Gluconeogenesis

Question 1

When does glycogenolysis happen? When does gluconeogenesis happen?

Answer 1

When blood glucose starts running lower, the liver performs glycogenolysis mostly.

When glycogen storage starts running low (e.g. sleep), then glycogenolysis falls and gluconeogenesis rises.

Question 2

Gluconeogenesis

Answer 2

Formation of glucose from non-carbohydrate precursors

Reverses glycolysis

Question 3

____ is performed in the cytosol of every cell of our body.

___ mainly occurs in hepatocytes, but also kidney and intestinal epithelium.

Answer 3

Glycolysis in every cell

Gluconeogenesis in liver, kidney, and intestine

Question 4

How does gluconeogenesis reverse the pyruvate kinase rxn? Where?

Answer 4

1. Pyruvate ^{–<strong><em>pyruvate carboxylase, ATP, biotin</em></strong>–>} oxaloacetic acid
   
   1. ​Ligase rxn
2. Oxaloacetic acid ^{–<strong>PEP carboxykinase (PEPCK), GTP, CO₂</strong> –>} PEP

both occur int he mitochondria + cytosol

Question 5

How to reverse the PFK-1 rxn? Where?

Answer 5

F16BP –FBPase-1 +Pi^{<strong><em> </em></strong>}–> F6P

Cytosol

Question 6

How to reverse the hexokinase reaction? Where?

Answer 6

Glucose-6-phosphate –^{glucose-6-phosphatase + Pi}–> Glucose

Occurs in the ER

Question 7

Muscle cells perform ___, but it doesn’t affect BLOOD glucose because it’s used internally.

Muscle cells CANNOT perform ___

Answer 7

Can perform glycogenlysis

CANNOT perform gluconeogenesis

Question 8

Which two gluconeogenesis-specific enzymes do adipose cells have that allow them to perofrm glyceroneogenesis??

Answer 8

Pyruvate carboxylaes

PEPCK

Question 9

Reaction of gluconeogenesis

Answer 9

2 pyruvate + 4ATP + 2GTP + 2NADH + 2H⁺ + 2H₂O

–>

Glucose + 4ADP + 2GDP + 6P_i + 2NAD⁺

Question 10

2 ATP were consumed in the pyruvate carboxylase rxn and 2 GTP were consumed in the following PEPCk reaction.

What about the other 2 ATP used in gluconeogenesis?

What about the 2 NADH that got used?

Answer 10

2ATP comes from reversing the phosphoglycerate kinase reaction (which generated 2 ATP in glycolysis)

2NADH comes from reversing the the glyceraldehyde 3-phosphate dehydrogenase reaction (generated 2NADH in glycolysis)

Question 11

Gluconeogenic precursors:

Ala (most common)

Glycerol

Other aa (e.g. Asp)

Lactic acid

Answer 11

• Ala -> pyruvate
• Glycerol -> DHAP
• Other aa (e.g. Asp) -> oxaloacetate
  
  • (Bypasses ATP hydrolyis of pyruvate carboxylase)
• Lactic acid -> pyruvate

Question 12

How to hormones mediate changes to enzymes?

Answer 12

Protein covalent modifications

Allosteric control mechanisms

Question 13

Glucose-6-phosphatase and hexokinase are both active in hepatic cells. How do liver cells regulate their opposing pahtways?

Answer 13

Glucokinase is in the cytosol

Glucose-6-phosphatase is in the ER

Question 14

When glucose is low, where is glucokinase? where is glucose 6phosphatase?

Answer 14

Glucokinase is sequestered to the nucleus

Glucose 6-phosphtase is active in the ER lumen

Question 15

When [glucose 6 phosphate] rises in the cell

Answer 15

It’s transported into the ER by a glucose 6-phosphate transporter to be hydrolyzed by the phosphatase to produce glucose.

Transported back to the cytosol, then out to the blood if blood glucose is lower than cytosol

Question 16

Both PFK-1 (glycolysis) and FBPase-1 (gluconeogenesis) are regulated how?

Answer 16

Allosteric regulation by Fructose 2,6-bisphosphate, which

Stimulates PFK-1

Inhibits FBPase-1

Question 17

___ catalyzes the production of F2,6BP from fructose-6-phosphate

Answer 17

PFK-2

Question 18

__ catalyzes the hydrolyzes the cabron-2 phosphate from F2,6BP to regenerate Fructose 6-phosphate

Answer 18

FBPase-2

Question 19

The bifuncitonal enzyme is

Answer 19

PFK-2 & FBPase2

Hormonal signals in response to blood glucose determine which of the opposing enzymatic activities is stimualted or repressed.

Question 20

If blood glucose is high, what happens to the bifunctional enzyme?

What if blood glucose is low?

