Gluconeogenesis

Question 1

What are the main carbon precursors of gluconeogenesis?

Answer 1

Lactate
AAs (((alanine)
Glycerol

Question 2

What role does gluconeogenesis have in the clearance of lactate?

Answer 2

Lactate is constantly being produced, even in times of inactivity. So, we need to have a way to clear it. The way we do this is by converting it to glucose via gluconeogenesis.

Question 3

What organ/s is/are responsible for gluconeogenesis?

Answer 3

Liver does 90%
Kidney dies 10% - only really during excessive starvation

• Muscle does NOT play a role in gluconeogenesis

Question 4

What is different with regards to the location of glycolysis vs gluconeogenesis?

Answer 4

Glycolysis - muscle and brain mostly

Gluconeogenesis - mainly in the liver

Question 5

What are the unique enzymes involved in gluconeogenesis?

Answer 5

Pyruvate Carboxylase (mitochondrial)
Phosphoenol Carbboxykinase (PEPCK) (cytoplasmic and mitochondrial)
Fructose 1,6-bisphosphatase (cytoplasmic)
Glucose 6-phosphate are (ER)

Question 6

Pyruvate Carboxylase

Answer 6

So essentially we need to go backwards from what we did in glycolysis. So we had lactate, which can reversible go back to Pyruvate. From Pyruvate, we need to convert it into Oxaloacetate.

• It used biotin as a cofactor and uses 1 ATP.
• Acetyl CoA upregulates this reaction
• Avidin, found in egg whites, can bind to biotin and disrupt this enzyme.
• This occurs in the mitochondria

Question 7

Phosphoenolpyruvate Carbboxykinase (PEPCK)

Answer 7

Oxaloacetate is brought into the cytosol and is converted into phosphoenolpyruvate via PEPCK (although on the slide it says that this can be mitochondrial also).

• Consumes a GTP.
• releases a CO2

Question 8

In what circumstances will PEPCK occur in the cytosol vs mito?

Answer 8

Mito - if straight up lactate is the precursor then. It. Will be in the mito.
Cytosol - if Pyruvate is the precursor then it is in the cytosol.

Question 9

What happens after the PEPCK step?

Answer 9

5 reversible reactions until we finally form fructose 1,6-bispphosphate
- remember, we need two molecules of PEP to make 1 molecule of fructose 1,6-bisphosphate

Question 10

Fructose 1,6-bisphosphatase-1 (FBP-1)

Answer 10

Removes the phosphate on carbon #1 of fructose 1,6-bisphosphate to produce fructose-6-phosphate

Question 11

What happens after we have fructose-6-phosphate?

Answer 11

It is isomerized into glucose-6-phosphate

Question 12

Glucose-6-phosphatase

Answer 12

Glucose-6-phosphate is transported from the cytosol into the ER where it interacts with Glucose-6-phosphatese.

• It is An ER membrane bound complex of proteins in the ER.
• It converts Glucose-6-phosphate into free glucose and releases it into the cytosol along with Pi.
• Not In the muscle, only in the liver
• —- therefore uses GLUT2

Question 13

Is gluconeogenesis a energy consuming or generating Process?

Answer 13

Consuming

- 6 total ATP

Question 14

Regulation of gluconeogenesis

Answer 14

Hormonal: glucagon will activate gluconeogenesis

Allosteric - Acetyl CoA will activate Pyruvate carboxylase

Question 15

What regulates FBP-1

Answer 15

AMP and Fructose 2,6 bisphosphate

• • both of these things indicate a low energy state
• • they turn on glycolysis

Question 16

Affects of insulin/glucagon on PFK-1/FBP-1 in the liver? - on a molecular level

Answer 16

1) A high glucagon:insulin ratio causes elevated cAMP–>PKA
2) PKA will phosphorylates PFK2/FBP2
3) Phosphorylated PFK2 is inactive and FBP2 is active. This impedes formation of fructose 2,6-bisphosphate
4) Decreased levels of fructose 2,6-bisphosphate decreases the inhibition of FBP-1, which leads to an increase in gluconeogenesis.

Question 17

Fructose-1,6-bisphosphatase deficiency

Answer 17

• usually hypoglycemic and have lactic acidosis within the first few days of life.
• frequent feeding with carbs prevents further problems.
• This enzyme deficiency prevents glucose formation f rom all gluconeogenic precursors. Therefore, normal glucose levels are dependent purely on glucose intake and breakdown of glycogen.

Question 18

WHt would fructose-1,6-bisphosphate se deficiency cause lactic acidosis?

Answer 18

Because gluconeogenesis is responsible for clearing lactate from the body.

Question 19

Which are the two amino acids that do not play a role in gluconeogenesis? In other words, which two AAs are ketogenic?

Answer 19

Leucine and Lysine

Question 20

WHat are the essential AAs

Answer 20

PVT TIM HALL

Question 21

Cori Cycle

Answer 21

Liver uptake of lactate and conversion into glucose

Question 22

Alanine’s. Role - Chaill cycle

Answer 22

When you are starving, skeletal muscle will break down. Alanine is used to soak up toxic ammonia from urea and bring It back to the liver.

Question 23

Why do we often see hypoglycemia in neonate so?

Answer 23

• during uterine development he was in a hyperglycemia environment. Therefore, he adapted by increasing endogenous insulin production - this has a growth hormone like activity, which results in being overweight.
• at birth, when placental delivery of glucose ceases, he has normal blood glucose but prior to birth he had hyperinsulinemia, which brings blood glucose down.
• hyperinsulinemia will also suppress gluconeogenic enzymes.

Question 24

What is gluconeogenesis?

Answer 24

Synthesis of new glucose from simple Caron precursors.
- remember, there are parts of the body that red glucose at all time. While we do get glucose from the diet, what happens if we fast? Then we dip into our liver glycogen stores. However, those stores are fully depleted into 24 hours, which is why gluconeogenesis is so important.