into UDP-glucose
3. UDP-glucose then binds to glycogenin which allows glycogen synthase to add on UDP-glucose to increase chain length
4. When chain has 11 monomers, some of the chain is removed by branching enzyme and this forms a branch.

Question 10

Why is glycogen a branched molecule?

Answer 10

It gives off loads of ends so that glucose can be mobilised from glycogen quicker

Question 11

What are the 2 main enzymes in glycogen synthesis?

Answer 11

• Glycogen synthase

- Branching enzyme

Question 12

Give reasons on why glycogen is important

Answer 12

• Glycogen is essential as glucose cannot be stores because it is osmotically active (draw water into the cell)
• Glycogen is denser than glucose (store more in less space)
• Glycogen is mobilised faster than fat
• Glycogen can be used as an energy source in the absence of oxygen while fats can’t

Question 13

Explain glycogen breakdown

Answer 13

1. Phosphorylase removes individual units breaking alpha 1,4-links. It stops cleaving 4 residues away from branch point (called terminal residues)
2. These individual units are glucose 1 phosphate. They are then converted to glucose 6 phosphate by phosphoglucomutase
3. Enzyme translocase breaks off end portion (3 residues) and this is moved onto the end of the main chain
4. Debranching enzyme moves final residue left on branch. This is glucose and it is converted to glucose 6-phosphate by hexokinase.

Question 14

What happens to G6P in muscle?

How does it differ to liver?

Answer 14

It can be used for ATP synthesis for its own use in the muscle.
Muscle cannot use this to control blood glucose as it doesn’t contain the enzyme to convert G6P to glucose.

The liver does contain this enzyme (Glucose-6-phosphatase) and so is able to control circulating blood glucose. (non reducing end)

Question 15

Name the 4 main enzymes involved in breakdown of glycogen

Answer 15

• Phosphorylase breaks the alpha 1-4 links
  
  • Translocase moves end portion of branch to main chain/adjacent chain
  • Debranching enzyme removes alpha 1-6 link, removing the final residue on the branch
    - Phosphoglucomutase converts G1P to G6P

Question 16

Where is glucose-6-phophatase found and what is its role?

Answer 16

It converts G6P to glucose.

It is present in liver and kidney but not muscle

Question 17

What is glycogen phosphorylase?

Answer 17

It is a key enzyme in glycogenolysis and its activity forms glucose-1-phosphate from glucose.

• It is a multi-subunit enzyme
• It is an allosteric enzyme that is activated by phosphorylation but modulated by other factors

It cleaves monomers (G-1-P) from glycogen

Question 18

How is glycogen phosphorylase an allosteric enzyme?

Answer 18

Glycogen phosphorylase b (inactive) is converted to glycogen phosphorylase a (active) by an enzyme phosphorylase b kinase.
- It can also be further regulated by a no. of different molecules related to the energy provision binding to allosteric sites

Activation of glycogen phosphorylase occurs through the cAMP cascade where PKA activates phosphorylase b kinase.

Question 19

What inactivates glycogen synthase?

Answer 19

Protein kinase A (PKA)

PKA converts glycogen synthase a to glycogen synthase b which is its inactive form. PKA does this by phophorylating glycogen synthase a.

This means that synthesis of glycogen is inactivated so synthesis and breakdown of glycogen is not occuring at the same time (PKA activates glycogen phosphorylase).

Question 20

List hormonal regulation of glycogenolysis

Answer 20

Insulin inhibits

Glucagon stimulates in liver

Adrenaline stimulates in muscle

Cortisol is a weak stimulus

Question 21

Explain control of glycogen phosphorylase in muscle or liver

Answer 21

MUSCLE=
Glycogen phosphorylase b can be activated by 5’-AMP without being phosphorylated. This is a form of allosteric regulation.
- ATP binds to the same site and blocks activation
- G6P blocks 5’-AMP activation (as enough energy in cell already so more glucose isn’t needed)

LIVER= Activated phosphorylase a is inhibited by glucose

Question 22

Explain activation of phosphorylase b kinase by Ca2+

Answer 22

• MUSCLE = Ca2+ activates phosphorylase b kinase allowing phosphorylation of phosphorylase b –> phosphorylase a so glycogenolysis can occur. This occurs in muscle, which allows mediation of glycogenolysis during muscle contraction (as Ca2+ will be high in muscle contraction and so will be demand for energy)

LIVER= alpha-adrenergic activation stimulates Ca2+ release (gq)

Hence, phosphorylase b kinase is under dual regulation via two different receptor types, most importantly through cAMP elevation (and subsequent PKA activation) as well as Ca2+ through adrenergic/IP3 pathway.

