Lecture 33 - Carbohydrate metabolism

Question 1

Hypoglycaemia + Symptoms (2,5)

Answer 1

Low blood sugar = lack of blood glucose.
Critical blood glucose 2.5 mM.
Muscle weakness
Loss of coordination
Mental confusion
Sweating
Hypoglycaemic coma and death

Question 2

Hyperglycaemia + Symptoms (5)

Answer 2

High blood sugar = excess of blood glucose.
Non-enzymatic modification of proteins
–> Cataracts
–> Lipoproteins important in atherosclerosis
Hyperosmolar coma

Question 3

Lack of blood glucose control (2)

Answer 3

Glycogen breakdown.

Gluconeogenesis.

Question 4

Excess blood glucose control (3)

Answer 4

Glycogenesis - Glucose –> Glycogen.
Pentose phosphate pathway.
Fatty acid synthesis.

Question 5

How the liver deals with glucose overview (7)

Answer 5

Main storage of excess glucose.
Converted into glycogen.
Glucose is not stored as it is osmotically active (draws water in- damages cell).
Requires glycogen synthase and requires protein glycogenin (in which glycogen is formed).
Glucose 6 phosphate is a key intermediate.
Glucose is phosphorylated by glucokinase - traps glucose in the cell.
Glycogen is compact and branched. Has 1,4 and 1,6 alpha links.

Question 6

Glycogen (4, vs fat 3)

Answer 6

Large branched molecule, branches are glucose residue linked by 1,4 (linear and 1, (branched) bonds.
Glycogen synthase key enzyme in glycogenesis.
Branching enzymes create 1,6 a bonds.
400 mM glucose stored as 0.01 mM glycogen.
Fat can not
–> be mobilised as readily.
–> be converted into glucose.
–> used as energy source in absence of O2.

Question 7

Glycogen synthase actual name (1)

Answer 7

UDP -glucose-glycogen glucosyltransferase.

Question 8

Glycogenesis - Glycogen synthesis (5)

Answer 8

G6P —> G1P (phosphoglucomutase).
G1P activated by UTP —> UDP-Glucose (UDP-Glucose-pyrophosphorylase).
Glycogenin reacts with UDP-Glucose and catalyses the addition of the first glucose molecule.
Acts as a substrate for glycogen synthase.
Stimulated by insulin, occurs in liver and muscle.

Question 9

Glycogenolysis - Glycogen breakdown (5)

Answer 9

Enzyme that breaks down glycogen will remove individual units (until it removes the whole branch).
Alpha 1,4 links are broken to remove individual units [enzyme: phosphorylase] —> G1P.
G1P —> G6P [enzyme: phosphoglucomutase].
Residues are removed until you get to a certain length left, then this portion is broken off and moved to end of a main chain [debranching enzyme: translocase].
Debranching enzyme removes final residue on branch [debranching enzyme: glucosidase] to make G6P (made into glucose in the liver [glucose-6-phosphatase]).

Question 10

Glycogen breakdown - Fate of G6P (3)

Answer 10

Fate of G6P varies depending on tissue.
Muscle - used for ATP synthesis (can’t control blood glucose as it does not contain enzyme required to convert G6P -> Glucose).

Liver - contains enzyme [Glucose-6-phosphatase] required to convert G6P -> Glucose (G1P) , so it controls blood glucose levels. Maintaining 5 mmol/L blood sugar.

Question 11

Glycogen breakdown - Enzymes requires to breakdown glycogen and form glucose. (5)

Answer 11

4 needed to breakdown glycogen
Phosphorylase
Phosphoglucomutase
Debranching enzyme –> Translocase –> Glucosidase.

5 needed to form glucose
Above 4 + Glucose-6-phosphatase.

Question 12

Glycogen breakdown - Glycogen phosphorylase ()

Answer 12

Forms glucose-1-phosphate.
Large, multi-subunit enzyme.
‘Allosteric’ enzyme - has a site away from AS. - Controls activity by inducing shape changes in protein.
Many phosphorylase bound to each glycogen particle - so glycogenolysis can be switched on rapidly.
Glycogen phosphorylase b (inactive) —> Glycogen phosphorylase a (active) [phosphorylase b kinase]. ATP is phosphorylated –> ADP + Pi (found on serine residue on each phosphorylase subunit).
Phosphorylase kinase is under dual-regulation via two different receptor types.

