Gluconeogenesis

Question 1

Gluconeogenesis is the synthesis of glucose from ….

Answer 1

non-carbohydrate sources.

Question 2

Gluconeogenesis occurs in the ….

Answer 2

liver & kidney

Question 3

Why is gluconeogenesis an essential metabolic pathway?

Answer 3

During prolonged fasting glycogen depletes and the body requires another method of receiving energy

Question 4

Gluconeogenesis is not a reversible because the reactions using ____, ____, and ___ are irreversible. So, the entire process of glycolysis cannot be reversed but these three reactions can, starting in the….

Answer 4

Hexokinase
Phosphofructokinase
Pyruvate Kinase

Cytosol

Question 5

1. (GLUCONEOGENESIS/Cytosol) Glucose-6-phosphotate → Glucose

Answer 5

Enzyme: Glucose 6 phosphatase (In liver, not in muscle, muscle cannot perform this step of gluconeogenesis)

Question 6

2. (GLUCONEOGENESIS/Cytosol) Fructose 1,6 bisphosphate → fructose-6-phosphate

Answer 6

Enzyme: Fructose 1,6 bisphosphatase

Question 7

3. (GLUCONEOGENESIS/Mitochondria) Pyruvate → Oxaloacetate (1/2)

Answer 7

Goal: Get pyruvate back to phosphoenolpyruvate

• Enzyme: Pyruvate Carboxylase
• Requires ATP

Question 8

3. (GLUCONEOGENESIS/Mitochondria) Pyruvate → Oxaloacetate (1.5/2)

Answer 8

Oxaloacetate → Malate
Malate → Oxaloacetate (goes both ways)

Malate exported to cytosol for next step

Question 9

4. (GLUCONEOGENESIS/Cytosol) Malate → Oxaloacetate, Oxaloacetate → Phosphoenolpyruvate (2/2)

Answer 9

• Enzyme: Phosphoenolpyruvate Carboxykinase
• NAD+ → NADH + H+
• GTP (from TCA cycle) → GDP + CO2

Question 10

Remember, no Glucose-6-phosphatase in the muscle

Answer 10

Remember, no Glucose-6-phosphatase in the muscle

Question 11

Glycerol to Glucose Process

Answer 11

1st Glycerol → Glycerol-3-Phosphate
* Enzyme: Glycerol Kinase
* Requires ATP

2nd Glycerol-3-Phosphate → Dihydroxyacetone Phosphate
* Enzyme: Glycerol-3-Phosphate Dehydrogenase
* NAD+ → NADH + H + (same products from oxaloacetate → phosphoenolpyruvate reaction)

Question 12

4. Explain gluconeogenesis using propionate as the substrate

Answer 12

Propionate enters via TCA

(1st) Propionate → Propionyl-CoA
* Enzyme: Acyl-CoA Synthetase
* Requires ATP

(2nd) Propionyl-CoA → D-Methyl-Malonyl-CoA
* Enzyme: Propionyl-CoA carboxylase
* Requires ATP

(3rd-) D-Methyl-Malonyl-CoA → L-Methyl-malonyl-CoA
* Enzyme: Methylmalonyl-CoA Racemase (race from D to L methyl-malonyl)

(4th) L-Methyl-Malonyl-CoA → Succinyl-CoA
* Enzyme: Methylmalonyl-CoA mutase (methyl-malonyl being muted (as in no longer existing) because it’s now succinyl-CoA, we keep the CoA!)

Question 13

Changes in rate of enzyme synthesis during glycogenolysis, glycolysis, and pyruvate oxidation

Answer 13

: During glycogenolysis, glycolysis, and pyruvate oxidation, Glycogen synthase, hexokinase, phosphofructokinase, pyruvate kinase, and pyruvate dehydrogenase are increased during feeding and decreased during fasting and diabetes.

o Glucokinase, Phosphofructokinase, and pyruvate kinase are induced by insulin (+fructose for pyruvate kinase) and repressed by glucagon.

Question 14

• Induced by insulin, glucokinase increases activity during feeding, reduced during fasting and diabetes (repressed by glucagon)

Answer 14

• Induced by insulin, Phosphofructokinase-1 increases activity during feeding, reduced during fasting and diabetes (repressed by glucagon)

Question 15

• Induced by insulin & fructose, Pyruvate kinase increases activity during feeding, reduced during fasting and diabetes (repressed by glucagon)

Answer 15

• Induced by insulin & fructose, Pyruvate kinase increases activity during feeding, reduced during fasting and diabetes (repressed by glucagon)

Question 16

• Activated by CoA, NAD+, Insulin, ADP, and pyruvate, Pyruvate dehydrogenase increases activity during feeding, reduced during fasting and diabetes (inhibited by Acetyl-CoA, NADH, ATP (fatty acids, ketone bodies).