Question 23

How do you get maximum activity of glycogenolysis?

Answer 23

To activate phosphorylase b kinase you need both Ca2+ and phosphorylation. This allows the body to regulate activity.

Question 24

Explain reciprocal regulation of glycogen synthesis and degradation

Answer 24

Glycogen synthase is activated by ATP and G6P (so high levels of these substances) whereas glycogen phosphorylase is inactivated by ATP and G6P (so active at low levels of these substances).

Glycogen synthase is inactivated by phosphorylation (by PKA), phosphorylase kinase is activated by phosphorylation (by ).
Glycogen synthase is activated by dephosphorylation (by protein phosphatase-1), whereas phosphorylase kinase is inactivated by dephosphorylation (by protein phosphatase-1).

The two are recicprocal, synthesis will occur in the absence of breakdown and breakdown will occur in the absence of synthesis.

Question 25

In what conditions is glycogen synthase and glycogen phosphorylase activated?

Answer 25

Glycogen synthase - activated in times of plenty

Glycogen phosphorylase - activated when glucose is in short supply

Question 26

What is the pentose phosphate pathway?

Answer 26

When there is excess glucose around, the pentose pathway deals with it (as well as glycogen synthesis).

• It is active all the time irrespective of excess glucose
• It produces NADPH (essential coenzyme e.g. synthesis of fatty acids)
• Produces nucleotides, coenzymes, DNA, RNA
• Produces glutathione (GSH) which prevents RBC from being oxidised

Question 27

What is gluconeogenesis?

Answer 27

Gluconeogenesis is the synthesis of glucose through non-carbohydrate stores.

• Usually converts pyruvate to glucose
• Takes place mostly in liver and a little in kidney

Question 28

What are the three most important substrates for gluconeogenesis?

Answer 28

Amino acid alanine
Lactate
Glycerol

Question 29

List the steps of gluconeogenesis

Answer 29

1. Pyruvate (cytosol) is converted to oxaloacetic acid (mitochondrial) by the enzyme pyruvate carboxylate
2. Oxaloacetic acid is then converted to phosphoenol pyruvate by the enzyme phosphoenol pyruvate carboxykinase
   
   3. Phosphoenol pyruvate then undergoes the reverse reactions of glycolysis to get back to glycerol-3-phosphate.
3. G3P is converted to fructose 1-6 –bisphosphate which is then converted to fructose-6-phosphate by fructose 1-6-bisphosphatase.
4. Fructose-6-phosphate undergoes conformational change to glucose-6-phosphate
5. G6P is then converted into glucose by glucose 6-phosphatase (present in liver and kidney, can reverse hexokinase)
   The glucose produced is for export only

Pyruvate is not the only molecule that can be converted back to glucose, various amino acids can join on and glycerol (backbone of a fatty acid, only feeding in point for fatty acids) which can feed into the C3.
Lactate which goes to the liver from muscle can also be used to synthesis glucose.

Question 30

What regulates gluconeogenesis?

Answer 30

Glucagon

Glucagon inhibits enzymes in the glycolytic pathway
This encourages molecules to be funneled into the gluconeogenesis pathway

Glucagon therefore raises blood glucose

Question 31

Why does pyruvate have to be transported to the mitochondria by a pyruvate carrier?

Answer 31

Oxaloacetate (conjugate base of oxaloacetic acid) is a mitochondrial molecule while pyruvate is synthesised in the cytosol.

Pyruvate is converted to oxaloacetic acid in the mitochondria

Question 32

Explain in detail how pyruvate is converted to oxaaloacetate?

Answer 32

Pyruvate will be converted to oxaloacetate by pyruvate carboxylase. Oxaloacetate is then converted to malate, which is then transported out into the cytosol.
Malate is then converted back into oxaloacetate which is then converted to phosphoenol pyruvate by phosphoenol pyruvate carboxykinase.