Question 13

Glycogen breakdown - Glycogen phosphorylase - In specific tissues (7)

Answer 13

Liver

• Glycogen breakdown inhibited by glucose.
• Even with activated, glycogen phosphorylase a.

Muscle
- Glycogen phosphorylase b can be activated without being phosphorylated.
- 5’-AMP binds to another allosteric site (nucleotide binding site).
- 5’ AMP forms when ATP is depleted.
- BUT
# ATP binds to same site and blocks activation.
# G6P blocks activation.

Question 14

Glycogen breakdown - Glycogen phosphorylase - Dual regulation (3,6)

Answer 14

1) Calcium mediated through a adrenergic IP3 pathway.
- Ca2+ ions activate phosphorylase b kinase in muscle, mediating glycogenolysis during muscle contraction.
- Max activity with Ca2+ and phosphorylation in liver a-adrenergic activation, stimulates Ca2+ release.

2) Elevation of cAMP and activation of protein kinase A (PKA)
- Noradrenaline/Adrenaline binds to GPCR (B adrenergic receptor, coupled to Gs), hence adenylate cyclase enzyme.
- Synthesis of cAMP, which activates PKA.
- PKA phosphorylates, phosphorylase kinase activating it.
- Phosphorylase kinase activated phosphorylase b by phosphorylating it into phosphorylase a.
phosphorylase a cleaves G1P from glycogen.
- PKA also converts glycogen synthase a to glycogen synthase b (inactive) (by phosphorylating it) which means synthesis of glycogen is inactivated, so synthesis and breakdown can’t occur at the same time.

Question 15

Hormonal regulation of glycogenolysis (4)

Answer 15

Insulin inhibits.
Glucagon stimulates in the liver.
Adrenaline stimulates in muscle.
Cortisol is a weak stimulus.

Question 16

Glycogen synthase (4)

Answer 16

• Activated in times of plenty.
• Activated by ATP and G6P (Glucose 6 phosphate).
• Inactivation by phosphorylation (by protein kinase A).
• Activated by dephosphorylation (by protein phosphatase-1).

Question 17

Glycogen phosphorylase (4)

Answer 17

• Activated when glucose is in short supply.
• Inactivated by ATP and G6P.
• Activated by phosphorylation (by phosphorylase b kinase.
• Inactivated by dephosphorylation (by protein phosphatase-1).

Question 18

Pentose phosphate pathway (6)

Answer 18

Activated when there is plenty of glucose.
Generates ribose 5 phosphate. G6P –> Ribose 5 phosphate, producing CO2.
Important precursor for the components of DNA/RNA and important for the coenzymes the body needs.

Active all the time (irrespective of excess glucose), because body requires nucleotides and coenzymes.

Important function in production of NADPH (essential coenzyme in the synthesis of FA). If pathway generates NADPH (synthesis only occurs when excess glucose is present).
The ribose 5 phosphate can be converted back to glucose 6 phosphate.

Question 19

Gluconeogenesis (7)

Answer 19

Blood glucose is the preferred fuel for the brain and the only fuel for RBC.
Daily requirement is 160g, the brain needs 120g. Total body reserves are 210g.
The gluconeogenic pathway is used to overcome low glucose reserves.
Takes place mostly in the liver and a little in the kidney. During starvation kidney production rises to 40% –> majority of which goes towards the function of the kidney medulla, NOT maintaining blood glucose levels.
Important substrates alanine,lactate and glycerol (can make glucose from backbone of FA).
Gluconeogenic aa can be converted back into glucose, to be fed into diff parts of TCA cycle.
Glucagon has an important role.

Question 20

Gluconeogenesis - Role of glucagon (5)

Answer 20

Inhibits glucose breakdown, stops glycolysis.
Stimulates glucose synthesis by gluconeogenesis.
-> occurs when BGL is low.
-> initiated by glucagon hormone (released from the liver).
Inhibits pyruvate kinase and phosphofructokinase (PFK). Preventing both pathways from occuring at the same time.

Question 21

Gluconeogenesis - Location (4)

Answer 21

• 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 must be converted into malate.
• This is transported out into the cytosol and is converted back to oxaloacetate. This is then further converted,
• Gluconeogenesis is usually accompanied by ketogenesis.