Answer 16

• Activated by CoA, NAD+, Insulin, ADP, and pyruvate, Pyruvate dehydrogenase increases activity during feeding, reduced during fasting and diabetes (inhibited by Acetyl-CoA, NADH, ATP (fatty acids, ketone bodies).

Question 17

(Gluconeogenesis Regulation) : Changes in rate of enzyme synthesis during gluconeogenesis

Answer 17

• Pyruvate carboxylase, phosphoenolpyruvate, and glucose-6-phosphate are decreased during feeding, increased during fasting. They are induced by glucocorticoids, glucagon, and epinephrine. Repressed by insulin (when fed).

o Makes sense when you consider that gluconeogenesis is increased during the fasting state as the body must make glucose from non-CHO sources due to a lack of glucose in the body.
o Pyruvate Carboxylase activated by Acetyl-CoA, inhibited by ADP.
o Phosphoenolpyruvate activated by glucagon.

Question 18

(Gluconeogenesis Regulation) : Covalent modification by reversible phosphorylation

Answer 18

Glucagon & Epinephrine

• Inhibit glycolysis; stimulate gluconeogenesis via ↑ cAMP → cAMP-dependent protein kinase activated → inactivation of pyruvate kinase.

Question 19

(Gluconeogenesis Regulation) : Allosteric effects of Acetyl-CoA

Answer 19

o (Gluconeogenesis) Pyruvate Carboxylase → (pyruvate → oxaloacetate)
 Needs Acetyl-CoA (Acetyl-CoA is the allosteric activator, it activates pyruvate carboxylase) - ACTIVATOR

o Glycolysis (Fed) Pyruvate dehydrogenase → (pyruvate (NOT CONVERTED TO) acetyl CoA)
 Needs Acetyl-CoA (Acetyl-CoA is the allosteric inactivator, it inhibits pyruvate dehydrogenase) - INHIBITOR

Question 20

____ inhibits glycolysis and stimulates gluconeogenesis

Answer 20

B-oxidation, alters metabolic fate of pyruvate with changes in CHO oxidation

Question 21

(Gluconeogenesis Regulation) : Allosteric effects of Phosphofructokinase

Answer 21

Phosphofructokinase

o Inhibited by citrate, normal intracellular concentrations of ATP
o Activated by 5’ AMP

Question 22

(Gluconeogenesis Regulation) : Allosteric effects of 5’AMP

Answer 22

5’ AMP indicator of energy status of cell
o 2 ADP  ATP + 5’ AMP
o Small ↓ ATP = Large ↑ AMP
o AMP stimulates phosphofructokinase (glycolysis), glycogen phosphorylase (glycogenolysis)

Question 23

(Gluconeogenesis Regulation) : Allosteric effects of fructose 1,6-bisphosphate (can DECREASE or INCREASE gluconeogenesis by altering glucose metabolism)

Answer 23

• Activates phosphofructokinase & increases affinity for fructose-6-phosphate.
• Inhibits fructose 1,6-bisphosphatase.
• ↑ glucose → ↑ fructose 2,6-bisphosphate = ↑ glycolysis & ↓ gluconeogenesis

If increased F 2,6 bisphosphate has the affect then the opposite is …
* ↓ Fructose 2,6-bisphophate = inactivates phosphofructokinase & stimulates fructose 1,6-bisphosphatase

• Fasting (↓ glucose) → ↓ Fructose 2,6-bisphophate = ↑ gluconeogenesis & ↓ glycolysis

Question 24

6. Describe the sources of glucose to maintain blood glucose homeostasis

Answer 24

• Galactose & fructose → glucose (liver)
• Lactate goes through Cori cycle → glucose (liver, kidney)
• Process of converting lactate → glucose = cori cycle
• Alanine (muscle) goes through glucose-alanine cycle → glucose (liver)
• In summary the sources of glucose are galactose & fructose, lactate through the cori cycle, and alanine in the muscle through the glucose-alanine cycle.

Question 25

7. Explain how insulin release is stimulated in order to parallel blood glucose concentration.

Answer 25

• Insulin release is stimulated by glucose, amino acids, nonesterified FAs, ketone bodies, secretin, and sulfonylureas.
• Increased blood glucose leads to increased glycolysis which leads to ATP formation.
• The increased ATP synthesis then inhibits ATP-sensitive K+ channels, resulting in cell membrane depolarization.
• Then, Ca2+ influx in cells from cell membrane depolarization stimulates insulin release.
• So, increased blood glucose increases insulin.

Question 26

8. List insulin stimulators and inhibitors. GEN K. SNAGS the insulin

Answer 26

Stimulators (K. SNAGS) = Ketone bodies, secretin, nonesterified fatty acids, amino acids, glucose, sulfonylureas

Inhibitors (GEN) = Glucose, Epinephrine, Norepinephrine