Answer 20

Dephosphorylation -> increases PFK-2 and decreases FBPase-2 -> glycolysis

Phosphorylation -> decreases PFK-2 and increases FBPase-2 –> gluconeogenesis

Question 21

Effect of glucagon

Answer 21

• Phosphorylate the bifunctional enzyme to inhibit PFK-2 and activate FBPase-2.
• Phosphorylation & inactivation of pyruvate kinase
  
  • –> Accumulates PEP to use directly in gluconeogenesis (saves ATP)
• Stimulate transcription of Glucose-6-phosphatase, FBPase-1, PEPCK
• Inhibit transcription of glucokinase, PFK-1, and pyruvate kinase

Question 22

3 ways acetyl CoA may build up

Answer 22

Indicates a well-fed state; produced from either

• Pryuvate metabolism
• B oxidation of fatty acids
• Breakdown of ketogenic aa (Leu & Lys)

Question 23

What does acetyl CoA activate? Why?

Answer 23

Acetyl CoA activates pyruvate carboxylase because it’s a sign that more oxaloacetic acid is required for gluconeogenesis

Also remember that it was an inhibitor for pyruvate kinase.

Question 24

Adipocytes can’t perform gluconeogenesis. What is glyceroneogenesis?

Answer 24

Process by which glycerol-3-phosphate is generated from pyruvate in liver and adipose cells.

Question 25

High serum fatty acids correlate with \_\_\_ed insulin sensitivity

Answer 25

High serum FA --\> **reduced** insulin sensitivity

Question 26

Why do some diabetes drugs stimulate glyceroneogenesis?

Answer 26

It re-esterifies fatty acis back into triglycerides among adipocytes to increase insulin sensitivity

Question 27

When glucagon is high, what do adipose tissues do?

Answer 27

Hydrolyze triglyceride fat stores into glycerol and free FA, released into the blood stream - Glycerol goes to liver as a precursor for gluconeogenesis - Free FAs are taken up by other tissues (like muscle) to be oxidized for energy to CO₂

Question 28

Free fatty acids that aren't metabolized go to the liver, where they get

Answer 28

Re-esterified to **glycerol-3-phosphate** from pyruvate during **glyceroneogenesis** to produce new triglycerides. These **triglycerides** are exported to the liver to provide FFAs to the fat cells, where new TGs can be synthesized and stored.

Question 29

Glyceroneogenesis uses pyruvate as a precursor and involves the enzymes pyruvate kinase and PEPCK; however, it doesn't include F1,6BPase-1 or Glucose-6-phosphatase, so ___ backs up and is reduced to ___ by \_\_\_\_.

Answer 29

**DHAP** backs up and is reduced to **glycerol 3-phosphate** by **glycerol 3-phosphate dehydrogenase**. gly 3 p is the final product of glyceroneogenesis

Question 30

Adipocytes lack \_\_\_, which is why glycerol from hydrolysis of TGs must travel to the liver in order to be phosphorylated to glycerol 3-phosphate.

Answer 30

glycerol kinase

Question 31

Rosiglitazone

Answer 31

Diabetes drug Stimulates transcription PEPCK and thus induces glyceroneogenesis --\> marked decrease in FFA release from adipose tissue (which usually happens in T2D)

Question 33

Can your body make glucose from fatty caids? Can i tmake it from triglycerides?

Answer 33

B-oxidation of FA yields only acetyl-CoA Wheras, triglycerides' glycerol can be converted to glucose

Question 34

"Second wind" of long-distance runners / Cori cycle

Answer 34

1. Muscles require ATP from glycogen breakdown. 2. When oxygen is low, the pyruvate of glycolysis is converted to lactate to regenerate NAD+. 3. Lactate is taken up by the liver, which converts it to glucose that goes back to the muscle to replenish glycogen supplies.

Question 35

What are teh energy requirements to make one glucose from 2 pyruvates? From 2 lactate molecules?

Answer 35

From 2 pyruvates: 4ATP + 2GTP + 2NADH From 2 lactates: 4ATP + 2GTP

Question 36

Cortisol stimulates

Answer 36

**Gluconeogenesis** in the liver by increasing PEPCK synthesis and increasing protein breakdown for glucose synthesis.

Question 37

Why is it important to coordinately control glycolysis and gluconeogenesis?

Answer 37

Gluconeogenesis is energetically expensive, so your liver & kidneys shouldn't be breaking down glucose via glycolysis when it's needed to supply the brain. The liver & other tissues can use FA for energy generation, but the brain can't because BBB

Question 38

Pyruvate kianse is inactivated by glucagon-stimulated cAMP-dependent protein kinase. Why?

Answer 38

It takes 2 enzymes, an ATP, and a GTP to convert pyruvate back to PEP. When you have low blood sugar, inactivating pyruvate kinase makes the process of gluconeogenesis instead more energetically favorable

Question 39

Where dose glyceroneogenesis occur

Answer 39

adipose and liver tissue